Molecular Psychiatry

Lucassen, P J; Fitzsimons, C P; Korosi, A; Joels, M; Belzung, C; Abrous, D N

doi: 10.1038/mp.2012.39pmid: 22547116

Lopez, J P; Mamdani, F; Labonte, B; Beaulieu, M-M; Yang, J P; Berlim, M T; Ernst, C; Turecki, G

doi: 10.1038/mp.2012.38pmid: 22547115

Pietrzak, R H; Henry, S; Southwick, S M; Krystal, J H; Neumeister, A

doi: 10.1038/mp.2012.60pmid: 22584868

Mota, N R; Rovaris, D L; Bertuzzi, G P; Contini, V; Vitola, E S; Grevet, E H; Roman, T; Callegari-Jacques, S M; Hutz, M H; Bau, C H D

doi: 10.1038/mp.2012.50pmid: 22565782

Anacker, K; Enge, S; Reif, A; Lesch, K-P; Strobel, A

doi: 10.1038/mp.2012.49pmid: 22565783

Looi, J C L; Walterfang, M

doi: 10.1038/mp.2012.54pmid: 22584865

The striatum, comprising the caudate nucleus, putamen and nucleus accumbens, occupies a strategic location within cortico-striato-pallido-thalamic–cortical (corticostriatal) re-entrant neural circuits. Striatal neurodevelopment is precisely determined by phylogenetically conserved homeobox genes. Consisting primarily of medium spiny neurons, the striatum is strictly topographically organized based on cortical afferents and efferents. Particular corticostriatal neural circuits are considered to subserve certain domains of cognition, emotion and behaviour. Thus, the striatum may serve as a map of structural change in the cortical afferent pathways owing to deafferentation or neuroplasticity, and conversely, structural change in the striatum per se may structurally disrupt corticostriatal pathways. The morphology of the striatum may be quantified in vivo using advanced magnetic resonance imaging, as may cognitive functioning pertaining to corticostriatal circuits. It is proposed that striatal morphology may be a biomarker in neurodegenerative disease and potentially the basis of an endophenotype.

Westmark, C J

doi: 10.1038/mp.2012.122pmid: 22925831

Accumulating evidence suggests that dysregulated levels of amyloid β-protein precursor (APP) and its catabolites contribute to the impaired synaptic plasticity and seizure incidence observed in several neurological disorders, including Alzheimer’s disease, fragile X syndrome, Down’s syndrome, autism, epilepsy and Parkinson’s disease as well as in brain injury. This review article summarizes what is known regarding the synaptic synthesis, processing and function of APP and amyloid-beta (Aβ), as well as discusses how these proteins could contribute to the altered synaptic plasticity and pathology of the aforementioned disorders. In addition, APP and its proteolytic fragments are emerging as biomarkers for neurological health, and pharmacological interventions that modulate their levels, such as secretase inhibitors, passive immunotherapy against Aβ and mGluR5 antagonists, are reviewed.

Ecker, C; Spooren, W; Murphy, D G M

doi: 10.1038/mp.2012.102pmid: 22801412

Discovering novel treatments for Autism Spectrum Disorders (ASD) is a challenge. Its etiology and pathology remain largely unknown, the condition shows wide clinical diversity, and case identification is still solely based on symptomatology. Hence clinical trials typically include samples of biologically and clinically heterogeneous individuals. ‘Core deficits’, that is, deficits common to all individuals with ASD, are thus inherently difficult to find. Nevertheless, recent reports suggest that new opportunities are emerging, which may help develop new treatments and biomarkers for the condition. Most important, several risk gene variants have now been identified that significantly contribute to ASD susceptibility, many linked to synaptic functioning, excitation–inhibition balance, and brain connectivity. Second, neuroimaging studies have advanced our understanding of the ‘wider’ neural systems underlying ASD; and significantly contributed to our knowledge of the complex neurobiology associated with the condition. Last, the recent development of powerful multivariate analytical techniques now enable us to use multi-modal information in order to develop complex ‘biomarker systems’, which may in the future be used to assist the behavioral diagnosis, aid patient stratification and predict response to treatment/intervention. The aim of this review is, therefore, to summarize some of these important new findings and highlight their potential significant translational value to the future of ASD research.

Lambert, J-C; Grenier-Boley, B; Harold, D; Zelenika, D; Chouraki, V; Kamatani, Y; Sleegers, K; Ikram, M A; Hiltunen, M; Reitz, C; Mateo, I; Feulner, T; Bullido, M; Galimberti, D; Concari, L; Alvarez, V; Sims, R; Gerrish, A; Chapman, J; Deniz-Naranjo, C; Solfrizzi, V; Sorbi, S;

Zhang, H; Etherington, L-A; Hafner, A-S; Belelli, D; Coussen, F; Delagrange, P; Chaouloff, F; Spedding, M; Lambert, J J; Choquet, D; Groc, L

doi: 10.1038/mp.2012.80pmid: 22733125

The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII–stargazin–PSD-95 pathway, to promote long-term synaptic plasticity.