Hundreds of proteins in the nervous system are modified by the monosaccharide O-GlcNAc. A single protein is often O- GlcNAcylated on several amino acids and the modification of a single site can play a crucial role for the function of the protein. Despite its complexity, only two enzymes add and remove O-GlcNAc from proteins, O-GlcNAc transferase (OGT) and O- GlcNAcase (OGA). Global and local regulation of these enzymes make it possible for O-GlcNAc to coordinate multiple cellular functions at the same time as regulating specific pathways independently from each other. If O-GlcNAcylation is disrupted, metabolic disorder or intellectual disability may ensue, depending on what neurons are affected. O-GlcNAc's promise as a clinical target for developing drugs against neurodegenerative diseases has been recognized for many years. Recent literature puts O-GlcNAc in the forefront among mechanisms that can help us better understand how neuronal circuits integrate diverse incoming stimuli such as fluctuations in nutrient supply, metabolic hormones, neuronal activity and cellular stress. Here the functions of O-GlcNAc in the nervous system are reviewed. Introduction understood (McCulloch and Pitts 1990; Denk et al. 2012; Huang and Zeng 2013;Sohnet al. 2013; Tovote et al. 2015; Neuronal circuits drive behavior Tsien 2015). Brain function relies on the concerted action of networks of neurons. Individual cells influence how thoughts and emo- Protein function is regulated by O-GlcNAc tions occur in the mind. Some behaviors are disrupted completely if specific neurons are damaged. Nevertheless, Connecting circuit structure with circuit function requires in- almost no function of the nervous system depends solely on vestigation of the molecular events by which participating a single cell type. Neuronal circuits with different effects on cells respond to incoming stimuli and signal to each other behavior often lie intermingled and stretch over large parts of (Kessels and Malinow 2009;O'Rourke et al. 2012; Shepherd the brain. Manipulation of anatomical regions often does not and Huganir 2007). Until the early 1980's, it was known that lend enough specificity to understand how behaviors are protein function could be modified by attaching complex car- encoded in the brain. However, the last decade has witnessed bohydrates to mainly their asparagine, serine or threonine res- an explosion in available tools to interrogate defined neuronal idues. This kind of glycosylation occurs in the cellular secre- circuits. Genetic identification of cells in particular has en- tory pathway on proteins that are expressed topologically out- abled mapping of distinct behaviors to discrete neuronal path- side the cell. Then Gerald W. Hart's laboratory at Johns ways. These studies emphasize that it is only by studying Hopkins University discovered that the monosaccharide D- communication between synaptically or otherwise coupled N-acetylglucosamine (GlcNAc) is covalently coupled through cells that information processing in the brain may be an O-glycosidic bond (O-GlcNAc) to many proteins in the cytoplasm and nucleus (Torres and Hart 1984; Holt and Hart 1986). O-GlcNAc is attached in β-linkage to the hydroxyl group of serine and threonine amino acid side chains. Unlike classical protein glycosylation O-GlcNAc is rarely elongated * Olof Lagerlöf and can cycle on and off proteins faster than the peptide back- email@example.com bone turns over and this on a time scale of minutes to hours 1 (Roquemore et al. 1996; Yuzwa et al. 2008;Songet al. 2008; Department of Neuroscience, Karolinska Institutet, 171 Chou et al. 1992). 77 Stockholm, Sweden 242 J Bioenerg Biomembr (2018) 50:241–261 O-GlcNAcylation of specific sites can affect, for example, vitro (Shen et al. 2012; Kreppel and Hart 1999). Numerous peptide structure, enzyme activity, ion channel conductivity reports show also that overall O-GlcNAcylation depends on and protein-protein interactions (Chen et al. 2006;Dias etal. the cell's access to nutrients in multiple ex vivo culture systems 2009;Ruan et al. 2014; Myers et al. 2016; Tarrant et al. 2012; and in organisms. We shall see in forthcoming sections that Hart et al. 2011; Tarbet et al. 2018). In the nervous system, though the metabolic control of O-GlcNAc is complex, OGT other important examples of O-GlcNAc function include pro- is today recognized as a central and global energy sensor in the tein stability and solubility (Yuzwa et al. 2012; Marotta et al. cell due to nutrient-dependent flux through the HBP (Slawson 2015). Today more than 4000 proteins modified by O- et al. 2010). GlcNAc have been described (Ma and Hart 2014). These reg- In reverse, complete deprivation of glucose can stimulate ulate numerous and diverse cellular events such as transcrip- global O-GlcNAc levels dramatically (Cheung and Hart 2008; tion, translation, signaling and ROS production in the mito- Taylor et al. 2008). As first shown by Zachara et al,O- chondria (Bond and Hanover 2013; Tan et al. 2017a). As we GlcNAc, in fact, responds to and regulates the cell's capacity shall see, O-GlcNAc is particularly abundant in the brain to handle multiple forms of stress (Zachara et al. 2004). The where neuron-specific proteins and proteins common to most mechanism is multifaceted and still under investigation but cells are O-GlcNAcylated. stress-induced O-GlcNAcylation results under some condi- tions from a higher total OGT activity because of altered flux O-GlcNAcylation is regulated by OGT and OGA through the HBP or transcription of Ogt (Wang et al. 2014a; Cheung and Hart 2008; Taylor et al. 2008). The adding and removing of O-GlcNAc is controlled by only The proteins that become O-GlcNAcylated during stress two enzymes. O-GlcNAc transferase (OGT) attaches and O- are at least partly different than the ones being modified GlcNAcase (OGA) detaches O-GlcNAc from proteins. Both during eu- or hyperglycemia (Taylor et al. 2008;Groves et OGT and OGA are expressed in the nucleus, cytosol and mi- al. 2017). Other stimuli can lead to highly compartmental- tochondria where they dynamically interact with the respec- ized regulation of O-GlcNAc. O-GlcNAcylation is some- tive substrates (Kreppel et al. 1997; Haltiwanger et al. 1992; times promoted, depressed or unaffected in different parts Dong and Hart 1994; Gao et al. 2001;Banerjee et al. 2015; of the cell simultaneously (Kearse and Hart 1991;Carrillo Hart et al. 2011). There is an O-GlcNAc transferase called et al. 2011; Griffith and Schmitz 1999;Yangetal. 2008). eOGT that has been identified in the secretory pathway, but If and when a particular protein is O-GlcNAc modified is this enzyme is distinct from OGT (Matsuura et al. 2008; thought to depend to a large extent on the context in Varshney and Stanley 2017). which OGT and OGA operate. OGT and OGA form com- Changes to the specific activity or expression levels of plexes with a large set of proteins and these binding- OGT or OGA can increase or decrease global O-GlcNAc partners can direct O-GlcNAcylation towards specific tar- levels (Hart et al. 2011). OGT's donor substrate is UDP- gets (Hartetal. 2011; Groves et al. 2017). Some GlcNAc. UDP-GlcNAc is produced in the cell through the interactors are associated with changes in OGT and hexosamine biosynthesis pathway (HBP) (Hart et al. 2011). OGA specific activity (Groves et al. 2017; Marz et al. In adipocytes, the HBP converts about 2-3% of all glucose 2006). Similarly, activity and substrate selectivity can be entering the cell to UDP-GlcNAc (Marshall et al. 1991). In affected also by direct phosphorylation (Bullen et al. 2014; addition to glucose, amino acid, fatty acid and nucleotide me- Whelan et al. 2008). tabolism also feed into the HBP (Hart et al. 2011). The con- In addition to extrinsic regulation of substrate targeting, version rate is controlled by the glutamine:fructose-6-phos- what proteins are O-GlcNAcylated at a given time and place phate amidotransferase (GFAT). The affinity of GFAT for its depends on factors intrinsic to OGT and OGA. Surprisingly, substrate, fructose-6-phosphate, is relatively poor and if nutri- whereas a raised UDP-GlcNAc concentration elevates O- ent availability increases, so do UDP-GlcNAc levels (Bouche GlcNAc on most targets, the relative increase of O-GlcNAc et al. 2004;Wangetal. 1998; Hawkins et al. 1997;Marshall et on peptides and proteins in vitro differs between substrates, al. 2004). GFAT affects the downstream effects of glucose suggesting that UDP-GlcNAc influences OGT's intrinsic over a wide range of glucose concentrations (Sayeski and specificity (Kreppel and Hart 1999;Shenet al. 2012). It Kudlow 1996). The regulation of the HBP is complex how- should also be noted that whereas much evidence argues that ever and whether diabetic glucose concentrations transduce there is no absolute consensus sequence for where O- into similar fluctuations of cellular UDP-GlcNAc levels has GlcNAcylation occurs, the local peptide environment and been challenged in adipocytes (Bosch et al. 2004;Schleicher neighboring amino acids do affect which serines or threonines and Weigert 2000). Nonetheless, the activity of OGT is sensi- are preferred (Hart et al. 2011; Nagel and Ball 2014). Plus, tive to altered UDP-GlcNAc levels from nano- to millimolar alternative splicing affects the subcellular expression of OGT concentrations (Slawson et al. 2010). Raised UDP-GlcNAc and OGA, and possibly intrinsic substrate preference (Nagel levels increase OGT activity against peptides and proteins in and Ball 2014). J Bioenerg Biomembr (2018) 50:241–261 243 While O-GlcNAc levels can fluctuate globally within the concentrated particularly in, for example, Purkinje cells in cell, the idea of OGT and OGA as holoenzymes functioning in the cerebellum and under some conditions pyramidal neurons complexes with other proteins in dynamic multicellular envi- of the CA1 region of the hippocampus (Taylor et al. 2014;Liu ronments opens up the possibility of local and substrate- et al. 2012; Akimoto et al. 2003;Rex-Mathes etal. 2001). The specific regulation of O-GlcNAcylation (Lagerlof and Hart staining pattern in the hippocampus is broadly similar between 2014;Hart et al. 2011). One way of synthesizing global and rodents and humans (Taylor et al. 2014). Total O-GlcNAc in local regulation would be to understand them as operating brain homogenate is the highest during pre- and perinatal de- simultaneously but on separate levels. There are, however, velopment and decreases during later development many aspects of OGT and OGA function that still are not (Yanagisawa and Yu 2009; Liu et al. 2012). In vitro, early understood. It has been shown, for example, that OGT can neuronal differentiation also has been associated with a de- act as a protease against at least one substrate (host cell factor crease in global O-GlcNAcylation, albeit the global O- 1) and may be important as a scaffold for other proteins, in GlcNAc levels appear to cycle from day to day (Andres et addition to its ability to O-GlcNAcylate proteins (Levine and al. 2017;Speakman et al. 2014). At around one month after Walker 2016). birth, overall O-GlcNAc plateaus at a relatively low level and then remains stable for most of adulthood (Liu et al. 2012). O-GlcNAc, brain function and disease While some have argued that these levels (in rats) persist in the geriatric brain (Liu et al. 2012), others have shown an increase How only two enzymes coordinate via O-GlcNAc the func- at similar ages in both mice and rats (Yang et al. 2012; Fulop et tion of thousands of proteins has only begun to be explored. If al. 2008). However, the pattern of O-GlcNAcylation using dysregulated, aberrant O-GlcNAcylation can lead to disease. western blotting has been reported consistently to change in It will be described below that the genes encoding OGT and the brain across all stages of life, including in the very old OGA are linked to late-onset diabetes, intellectual disability animal (Yang et al. 2012; Liu et al. 2012; Fulop et al. 2008). and several neurodegenerative disorders. OGT and OGA Hence, the relative abundance of O-GlcNAc between proteins function in homeostasis where too high or too low O- continuously fluctuates. GlcNAc levels can deter cellular physiology (Yang and Qian The proteins in the brain and the peripheral nervous sys- 2017; Zhang et al. 2014; Bond and Hanover 2013). O- tem that are O-GlcNAcylated belong to a wide array of GlcNAc is a nutrient and stress sensor in the nervous system. functional categories (Lagerlof and Hart 2014; Kim et al. The cellular identity and the extended morphology of neurons 2016; Wang et al. 2017). Just like in other tissues, mass and glia, however, determine the response and functional con- spectrometry has mapped O-GlcNAc sites on proteins in- sequence of O-GlcNAc to common and neuron-specific stim- volved in, for example, signaling, transcription, translation and cytoskeletal regulation (Alfaro et al. 2012;Wangetal. uli. Specific neuronal circuits drive behavior and it is only from their perspective the function of O-GlcNAc can be un- 2010a; Khidekel et al. 2004). While many of these proteins derstood. There are many extensive reviews on O-GlcNAc are shared with non-neuronal organs, some play specialized function in general (Hart et al. 2011;Ruan et al. 2013; Bond roles in neurons, e.g. the transcription factor cAMP respon- and Hanover 2013; Hardiville and Hart 2014; Levine and sive element-binding protein (CREB) (Altarejos and Walker 2016; Yang and Qian 2017; Nagel and Ball 2014). Montminy 2011; Feldman 2009; Rexach et al. 2012). Here major roles played by O-GlcNAc in the nervous system Other O-GlcNAc proteins such as neurotransmitter receptors are discussed. or some synaptic proteins are expressed mainly or only in the nervous system (Trinidad et al. 2012; Vosseller et al. 2006;Schochetal. 1996). Immuno-electron microscopy O-GlcNAc and its regulation in the nervous and biochemical fractionation coupled with western blotting system have shown that O-GlcNAc is enriched in synapses, the specialized cell-cell junctions over which neurons communi- The O-GlcNAc modification in the nervous system cate (Akimoto et al. 2003; Tallent et al. 2009; Cole and Hart 2001). More than 19% of all synaptic proteins are O- Almost all studies characterizing O-GlcNAc in the nervous GlcNAcylated (Trinidad et al. 2012). In the presynaptic ter- system have focused on the forebrain and the cerebellum. minal, there is dense staining around synaptic vesicles Immunohistochemistry indicates that O-GlcNAc is compara- (Akimoto et al. 2003) - the presynaptic proteins bassoon tively more abundant under basal conditions in some brain and piccolo are among the most heavily O-GlcNAcylated regions and some cells within a given area (Liu et al. 2012; proteins identified (Trinidad et al. 2012). In addition to syn- Rex-Mathes et al. 2001; Akimoto et al. 2003; Taylor et al. apses, there is dense immunostaining in the nucleus in many 2014; Lagerlof et al. 2016). No quantitative comparison has neurons (Akimoto et al. 2003; Rex-Mathes et al. 2001;Liu been made but authors have argued O-GlcNAc to be et al. 2012). 244 J Bioenerg Biomembr (2018) 50:241–261 On individual proteins, O-GlcNAc sites tend to cluster in Through alternative splicing, at least five major transcripts disordered regions or on amino acid chain turns. A subset is coding for OGT have been described in mammals (Nolte and found in local contexts rich in prolines (Trinidad et al. 2012; Muller 2002; Kreppel et al. 1997; Lubas et al. 1997;Hanover Alfaro et al. 2012; Vosseller et al. 2006;Wanget al. 2017). et al. 2003; Shafi et al. 2000). These are thought to give rise to Both functionally and structurally, O-GlcNAc is known to three major protein isoforms, nucleocytoplasmic OGT cross-talk with phosphorylation (Wang et al. 2010b;Hart et (ncOGT), mitochondrial OGT (mOGT) and short OGT al. 2011;Wanget al. 2008). In whole-cell preparations from (sOGT). The isoforms differ in their N-terminal domain, cortex many O-GlcNAc sites are the same as or in close prox- whichisbelievedtoconstitute the substrate for many imity to phosphorylation sites (Alfaro et al. 2012). Kinases in protein-protein interactions. The full-length isoform, ncOGT, the brain seem to become modified by O-GlcNAc more fre- and the shortest isoform, sOGT, are present in the nucleus and quently than other proteins (Alfaro et al. 2012; Trinidad et al. cytosol. The N-terminus of mOGT includes a mitochondrial 2012). In reverse, OGT and OGA are phosphorylated (Hart et signal sequence and is present in the mitochondria (Hanover et al. 2011). As discussed below, there are many instances in the al. 2003;Hart et al. 2011). The transcript believed to corre- brain where O-GlcNAcylation and phosphorylation regulate spond to ncOGT is identified consistently in cDNA derived each other. Though, a comparison between thousands of O- from brain (Lubas et al. 1997; Hanover et al. 2003; Nolte and GlcNAc and phosphorylation sites in synapses did not find Muller 2002; Kreppel et al. 1997; Shafi et al. 2000). Similarly, that their sites were more often the same or closer together four out of five papers appear to describe the transcript corre- than what is predicted by chance (Trinidad et al. 2012). sponding to mOGT in brain (Kreppel et al. 1997; Nolte and To summarize, O-GlcNAc modifies a diverse set of pro- Muller 2002; Lubas et al. 1997; Shafi et al. 2000). Whether teins in the nervous system. What particular proteins become this transcript is translated to protein has been questioned be- modified, even under basal conditions, depends on brain area, cause the mOGT open reading frame in most species, includ- cell type within each area and on the age of the organism. ing mouse but not human, includes a stop codon (Trapannone et al. 2016). From which transcript sOGT originates has not been defined definitively, but two papers that used human The expression of OGT in the nervous system cDNA failed to identify in brain any transcripts other than the ones coding for ncOGT and mOGT (Lubas et al. 1997; Brain is one of the organs where OGT expression and activity Nolte and Muller 2002). However, transcripts that may give are the highest (Kreppel et al. 1997; Okuyama and Marshall rise to sOGT were discovered in brain cDNA in three papers 2003). Overall OGT protein levels and activity in vivo are that used rat or mouse tissue (Kreppel et al. 1997;Hanover et mostly stable during development through adulthood al. 2003; Shafi et al. 2000). In whole-cell material, multiple (Yanagisawa and Yu 2009; Liu et al. 2012). Neuronal differ- subcellular fractions or immunoprecipitates, western blotting entiation in vitro, in contrast, has been associated with a small for OGT using several different antibodies, including antibod- decrease in OGT mRNA and protein abundance (Andres et al. ies known to recognize a band running at the proper size for 2017; Maury et al. 2013). In the very old brain, the total sOGT in other tissues, typically picks up only ncOGT with protein level may go down slightly (Fulop et al. 2008). The certainty (Kreppel et al. 1997;Marz et al. 2006; Lagerlof et al. hippocampus and the cerebellum, similar to what was de- 2017; Okuyama and Marshall 2003; Cole and Hart 2001). scribed above for O-GlcNAc, are areas with particularly high Though, sOGT may become increasingly prominent with OGT expression (Liu et al. 2004a; Liu et al. 2012). age (Liu et al. 2012). Experiments based on tools that can Biochemical fractionation has identified OGT in all major identify the OGT isoforms unequivocally to measure the rel- subcellular compartments of neurons (Lagerlof et al. 2017; ative amounts of ncOGT, mOGT and sOGT in the brain are Tallent et al. 2009). OGT is enriched in the presynaptic and needed. Notwithstanding, the current data suggest that ncOGT postsynaptic terminals, where its specific activity is higher is highly abundant in neuronal synapses and is the major iso- than in the whole-brain homogenate (Tallent et al. 2009; form present in the brain, albeit with possible species and age Lagerlof et al. 2017; Akimoto et al. 2003; Cole and Hart differences in OGT expression patterns. 2001). At least 80% of all excitatory postsynaptic terminals stain positive for OGT (Lagerlof et al. 2017). As might be The expression of OGA in the nervous system expected from its broad localization pattern within neurons and the wide variety of neuronal proteins that are O- As for OGT, the expression and specific activity of OGA GlcNAcylated, a yeast two-hybrid screen looking for OGT- in the brain are among the highest of all organs (Dong and binding partners in a fetal brain cDNA library identified 27 Hart 1994; Gao et al. 2001). Total activity appears to proteins from diverse functional categories such as transcrip- decrease postnatally and, in vitro, neuronal differentiation tion factors, scaffolding proteins and transmembrane receptors is associated with lower total OGA protein levels (Liu et (Cheung et al. 2008). al. 2012; Maury et al. 2013;Andresetal. 2017). There are J Bioenerg Biomembr (2018) 50:241–261 245 two splice variants of OGA, full-length OGA (OGA) and energy over time scales measured in minutes. Exposing the short OGA (sOGA). sOGA lacks an acetyltransferase-like axons only to glucose, by culturing the cells in a microfluidic C-terminal domain (Butkinaree et al. 2008;Comtesseet system, appeared to hinder mitochondrial movement locally al. 2001;Heckeletal. 1998; Toleman et al. 2004). Both (Pekkurnaz et al. 2014). Removing leptin, an adipokine, isoforms are present in the brain (Comtesse et al. 2001; causes hyperphagia and obesity (Williams and Elmquist Heckel et al. 1998). With western blotting it was shown 2012). Despite the surplus of available energy, Ob/Ob mice, that a band reactive to an anti-OGA antibody migrating at where the gene producing leptin has been knocked out (KO), the size of sOGA is downregulated at birth. The general showed, in contrast, lower levels, and altered subcellular dis- abundance of OGA in vivo remains at a consistent level tribution of O-GlcNAc in the hippocampus, possibly due to a throughout life, apart from a peak perinatally (Liu et al. reduction in OGT. Caloric restriction reversed the effects on 2012). Immunohistochemistry for OGA in the adult brain O-GlcNAc and OGT but only in some parts of the hippocam- resembles the staining pattern for OGT (Liu et al. 2012; pus (Jeon et al. 2016). The mechanism behind these findings Yang et al. 2017). OGT and OGA sometimes co-exist in is difficult to interpret because leptin may regulate O-GlcNAc the same complex in peripheral cells and the directly, independently of the metabolic state of the animal abovementioned yeast-two hybrid study on binding part- (Zimmerman and Harris 2015; Harris and Apolzan 2015; ners to OGT using brain cDNA picked up OGA Buse et al. 1997). There is much evidence showing that insu- (Whisenhunt et al. 2006; Slawson et al. 2008; Cheung et lin, another metabolic hormone, phosphorylates and activates al. 2008). OGA is present, phosphorylated and highly ac- OGT through the insulin receptor (Whelan et al. 2008). tive in purified synaptosomes from brain (Cole and Hart Feeding animals a ketogenic diet, which may affect HBP flux, 2001;Trinidadetal. 2012). When separating the postsyn- altered OGT and OGA gene expression without affecting total aptic density (PSD) from the presynaptic fraction OGA in O-GlcNAc content in the prefrontal cortex (Newell et al. contrast to OGT was largely excluded from the PSD under 2017). Hence, in the hippocampus, there is clear evidence that basal conditions (Lagerlof et al. 2017). The lack of neuronal O-GlcNAc levels are nutrient-dependent. completely overlapping subcellular localization between Nevertheless, the metabolic history of the animal or metabolic OGT and OGA may explain in part why manipulation of hormones such as leptin and insulin affect when and where O- OGT or OGA does not always yield the complimentary GlcNAc is incorporated. There is no simple relationship be- result. tween acute energy availability and overall O-GlcNAcylation, at least not in vivo. The regulation of O-GlcNAc in the nervous system Adding sucrose to the diet elevates global O-GlcNAc in a brain region ventral to the hippocampus, the hypothalamus (Zimmerman and Harris 2015). In the hypothalamus, how- Complex nutrient and stress sensing ever, there are cells where O-GlcNAc has been shown to be Fasting mice for 24 hours or longer leads to a strong reduction positively, negatively or (so far) not regulated by changes in in global O-GlcNAc in the hippocampus and cortex. O- energy flux. In agouti-related peptide (Agrp) neurons in the GlcNAc returns to its original levels after re-introducing food arcuate nucleus of the hypothalamus, fasting increased O- to the animals, but only after several hours (Li et al. 2006;Liu GlcNAc and OGT protein levels (Ruan et al. 2014). A sim- et al. 2004a). There is a delay between postprandial surges in ilar phenomenon was discovered in cultured neuroblasts. blood glucose and the glucose concentration in cerebrospinal Depriving Neuro-2a (N2a) neuroblastoma cells completely fluid (CSF) that is probably due to the blood-brain barrier. of glucose decreased O-GlcNAc after one hour but caused However, feeding increases CSF glucose within 40 minutes a marked induction after 6-9 hours. The initial drop in O- (Steffens et al. 1988; Silver and Erecinska 1994)and while the GlcNAc occurred simultaneous to higher OGA activity and glucose must be metabolized to UDP-GlcNAc once it has reduced UDP-GlcNAc concentration. The subsequent O- been taken up by the cell until the rise in nutrient availability GlcNAc incorporation was related to AMP-activated protein can be detected by OGT, the HBP prolongs the lag by merely a kinase (AMPK)-dependent stimulation of Ogt transcription few minutes, as extrapolated from results in adipocytes (Cheung and Hart 2008), possibly as part of a stress re- (Marshall et al. 2004). The reason behind the comparatively sponse (Zachara et al. 2004). I will discuss below that O- slow restoration of hippocampal O-GlcNAc levels in vivo is GlcNAc regulates and is regulated by the response to acute unclear. Glucose-stimulated arrest of mitochondrial motility in cerebral insults, like stroke, and neurodegeneration occurring dissociated cultures of hippocampal neurons was prevented over months or years. There is no evidence that the O- by inhibiting flux through HBP. Affecting OGT or OGA func- GlcNAc response in Agrp neurons upon fasting, though, tion or O-GlcNAcylation of the protein Milton had the same should be interpreted as a cytoprotective reaction. Ghrelin, effect, indicating that O-GlcNAcylation on some proteins in a hormone released by the stomach in times of food depri- hippocampal neurons may respond in vitro to changes in vation, had the same effect as fasting in Agrp neurons - it 246 J Bioenerg Biomembr (2018) 50:241–261 increased OGT abundance (Ruan et al. 2014). It was not Neuronal activity-dependent regulation of O-GlcNAc tested whether AMPK mediates the effect of ghrelin and fasting on OGT protein levels in Agrp neurons but it is Particularly in some parts of the hypothalamus, physiological known that ghrelin activates AMPK in the hypothalamus changes in glucose concentration promote or suppress neuro- (Ronnett et al. 2009). The available data suggest that the nal firing (Marty et al. 2007). Neuronal firing by itself is a induction of OGT in Agrp neurons may signal the need highly energetic event (Rangaraju et al. 2014). There is evi- for preserving energy on the whole-body level (see below). dence nonetheless that neuronal activity regulates O- In another part of the hypothalamus, in the paraventricular GlcNAcylation independently of indirect changes in energy nucleus (PVN), fasting decreased cellular O-GlcNAc levels consumption of the firing neuron. in αCaMKII-positive neurons but not in αCaMKII-negative Depolarizing NG-108-15 cells - a neuroblast-glioma hy- neurons. This effect could be replicated ex vivo.Using brid cell type - with potassium chloride or glutamate increased organotypic PVN cultures, switching from 1mM to 5mM global O-GlcNAc. The increase occurred within one minute, glucose for one hour increased somatic O-GlcNAc in probably by direct activation of OGT (Song et al. 2008). αCaMKII-positive neurons. There was a further increase Unlike many other glycosyltransferases utilizing a UDP-sug- when comparing 5mM with 16 hours of 25mM glucose. ar, divalent cations like calcium ions are not required for OGT Neighboring αCaMKII-negative cells, in contrast, did not activity in vitro (Haltiwanger et al. 1990). Neither do calcium react in terms of O-GlcNAc to these treatments (Lagerlof ions or ethylenediaminetetraacetic acid (EDTA) have any ef- et al. 2016). These data suggest that the variability among fect on OGA activity (Dong and Hart 1994). Rather, inhibiting neurons in how their O-GlcNAc levels are regulated by en- voltage-dependent calcium ion influx or calcium-/calmodulin- ergy availability cannot solely be explained by elements ex- dependent protein kinases (CaMK) blocked the effect and trinsic to the cells such as differential exposure in vivo to CaMKIV phosphorylated OGT (Song et al. 2008). Similarly, factors deriving from whole-body metabolism. Rather, the depolarization of cultured neurons induced O-GlcNAcylation data could be explained by different intrinsic sensitivity to of CREB at S40. The effects could be blocked by inhibiting nutrient and hormonal access between different types of CaMKs but also mitogen-activated protein kinase (MAPK) neurons. The reason behind this difference is entirely unex- (Rexach et al. 2012). Raising network firing through blocking plored but may be partly related to alternative regulation of inhibitory neurotransmission in cultured primary cortical cells flux through the HBP via GFAT phosphorylation or isoform also was associated with an increase of O-GlcNAc on many expression or the obesity-linked enzyme that can counteract proteins in the PSD (Lagerlof et al. 2017). These observations GFAT, Gnpda (Oikarietal. 2016; Oki et al. 1999; indicate that neuronal activity can evoke other pathways than Schleicher and Weigert 2000;Ouyang etal. 2016). HBP flux, such as activity-dependent phosphorylation to af- Within the same neuron, nutrient-dependent O- fect O-GlcNAcylation. GlcNAcylation may not impress on all proteins equally. In Surprisingly, the activity-dependent O-GlcNAcylation of the Introduction it was described that UDP-GlcNAc levels CREB did not reach its maximum until after 6 hours affect OGT substrate specificity and that OGT is thought to (Rexach et al. 2012). Plus, inducing seizures in mice with operate like a holoenzyme where its binding partners contrib- injections of kainic acid raised O-GlcNAc on many proteins ute to determining its targets. Removing leptin seems to alter in cortex, for example on the transcription factor early growth the subcellular distribution of O-GlcNAc in the CA3 region of response-1 (EGR-1), not at maximum seizure activity (two the hippocampus (Jeon et al. 2016). In Agrp neurons fasting and a half hours post injection) but when the animals had increased the binding of OGT to the potassium channel Kcnq3 started to rest (six hours post injection) (Khidekel et al. (Ruan et al. 2014) and glucose deprivation in N2a cells 2007). Complex modulation of neuronal activity through targeted OGT via the protein p38 to a different set of sub- chemical long-term potentiation and depression, cLTP and strates (Cheung and Hart 2008). Under basal conditions, in cLTD, respectively, of hippocampal synapses in slices appear neuronal cells, the protein phosphatase-1 interactor myosin to increase global O-GlcNAc (Yang et al. 2017). In contrast, phosphatase targeting subunit 1 (MYPT1) affects the substrate inducing LTD with low-frequency stimulation or inhibiting specificity of OGT (Cheung et al. 2008). OGT-binding pro- gamma-aminobutyric (GABA) receptors in hippocampal teins in brain may regulate also the specific activity of OGT, as slices or in vivo, which leads to hyperexcitability, did not suggested for the neurodegenerative disease protein Ataxin- affect total O-GlcNAc levels in the hippocampus (Stewart et 10 (Marz et al. 2006). al. 2017; Taylor et al. 2014). In sum, O-GlcNAc levels have been shown to fluctuate How neurotransmission may regulate O-GlcNAc was an- depending on nutrient availability in neuronal cell culture, ticipated in an early study done in cultured, immature cerebel- brain slice preparations and in the brain of living animals. lar neurons. Directly stimulating or inhibiting various activity- The mechanism by which this occurs, however, is multiface- dependent kinases and phosphatases showed that while sever- ted and differs between types of neurons. al change the O-GlcNAcylation of many proteins, the effect J Bioenerg Biomembr (2018) 50:241–261 247 differs depending on substrate cohort. Inhibiting protein ki- The developmental decrease in O-GlcNAc appears to be nase C (PKC), for example, increased O-GlcNAc on cytoskel- important for the early differentiation and organization of the etal proteins but decreased O-GlcNAc on membrane and some nervous system. O-GlcNAc's general and essential function in cytosolic proteins (Griffith and Schmitz 1999;Giese and cell proliferation critically affects early embryogenesis (Shafi Mizuno 2013). Hence, the difficulty in identifying activity- et al. 2000; Slawson et al. 2005; Webster et al. 2009; dependent changes in overall O-GlcNAc levels may result Dehennaut et al. 2007; Dehennaut et al. 2008). O-GlcNAc from simultaneous up- and downregulation or subcellular- may have additional effects on stem cell renewal and differ- specific regulation of OGT or OGA. The conflicting results entiation. Several transcription factors that regulate regarding whether, and under what time scale, neuronal activ- pluripotency - such as Octamer-binding protein 4 (Oct4) - ity directly regulates O-GlcNAcylation may be resolved by are O-GlcNAcylated in stem cells. There are several O- studying what signaling pathways affect OGT and OGA func- GlcNAc sites on Oct4 and its transcriptional activity is in- tion in specific subcellular compartments. creased by overexpression of OGT. Upon differentiation, the O-GlcNAc modification is lost (Jang et al. 2012). Mutating the O-GlcNAc site T228 to alanine on Oct4 repressed its tran- Summary scriptional activity and the renewal of mouse embryonic stem cell colonies. Partly due to other O-GlcNAc sites, the role of Cross-talk between phosphorylation and O-GlcNAc, enzy- O-GlcNAc for Oct4 and stem cell biology is however multi- matic targeting, metabolic and stress signaling are regulatory faceted (Jang et al. 2012; Constable et al. 2017; Miura and principles that apply to O-GlcNAc cycling in the nervous Nishihara 2016). Whereas the effect may differ depending on system, just like in peripheral cells (Hart et al. 2011; culturing protocol, inhibiting OGT or OGA pharmacological- Lagerlof and Hart 2014). Nevertheless, the identity of the cell, ly in vitro has been shown not to affect human stem cell its localization within the nervous system and its extended pluripotency, as measured by the expression of, e.g., Oct4 morphology, will modify the O-GlcNAc response to a given (Andres et al. 2017; Maury et al. 2013;Speakmanetal. stimuli. Stress-, activity- and nutrient-dependent regulation of 2014). Rather, globally decreasing or increasing O-GlcNAc O-GlcNAc seem to occur through different pathways, but may levels respectively accelerated or delayed the commitment to interact as well. The activity-dependent protein kinase A a neuronal fate (Andres et al. 2017; Maury et al. 2013). (PKA) phosphorylates the two GFAT isoforms that are Stimulating the differentiation of orexin neurons, a cell type expressed in brain, GFAT1 and, which appears to be the main regulating the sleep/wake cycle and feeding behavior, is asso- brain isoform, GFAT2. Whereas PKA can activate GFAT1, ciated with a switch from OGT to OGA occupancy in the PKA inhibits GFAT2 (Hu et al. 2004; Chang et al. 2000; Orexin gene promotor region. OGA activity increases and Oki et al. 1999). Another example of neuronal firing - HBP OGT decreases orexin expression (Hayakawa et al. 2013). flux co-regulation exploits astrocytes. After the neurotransmit- Surprisingly, deletion of OGA in all tissues in vivo may lead ter glutamate has been released at synapses, it is taken up by to a general developmental retardation but no gross intrauter- astrocytes. Astrocytes convert glutamate to glutamine by glu- ine histological defects (Yang et al. 2012; Keembiyehetty et al. tamate synthetase (GS) (Schousboe et al. 2014). Glutamine, in 2015). In contrast, altering global O-GlcNAc levels in turn, feeds into the HBP (Hart et al. 2011). Treating astrocytes Zebrafish embryos in either direction was associated with cell with ammonia dramatically elevated global O-GlcNAc levels. death and dramatic changes in brain structure. Only increased The effect was not related to changes in pH or osmolarity but O-GlcNAc levels, however, disrupted the gross patterning of rather stimulation of GS and increased UDP-GlcNAc produc- the central nervous system (Webster et al. 2009). Removing tion (Karababa et al. 2014). In the behaving animal with intact OGA in mice from ectoderm, the tissue lineage giving rise to neuronal circuits many factors are brought together to deter- the nervous system, leads to severe developmental perturba- mine the O-GlcNAcylation of a particular protein at a partic- tion in several brain regions such as cortex, the hippocampus ular subcellular localization in a particular cell. and the pituitary. The number of dividing and neuronal pre- cursor cells was elevated, but loss of OGA suppressed pro- gression to mature neurons in vivo and in vitro (Olivier-Van The role of O-GlcNAc in the development Stichelen et al. 2017). of the nervous system Hyperglycemia is linked to several developmental defects, including failure of the neural tube to close (Tan et al. 2017b). Above it was described that the expression of the O-GlcNAc Neural tube closure is regulated by Paired box 3 (PAX3), a modification and its regulatory enzymes OGT and OGA transcription factor believed to cause many cases of the devel- change during brain development. After fluctuating during opmental condition called the Waardenburg syndrome. PAX3, early neuronal differentiation, later development was associ- or a PAX3-binding protein, has been found to be O- GlcNAcylated. Raising O-GlcNAc levels by injecting glucose ated with a global decrease in O-GlcNAc levels. 248 J Bioenerg Biomembr (2018) 50:241–261 or the highly specific OGA inhibitor Thiamet G (TMG) into neuronal differentiation, extension and organization. chicken egg embryos decreased PAX3 protein expression, Though, knocking out OGT specifically in neurons, thereby while hyperglycemia did not affect PAX3 mRNA levels. In decreasing O-GlcNAc dramatically, lead to fewer KO pups reverse, the glucose-induced loss of PAX3 could be rescued born than expected and those animals that survived until term by blocking OGT and O-glycosylation in the Golgi apparatus never developed locomotor behavior but died within ten days with benzyl-2-acetamido-2-deoxy-α-D-galactopyranoside (O'Donnell et al. 2004). Culturing neurons dissociated from (BG) (Tan et al. 2017b). Applying the putative OGT inhibitor dorsal root ganglia in the peripheral nervous system of four- ST045849 to pregnant diabetic mice similarly decreased the week-old mice demonstrated in addition that deleting OGT number of pups suffering from neural tube closure defects reduced axon growth (Su and Schwarz 2017). At least three (Kim et al. 2017). Hence, another mechanism by which O- different mutations in Ogt have been discovered to segregate GlcNAc regulates the early development of the nervous sys- in humans with severe intellectual disability. The mutations tem may be through inducing PAX3 degradation and thus were associated with lower OGT protein levels. Nonetheless, affect neural tube closure. global steady-state O-GlcNAc did not change, possibly due to Culturing primary neurons has indicated that later neuronal compensation in OGA. How disease results from these muta- maturation depends on relatively low O-GlcNAc levels. tions is unclear but instead of altered total O-GlcNAc, the Overexpressing OGA stimulates neuronal polarization, in- underlying explanation may be altered O-GlcNAc cycling ki- creases the density of filopodia on axons and the number of netics or substrate targeting of OGT; the mutations lie in the neurons displaying branched processes. Inhibiting OGA phar- TPR-domain of OGT which mediates many protein-protein macologically decreased the number of axonal protrusions, interactions (Willems et al. 2017; Vaidyanathan et al. 2017). probably at least in part by inhibiting PKA (Francisco et al. The role of O-GlcNAc during development has only begun to 2009). In another study, OGT overexpression decreased and be investigated. Once the molecular mechanisms are dissected OGT KO increased axon length. Knocking down CREB, further, other principles than overall fluctuations may arise. which is known to regulate axon growth, prevented the effect Global and pathway-specific rules of O-GlcNAc functioning of OGT overexpression or KO (Rexach et al. 2012). OGT has are bound to intersect to assure proper development of the been shown to stimulate PKA activity and phosphorylation of peripheral and central nervous system. the activating PKA site S133 on CREB (Xie et al. 2016). However, the OGT-dependent effect on axons was related to direct O-GlcNAcylation of CREB on S40. S40 O- The regulation of animal behavior GlcNAcylation is induced by neuronal depolarization, as and neuronal function by O-GlcNAc discussed above, but only after S133 has become phosphory- lated. O-GlcNAc appears to turn off further CREB-dependent The previous sections have showed that O-GlcNAc cycling in transcription by disrupting the binding of CREB to its co- the nervous system occurs on proteins in many functional activator CREB-regulated transcription coactivator (CRTC). categories and is regulated by many stimuli that differ depend- O-GlcNAcylation of S40 regulated dendritic growth as well. ing on the identity of the cell. The roles played by O-GlcNAc The effect on dendritic versus axonal elongation was mediated in the brain and the peripheral nervous system are bound to be by different downstream CREB gene products; Wnt2 for den- equally diverse. Here the main functions in mature neurons drites and BDNF for axons (Rexach et al. 2012). O- and adult animal behavior that have been addressed in previ- GlcNAcylation of CREB may inhibit activity-independent ous research are discussed. transcription also by perturbing the complex between CREB and TAFII130, a component of the TFIID transcriptional com- Animal behavior plex, and total CREB protein levels (Lamarre-Vincent and Hsieh-Wilson 2003; Rexach et al. 2012; Xie et al. 2016). Metabolism Establishing neuronal networks relies at the end on neurons forming synapses. The neuronal networks present when de- Much evidence holds that the brain is a master regulator of velopment has run its course should not however be conceived whole-body metabolism. The brain keeps track of energy stor- of as finished products. The number and strength of neuronal age levels, detects acute fluctuations in nutrient supply and synapses continue to be molded in adulthood. So-called syn- directs feeding behavior, energy expenditure and other com- aptic plasticity too is affected by O-GlcNAc; O-GlcNAc's role ponents of metabolism. This control is shared by very many in these processes will be discussed below. areas within the brain. Nevertheless, some neuronal circuits O-GlcNAc cycling regulates numerous steps throughout are thought to be more directly involved. The function of such the development of the nervous system. A common theme metabolic circuits relies on information about the body's met- in the central nervous system appears to be that decreasing abolic status they receive from hormonal, nutrient and neuro- O-GlcNAc promotes, while increasing O-GlcNAc inhibits nal signals from peripheral organs (Schwartz et al. 2000; J Bioenerg Biomembr (2018) 50:241–261 249 Blouet and Schwartz 2010;Sohnet al. 2013; Rossi and Stuber targeting OGT mutations to specific neurons in the hypothal- 2018). Recent observations suggest that O-GlcNAc is integral amus - a brain region known to influence metabolic behavior to the way body-to-brain signals are sensed by the retrieving directly - indicates that O-GlcNAc plays different roles in neuron and integrated into its larger network. different types of neurons. Many genes linked to obesity are believed to act in the Agrp neurons in the hypothalamus become activated upon brain (Locke et al. 2015). One of the most common obesity fasting and are associated classically with the control of for- genes, Gnpda2, regulates flux through the HBP (Speliotes et aging behavior and food intake in adult animals (Williams and al. 2010; Gutierrez-Aguilar et al. 2012; Wolosker et al. 1998). Elmquist 2012;Aponteetal. 2011;Sohnet al. 2013). Ablating The gene for Oga is linked to late onset diabetes in Mexican Agrp neurons during development does not lead to any major Americans and possibly spontaneously occurring diabetes in effects on food intake, probably due to compensation from so-called Goto-Kakizaki rats (Duggirala et al. 1999; Lehman other pathways (Luquet et al. 2005; Williams and Elmquist et al. 2005; Keembiyehetty et al. 2015; Xue et al. 2015). The 2012). The Agrp neurons also regulate energy expenditure effects of removing OGA in mice during embryogenesis on and glucose homeostasis (Wang et al. 2014b; Small et al. brain development have differed markedly depending on how 2001). It was recently reported that Agrp neurons upon fasting the mouse line was established. Results show consistently, decrease energy expenditure at least in part by inhibiting the however, that OGA KO homozygotes are born with lower thermogenic effect (TE) in retroperitoneal white fat (rWAT), body weight and die within a few days. The cause of death so-called browning (Ruan et al. 2014). Upon deleting OGT has been associated with either pulmonary malfunction or from Agrp neurons during development, there were no hypoglycemia (Keembiyehetty et al. 2015;Yangetal. discussed effects on cellular or animal viability. Whole-cell 2012). Heterozygotes, on the other hand, survive development patch clamp did not show any difference in membrane poten- and are fertile (Yang et al. 2015; Keembiyehetty et al. 2015). tial between OGT KO and Wt cells. There was neither any Total food intake is not disturbed in these mice but the respi- change in daily food intake or body weight in freely behaving ratory exchange ratio (RER) is increased, suggesting height- mice, but glucose tolerance was improved and energy expen- ened preference for utilizing carbohydrates instead of fatty diture decreased less than in Wts upon subjecting the mice to a acids in energy expenditure. One group has demonstrated in- fast. Loss of OGT made the mice partly resistant to detrimen- creased overall energy expenditure, improved glucose toler- tal effects of HFD. As described above, fasting induces OGT ance and lower body weight due to a more lean body type. and O-GlcNAc abundance in Agrp neurons. OGT removal Their mice were partly resistant also against obesity when fed decreased the Agrp neuron firing frequency, possibly through a high-fat diet (HFD) (Yang et al. 2015). Heterozygote fe- modifying the Kcnq3 potassium channel at T665. It seems males from another line of OGA KO mice, in contrast, were that in Agrp neurons OGT prevents energy expenditure during heavier than controls on either regular chow or HFD, whereas periods of caloric restriction (Ruan et al. 2014). there was no change in body weight or composition for males In adult mice, deleting OGT in αCaMKII neurons in- (Keembiyehetty et al. 2015). Systemic application of OGA creased body weight rapidly. Daily food intake more than inhibitors over weeks in adult mice and rats has been reported doubled. There was no change in meal frequency but KO to not alter total food intake, body weight or glucohomeostasis animals ate larger and longer meals. Energy expenditure in (Yuzwa et al. 2012; Macauley et al. 2010). mice fed ad libitum was elevated also, at least to some extent It has been speculated that the phenotype of the whole- due to higher physical activity. Allowing the OGT KO mice to body deletion of OGA derives from adipose tissue, but these eat only as much as Wts blocked any change in body weight. studies did not rule out other organs (Yang et al. 2015). Removing OGT locally from αCaMKII neurons in the PVN Removing in mice OGA selectively in ectoderm, which in- in adult mice by stereotactic virus injection caused hyperpha- cludes neurons, does not cause premature death or affect fer- gia and obesity as well. Fasting decreased and glucose in- tility. Without affecting overall body weight or food intake, creased O-GlcNAc abundance in the αCaMKII PVN neurons, adipose levels were increased (Olivier-Van Stichelen et al. as discussed above. It has been shown that removing OGT 2017). Neuronal KO of OGT during development leads to from αCaMKII neurons during early postnatal development lower body weight but the effect on locomotor behavior is leads to cellular degeneration of αCaMKII neurons in the so severe that no straightforward argument can be made for hippocampus or cortex (Wang et al. 2016). Cell number in a direct effect on metabolic regulation (O'Donnell et al. 2004). the PVN, or in the hippocampus, was not affected by acute A thorough metabolic analysis of the known OGT mutations deletion of OGT in adults, and just like in Agrp cells there was in human subjects has not been performed (Willems et al. no effect on membrane potential (Lagerlof et al. 2016). 2017; Vaidyanathan et al. 2017). Glutamatergic neurotransmission in the PVN has been shown Systemic and brain-wide perturbations suggest that neuro- to inhibit feeding (Hettes et al. 2003;Fenselau etal. 2017). nal O-GlcNAc regulates metabolism. But the data are conflict- Loss of OGT was associated with a decrease in excitatory ing as to what may be the underlying mechanism. Instead, synapses and blocked feeding-induced activation of the 250 J Bioenerg Biomembr (2018) 50:241–261 αCaMKII PVN neurons, as measured by immunohistochem- has been described to increase O-GlcNAcylation on CREB. istry for the immediate-early gene cfos (Lagerlof et al. 2016; Above it was discussed that mutating the O-GlcNAc site S40 Lagerlof et al. 2017). Optogenetic stimulation of these cells on CREB to alanine (S40A) increases the transcription of sev- decreased food intake and meal size. These data suggest that eral genes known to affect learning and memory, e.g. Bdnf. OGT in adult animals couples food intake with caloric need at Injecting S40A CREB into the amygdala, as compared to least in part by its regulation of excitatory synapses in injecting Wt CREB, enhanced freezing in FC two hours after αCaMKII PVN neurons (Lagerlof et al. 2016). training, suggesting that inhibiting CREB O-GlcNAcylation Thus, there are many indications that energy availability improved memory formation (Rexach et al. 2012). regulates O-GlcNAc signaling in the brain and that O- Pharmacological, genetic and site-specific data indicate GlcNAc cycling in neurons affects whole-body metabolism. that several short- and long-term learning and memory behav- The precise role played by O-GlcNAc, however, depends on iors rely on O-GlcNAc cycling. In reverse, as discussed the type of cell and the age of the animal. above, perturbed O-GlcNAcylation is associated with intellec- tual disability in humans (Vaidyanathan et al. 2017; Willems Learning and memory et al. 2017). Below will show that the mechanism underlying this phenotype is probably complex and requires interrogation Animal behavior relies on processes where information about of discrete pathways in specific cell-types. previous experience is used to overcome challenges like avoiding predators and locating food (Bailey and Kandel The peripheral nervous system 1993;Bhatt et al. 2009; Verpelli and Sala 2012;Grant 2012). Many forms of learning and memory depend on the The peripheral nervous system lies mainly outside the blood- hippocampus (Lynch 2004). Two such behaviors are novel brain barrier. Here, cells are likely to experience larger fluctu- object and placement recognition (NOR and NOP, respective- ations in energy availability and to some extent different met- ly) (Taylor et al. 2014; Antunes and Biala 2012; Vogel-Ciernia abolic hormonal signaling (Hoyda et al. 2009;Suand and Wood 2014). The animal is habituated initially to two Schwarz 2017). In mice, removing OGT during early devel- objects and then, when put back in the same arena two hours opment from Schwann cells, the glia that myelinate peripheral later, tested for its ability to recognize that one of the objects or nerves, lead to several behavioral stigma associated with neu- its location has been switched. Injecting TMG systemically romuscular dysfunction such as muscle weakness and gait prior to habituation impaired the performance in NOR and abnormalities at six months of age. Electrophysiological in- NOP, indicating that memory acquisition or retrieval were vestigations verified that the function of motor and sensory compromised (Taylor et al. 2014). In a different neurons was severely defective. While the number of hippocampal-dependent spatial learning task, both learning Schwann cells had not changed, there was a clear and progres- and memory were interpreted as diminished in OGA KO het- sive loss of axons. Demyelination occurred, but the axonal erozygotes (Yang et al. 2017). Contextual fear conditioning degeneration started prior to that. O-GlcNAc mapping of pro- (CFC) pairs a new environment with foot shocks and mea- teins in sciatic nerve tissue identified among 122 others a sures the degree of freezing in the same environment 24 hours myelinproteincalledperiaxin(PRX) whichisknownin later. CFC relies on the hippocampus but also brain areas such humans to be associated with neuropathy. PRX was mislocal- as the amygdala. Injection of TMG prior to conditioning did ized in OGT KOs and may explain in part how OGT in not affect the fear response 24 hours later (Taylor et al. 2014). Schwann cells regulates myelin homeostasis and supports ax- In contrast, OGA KO heterozygotes exhibited markedly de- on integrity (Kim et al. 2016). Knocking out OGT in periph- creased freezing in a similar CFC task (Yang et al. 2017). eral sensory neurons directly caused striking hyposensitivity Another group lowered global O-GlcNAc in the brain by to mechanical and thermal stimulation. Regardless if OGT injecting 6-diazo-5-oxo-norleucine (DON), a glutamine ana- was deleted during development or in adults, the deletion log that inhibits glutamine-utilizing pathways like the HBP and was associated with cell loss, suggesting that OGT is essential many others (Hart et al. 2011), into the cerebral ventricles prior for sensory neuron maintenance (Su and Schwarz 2017). to a contextual and cued FC task by which the learning and memory components can be addressed, to some extent, sepa- The regulation of synapses and neuronal signal rately. DON impaired both the learning and memory retrieval transmission phases of the experiment (Xie et al. 2016). As there were no effects in the open-field or the rotarod tests, the behavior in Excitatory synapses and AMPA receptor trafficking these tasks from globally perturbing O-GlcNAc levels geneti- cally or pharmacologically cannot be explained by generally It is believed that the brain learns and establishes new memo- detrimental effects on motor coordination or exploratory be- ries through modulating the number or strength of synapses, havior (Taylor et al. 2014;Yanget al. 2017). Fear conditioning so-called synaptic plasticity (Bailey and Kandel 1993;Bhatt et J Bioenerg Biomembr (2018) 50:241–261 251 al. 2009; Zuo et al. 2005a; Jontes and Phillips 2006; Shepherd TMG directly to hippocampal slices leads to an almost imme- and Huganir 2007). Much research has focused on how excit- diate depression of synaptic strength. Raising O-GlcNAc atory synapses in the hippocampus encode experience. The using GlcN had the same effect. The depression persisted for majority of fast excitatory neurotransmission in the brain is at least 60 minutes and continued after global O-GlcNAc conducted by α-amino-3-hydroxy-5-methyl-4- levels had returned to normal. The concept of a transient in- isoxazolepropionic acid (AMPA) receptors. The AMPA re- crease in O-GlcNAc leading to a long-lasting synaptic depres- ceptor is a tetrameric glutamate receptor composed of four sion was dubbed O-GlcNAc LTD (Taylor et al. 2014). A sep- subunits, GluA1-4. In forebrain neurons, two major isoforms arate report observed that simultaneous short-term administra- are GluA1/2 and GluA2/3 (Shepherd and Huganir 2007). At tion of TMG and GlcN dampened also induced hyperexcit- least in the adult cortex and hippocampus, most excitatory ability in slices and seizure activity in vivo (Stewart et al. synapses occur on dendritic protrusions called spines. 2017). It has been speculated that O-GlcNAc LTD results AMPA receptors trafficking in or out of synapses while spines from the actual O-GlcNAc increase, rather than altered abso- enlarge and stabilize or become thinner and retract leading to lute O-GlcNAc levels (Taylor et al. 2014). synaptic LTP or LTD is believed to constitute the substrate of The O-GlcNAc LTD was completely blunted in GluA2 KO many memory procesess (Collingridge et al. 2004;Salaand animals, suggesting a shared mechanism between O-GlcNAc Segal 2014; Bailey and Kandel 1993; Bhatt et al. 2009;Jontes and LFS LTD. Notwithstanding, blocking some pathways that and Phillips 2006; Zuo et al. 2005b). Several lines of evidence have been associated with classical AMPA receptor-related show that dynamic properties of excitatory synapse biology LFS LTD like N-methyl-D-aspartate (NMDA) receptors and including AMPA receptor-dependent synaptic plasticity de- PKC did not inhibit the O-GlcNAc-induced LTD. Plus, satu- pend on O-GlcNAc cycling. rating O-GlcNAc LTD with repeated application of GlcN did Insertion of AMPA receptors into the synaptic cleft con- not occlude LFS LTD. Repeated LFS did, though, block fur- tributes to high-frequency stimulated (HFS) LTP of hippo- ther TMG-dependent LTD (Taylor et al. 2014). Global or campal synapses in the CA1 region (Collingridge et al. sparse genetic deletion of OGT in primary cultured neurons 2004). HFS LTP diminished after acutely elevating O- reduced the surface expression of GluA2 and GluA3 and the GlcNAc levels by either inhibiting OGA with TMG or stimu- synaptic expression of GluA3. There was no significant de- lating the production of UDP-GlcNAc with glucosamine crease in GluA1 (Lagerlof et al. 2017). OGT co- (GlcN) (Taylor et al. 2014). Similarly, hippocampal HFS immunoprecipitates with GluA2, but not GluA1, and may LTP was decreased in OGA KO hetereozygotes (Yang et al. modify GluA2 directly (Taylor et al. 2014). Deleting OGT 2017). Several hours after another inhibitor of OGA, 9d, had lead to fewer and immature spines and lower synapse number, been injected systemically in vivo,however, the HFSLTP in as determined by immunohistochemistry (Lagerlof et al. the hippocampus increased (Tallent et al. 2009). Attempting to 2017). These data concord with experiments in vivo where inhibit OGT using the drug Alloxan has shown both enhanced the frequency and amplitude of excitatory synaptic inputs on and diminished LTP (Kanno et al. 2010; Tallent et al. 2009). αCaMKII PVN neurons upon KO of OGT in adult mice di- Whether the Alloxan-dependent observations are due to per- minished (Lagerlof et al. 2016). While it was not tested wheth- turbations of O-GlcNAcylation is questionable, though, be- er the effects on spines and AMPA receptors are mediated by cause Alloxan is well-known for its many and unspecific the same mechanism, the data suggest in all that O-GlcNAc targeting (Taylor et al. 2014). The induction of LTD with regulates the synaptic abundance of the GluA2/3 AMPA re- low-frequency stimulation (LFS), a protocol associated with ceptor isoform. Withal, cLTP and cLTD in hippocampal slices the removal of AMPA receptors from synapses, was from OGA KO heterozygotes was associated with impaired destabilized in a situation where O-GlcNAc levels had been phosphorylation of sites on GluA1 known to affect GluA1/2 elevated for a long period of time by deleting one copy of Oga trafficking (Yang et al. 2017). during development (Yang et al. 2017; Collingridge et al. Many proteins that regulate AMPA receptor trafficking and 2004). While these experiments are contradictory as to the spine dynamics are modified by O-GlcNAc, including in syn- exact timing and direction of regulation, they strongly indicate apses (Trinidad et al. 2012;Alfaro etal. 2012). αCaMKII, for that O-GlcNAc affects dynamic synaptic properties. example, is O-GlcNAcylated at T306 (Trinidad et al. 2012). The data on whether and how O-GlcNAc regulates basal Phosphorylation of T305 and/or T306 inhibits αCaMKII and synaptic properties are more tentative. There was no change in impairs HFS LTP and learning (Elgersma et al. 2002). TMG basal synaptic transmission in the hippocampus five hours has been shown to increase αCaMKII phosphorylation at after systemic injection in vivo of 9d (Tallent et al. 2009). T286/7, which activates αCaMKII (Tallent et al. 2009). Neither did permanently elevated O-GlcNAc levels upon ge- Phosphorylation of S831 on GluA1, a known αCaMKII site, netically removing Oga yield any change in basal synaptic was blocked in a cLTP protocol in OGA KO mice (Yang et al. properties or spine number in hippocampal cells (Yang et al. 2017; Shepherd and Huganir 2007). Whether O- 2017). Another study showed in contrast that acutely applying GlcNAcylation of αCaMKII mediates any of the effects on 252 J Bioenerg Biomembr (2018) 50:241–261 synaptic plasticity or animal behavior associated with global different. Between circuits, there are also shared mechanisms. alterations of O-GlcNAc levels has not been tested. Another Effects on synaptic plasticity, for example, may underlie both kinase that has been reported to be O-GlcNAcylated and in- hippocampal-dependent memory behavior and hypothalamic volved in the regulation of GluA1 trafficking and experience- feeding behavior. The current literature abounds with conflict- dependent behavior is PKA (Kessels and Malinow 2009;Xie ing results. Some conflicts likely depend on factors such as et al. 2016). Modulation of OGT or OGA pharmacologically type of preparation and length of O-GlcNAc perturbation. The or by overexpression affects PKA function consistently, but most fundamental questions remain unanswered. How does different papers report in opposite directions (Xie et al. 2016; the energy-sensing properties of O-GlcNAc relate to its Francisco et al. 2009). activity-dependent regulation? At very low energy levels, as Much data suggest that O-GlcNAcylation affects many as- discussed above and below O-GlcNAc helps neurons to avoid pects of AMPA receptor trafficking and excitatory postsynap- cytotoxicity. However, O-GlcNAc also fluctuates in response tic function. Whereas manipulations of global O-GlcNAc to mild and physiological changes in energy availability. In the levels have opened up the field, teasing apart the underlying hypothalamus, the data favor the interpretation that O- mechanism(s) will require investigations of specific signaling GlcNAc detects body-to-brain metabolic signaling to regulate pathways. energy expenditure and food intake. But what role does nutrient-dependent O-GlcNAcylation play in the hippocam- Presynaptic and other functions regulated by O-GlcNAc pus? Is O-GlcNAc a mechanism by which our diet affects memory performance? Future studies linking molecular It was described above that O-GlcNAc is highly abundant in mechanisms to the function of specific neuronal circuits will postsynaptic terminals but also in in presynaptic terminals. In uncover important concepts not only for the field of O- presynaptic terminals, synapsin 1 binds to synaptic vesicles GlcNAc but for the field of neuroscience. and regulates synapse number and function (Skorobogatko et al. 2014). At least 16 O-GlcNAc sites have been identified on synapsin 1 (Vosseller et al. 2006;Trinidadetal. 2012; The role of O-GlcNAc in aging, Skorobogatko et al. 2014). Mutating the T87 O-GlcNAc site neurodegenerative disorders and acute to alanine in cultured primary neurons enhanced the targeting cerebral insults of synapsin 1 to synapses, enlarged the size of the synaptic vesicle reserve pool and increased synapse density For more than two decades, O-GlcNAc has been known to (Skorobogatko et al. 2014). Though, global manipulations of modify proteins involved in the pathology behind aging- O-GlcNAc levels by inhibiting or deleting OGA have had related diseases (Griffith et al. 1995; Griffith and Schmitz both no effect and a decreased presynaptic release probability, 1995). Today, most pathways involved in neurodegenerative as measured by electrophysiology in the hippocampus disorders have been shown to contain O-GlcNAc (Banerjee et (Tallent et al. 2009; Taylor et al. 2014;Yang et al. 2017). al. 2016;Hart et al. 2011; Trinidad et al. 2012;Wangetal. In addition to direct effects on synaptic neurotransmission, 2017;Alfaroetal. 2012; Lagerlof and Hart 2014). O- O-GlcNAc may influence synapse function and neuronal GlcNAcylation levels are changed in many cases of transmission by modulating activity-dependent gene tran- Alzheimer's and Parkinson's diseases (Forster et al. 2014; scription (Rexach et al. 2012; Song et al. 2008; Dias et al. Liu et al. 2004a; Griffith and Schmitz 1995; Wanietal. 2009). We have also seen that OGT critically regulates the 2017). OGA is linked genetically and through alternative spontaneous firing frequency of Agrp neurons in the hypothal- splicing to Alzheimer's disease (Bertram et al. 2000;Heckel amus, at least in part due to its modulation of Kcnq3 (Ruan et et al. 1998; Twine et al. 2011). The gene for OGT is associated al. 2014). In comparison, intrinsic excitability of hippocampal with parkinsonian dystonia (Mazars et al. 2010; Nolte and neurons did not differ between wildtype and OGA KO het- Muller 2002;Muller etal. 1998). Metabolic disease is a risk erozygotes (Yang et al. 2017). Also, through the protein factor for developing dementia, and symptom progression in Milton as described above, O-GlcNAc may link the high en- dementia has been slowed with drugs potentiating insulin sig- ergy demand of neuronal transmission to mitochondrial move- naling in rodents and in humans (Gudala et al. 2013;Moreira ment and ATP production (Rangaraju et al. 2014; Tan et al. 2012; Bobsin and Kreienkamp 2015; Cooper et al. 2015; 2014; Pekkurnaz et al. 2014). Bomfim et al. 2012;De Felice et al. 2009; Escribano et al. 2010; Querfurth and LaFerla 2010). Coupling between energy Summary availability, neuronal function and cell stress management makes O-GlcNAc an etiologic candidate for many neurode- O-GlcNAc has many functions in the nervous system. generative disorders. Several reviews on the connection be- Depending on the cell, the regulation of O-GlcNAc cycling tween O-GlcNAc, aging and aging-related diseases have been and the effects of increased or decreased O-GlcNAcylation are published recently (Hart et al. 2011; Zhu et al. 2014;Bondand J Bioenerg Biomembr (2018) 50:241–261 253 Hanover 2013;Banerjeeet al. 2016; Yuzwa and Vocadlo In peripheral tissues, O-GlcNAc has been characterized 2014;Maet al. 2017). Here, only larger themes will be as a general stress sensor and regulator of reactive oxygen discussed. species (ROS) (Hart et al. 2011; Tan et al. 2017a). Inducing Histopathological hallmarks of Alzheimer's disease, a com- stroke by stopping blood flow to specific areas of the brain mon cause of dementia, are neurofibrillary tangles and leads to a rapid increase in total O-GlcNAc in rodents, in- amyloid-β (Aβ) plaques. Tangles consist of aggregates of cluding in the stroke penumbra zone. The penumbra zone is the protein tau (Masters et al. 2015). Tau is multiply modified important clinically as it contains cells that are damaged but by O-GlcNAc (Arnold et al. 1996; Yuzwa et al. 2011). O- that are possible to rescue from cell death (Jiang et al. 2017; GlcNAc levels correlate negatively with tau phosphorylation Gu et al. 2017). Infarction size is smaller upon systemic or (Liu et al. 2004a;Li etal. 2006). Either by a direct effect on intraventricular injection of TMG or GlcN. The behavioral solubility or by protecting against hyperphosphorylation, or deficits e.g. motor function, are alleviated upon global ele- both, O-GlcNAcylation of tau inhibits tau aggregation vation of O-GlcNAc as well (Gu et al. 2017; Jiang et al. (Graham et al. 2014; O'Donnell et al. 2004; Yuzwa et al. 2017;He et al. 2017). Inhibition of the HBP has the oppo- 2008; Smet-Nocca et al. 2011; Yuzwa et al. 2014a;Zhu et site effect (Gu et al. 2017). A very high dose of TMG, al. 2014;Hastings et al. 2017). Increased O-GlcNAc protects however, aggravated stroke outcome (Gu et al. 2017). An against Aβ plaque formation also (Yuzwa et al. 2014b; Kim et older study shows that intraventricular injection of al. 2013). O-GlcNAc has been suggested to regulate the cleav- streptozotocin leads to apoptosis in the hippocampus (Liu age of amyloid precursor protein (APP), which produces Aβ et al. 2004b). Streptozotocin blocks OGA activity but may or non-pathological species, and to be associated with down- have additional targets (Roos et al. 1998;Pathaket al. stream effects or the removal of Aβ (Yuzwa et al. 2014b;Kim 2008). Primary cultured neurons that were treated with et al. 2013;Griffithet al. 1995; Jacobsen and Iverfeldt 2011; TMG for seven days increased monomeric α-synuclein Cha et al. 2015;Wang et al. 2012; Zhang et al. 2003;Chun et levels and were less viable (Wani et al. 2017). In aged mice, al. 2017). In mouse models where mutated tau or Aβ is the O-GlcNAc increase upon transient ischemia was absent overexpressed, pharmacological inhibition of OGA alleviates (Liu et al. 2016). neuronal degeneration and improves behavioral outcome O-GlcNAcylation plays a variety of roles that can be either (Borghgraef et al. 2013; Yuzwa et al. 2012; Graham et al. protective or harmful to conditions associated with neuronal 2014; Yuzwa et al. 2014b; Kim et al. 2013). degeneration or acute insults. The result of global elevation or Parkinson's disease and Huntington's chorea are other neu- depression of O-GlcNAc differs depending on the precipitat- rodegenerative disorders distinguished by accumulation of ing stimuli and the timing of the event. It is also cell-specific. toxic protein aggregates (Banerjee et al. 2016). Similar to OGT is not necessary for Agrp neuron or Schwann cell main- tenance (Kim et al. 2016;Ruan et al. 2014). But above it was the effect on tau, O-GlcNAcylation at T72 on α-synuclein, a protein associated with parkinsonian inclusion bodies, pre- described that removing OGT from sensory neurons in the vents its aggregation and toxicity when added to cells exoge- peripheral nervous system was associated with neuronal nously (Marotta et al. 2012; Marotta et al. 2015;Wang et al. death, possibly from an axonal dieback mechanism (Su and 2010a). Based on these and other data, it has been suggested Schwarz 2017). In αCaMKII neurons, OGT is essential dur- that O-GlcNAc may serve a general function of impeding ing early postnatal development but not in young adulthood protein aggregation (Yuzwa et al. 2012). In Huntington's cho- (Wang et al. 2016;Lagerlof etal. 2016). rea, expansion of CAG repeats in the gene coding for The systemic or brain-wide application of the drugs huntingtin leads to the production of a polyglutamine mutant that have been used to manipulate O-GlcNAc affect neu- protein that aggregates in the cell. TMG was shown to im- rons and glia. The involvement of glia in stress reactions prove cell viability upon overexpressing mutant huntingtin in in the brain has been recognized for decades and is be- primary cultured neurons, but possibly via rescuing coming increasingly discussed as a potential drug target. nucleocytoplasmic transport (Grima et al. 2017). In contrast The function of O-GlcNAc in these cells is almost entirely to the situation in Parkinson's and Alzheimer's disease, de- unknown but the protective effect of increased O-GlcNAc creasing global O-GlcNAc was shown to be protective against may to some extent relate to modulation of the inflamma- overexpression of huntingtin aggregation and cytotoxicity in tory response (Salter and Stevens 2017; van den Hoogen neuroblastoma cells and in flies (Kumar et al. 2014). In fact, et al. 2017; Mizuma and Yenari 2017;Maetal. 2017;He expressing toxic species of huntingtin, tau or Aβ in worms et al. 2017). In fact, the connection between O-GlcNAc was associated with improved or exacerbated outcome upon and immune cells in the periphery was identified in the removing OGT or mutating OGA, respectively (Wang et al. very first paper on O-GlcNAc (Torres and Hart 1984). 2012). 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