Developmental Neuroscience

doi: 10.1159/000501871pmid: N/A

doi: 10.1159/000502315pmid: N/A

doi: 10.1159/000501784pmid: N/A

Dean, Justin M.; Levison, Steven W.

doi: 10.1159/000500983pmid: 31256168

Magtanong, Leslie; Dixon, Scott J.

doi: 10.1159/000496922pmid: 30820017

Ferroptosis is a nonapoptotic form of cell death characterized by the iron-dependent accumulation of toxic lipid reactive oxygen species. Small-molecule screening and subsequent optimization have yielded potent and specific activators and inhibitors of this process. These compounds have been employed to dissect the lethal mechanism and implicate this process in pathological cell death events observed in many tissues, including the brain. Indeed, ferroptosis is emerging as an important mechanism of cell death during stroke, intracerebral hemorrhage, and other acute brain injuries, and may also play a role in certain degenerative brain disorders. Outstanding issues include the practical need to identify molecular markers of ferroptosis that can be used to detect and study this process in vivo, and the more basic problem of understanding the relationship between ferroptosis and other forms of cell death that can be triggered in the brain during injury.

Rasika, Sowmyalakshmi; Passemard, Sandrine; Verloes, Alain; Gressens, Pierre; El Ghouzzi, Vincent

doi: 10.1159/000497035pmid: 30878996

The Golgi apparatus (GA) is involved in a whole spectrum of activities, from lipid biosynthesis and membrane secretion to the posttranslational processing and trafficking of most proteins, the control of mitosis, cell polarity, migration and morphogenesis, and diverse processes such as apoptosis, autophagy, and the stress response. In keeping with its versatility, mutations in GA proteins lead to a number of different disorders, including syndromes with multisystem involvement. Intriguingly, however, > 40% of the GA-related genes known to be associated with disease affect the central or peripheral nervous system, highlighting the critical importance of the GA for neural function. We have previously proposed the term “Golgipathies” in relation to a group of disorders in which mutations in GA proteins or their molecular partners lead to consequences for brain development, in particular postnatal-onset microcephaly (POM), white-matter defects, and intellectual disability (ID). Here, taking into account the broader role of the GA in the nervous system, we refine and enlarge this emerging concept to include other disorders whose symptoms may be indicative of altered neurodevelopmental processes, from neurogenesis to neuronal migration and the secretory function critical for the maturation of postmitotic neurons and myelination.

Carrasco, Melisa; Stafstrom, Carl E.

doi: 10.1159/000497471pmid: 30947192

Seizures in neonates represent a neurologic emergency requiring prompt recognition, determination of etiology, and treatment. Yet, the definition and identification of neonatal seizures remain challenging and controversial, in part due to the unique physiology of brain development at this life stage. These issues are compounded when considering seizures in premature infants, in whom the complexities of brain development may engender different clinical and electrographic seizure features at different points in neuronal maturation. In extremely premature infants (< 28 weeks gestational age), seizure pathophysiology has not been explored in detail. This review discusses the physiological and structural development of the brain in this developmental window, focusing on factors that may lead to seizures and their consequences at this early time point. We hypothesize that the clinical and electrographic phenomenology of seizures in extremely preterm infants reflects the specific pathophysiology of brain development in that age window.

Krystofova, Jana; Pathipati, Praneeti; Russ, Jeffrey; Sheldon, Ann; Ferriero, Donna

doi: 10.1159/000496467pmid: 30995639

Brain damage after hypoxia-ischemia (HI) occurs in an age-dependent manner. Neuroprotective strategies assumed to be effective in adults might have deleterious effects in the immature brain. In order to create effective therapies, the complex pathophysiology of HI in the developing brain requires exploring new mechanisms. Critical determinants of neuronal survival after HI are the extent of vascular dysfunction, inflammation, and oxidative stress, followed later by tissue repair. The key enzyme of these processes in the human body is arginase (ARG) that acts via the bioavailability of nitric oxide, and the synthesis of polyamines and proline. ARG is expressed throughout the brain in different cells. However, little is known about the effect of ARG in pathophysiological states of the brain, especially hypoxia-ischemia. Here, we summarize the role of ARG during neurodevelopment as well as in various brain pathologies.

Wood, Thomas R.; Stubbs, Brianna J.; Juul, Sandra E.

doi: 10.1159/000499563pmid: 31085911

Ketone bodies are a promising area of neuroprotection research that may be ideally suited to the injured newborn. During normal development, the human infant is in significant ketosis for at least the first week of life. Ketone uptake and metabolism is upregulated in the both the fetus and neonate, with ketone bodies providing at least 10% of cerebral metabolic energy requirements, as well as being the preferred precursors for the synthesis of fatty acids and cholesterol. At the same time, ketone bodies have been shown to have multiple neuroprotective effects, including being anticonvulsant, decreasing oxidative stress and inflammation, and epigenetically upregulating the production of neurotrophic factors. While ketogenic diets and exogenous ketosis are largely being investigated in the setting of adult brain injury, the adaptation of the neonate to ketosis suggests that developmental brain injury may be the area most suited to the use of ketones for neuroprotection. Here, we describe the mechanisms by which ketone bodies exert their neuroprotective effects, and how these may translate to benefits within each of the phases of neonatal asphyxial brain injury.

Mikrogeorgiou, Alkisti; Xu, Duan; Ferriero, Donna M.; Vannucci, Susan J.

doi: 10.1159/000496921pmid: 30991389

Brain development is an energy-expensive process. Although glucose is irreplaceable, the developing brain utilizes a variety of substrates such as lactate and the ketone bodies, β-hydroxybutyrate and acetoacetate, to produce energy and synthesize the structural components necessary for cerebral maturation. When oxygen and nutrient supplies to the brain are restricted, as in neonatal hypoxia-ischemia (HI), cerebral energy metabolism undergoes alterations in substrate use to preserve the production of adenosine triphosphate. These changes have been studied by in situ biochemical methods that yielded valuable quantitative information about high-energy and glycolytic metabolites and established a temporal profile of the cerebral metabolic response to hypoxia and HI. However, these analyses relied on terminal experiments and averaging values from several animals at each time point as well as challenging requirements for accurate tissue processing.More recent methodologies have focused on in vivo longitudinal analyses in individual animals. The emerging field of metabolomics provides a new investigative tool for studying cerebral metabolism. Magnetic resonance spectroscopy (MRS) has enabled the acquisition of a snapshot of the metabolic status of the brain as quantifiable spectra of various intracellular metabolites. Proton (¹H) MRS has been used extensively as an experimental and diagnostic tool of HI in the pursuit of markers of long-term neurodevelopmental outcomes. Still, the interpretation of the metabolite spectra acquired with ¹H MRS has proven challenging, due to discrepancies among studies, regarding calculations and timing of measurements. As a result, the predictive utility of such studies is not clear. ¹³C MRS is methodologically more challenging, but it provides a unique window on living tissue metabolism via measurements of the incorporation of ¹³C label from substrates into brain metabolites and the localized determination of various metabolic fluxes. The newly developed hyperpolarized ¹³C MRS is an exciting method for assessing cerebral metabolism in vivo, that bears the advantages of conventional ¹³C MRS but with a huge gain in signal intensity and much shorter acquisition times. The first part of this review article provides a brief description of the findings of biochemical and imaging methods over the years as well as a discussion of their associated strengths and pitfalls. The second part summarizes the current knowledge on cerebral metabolism during development and HI brain injury.