Molecular evidence of synaptic pathology in the CA1 region in schizophrenia
Natalie Matosin,Francesca Fernandez-Enright,Francesca Fernandez-Enright,Jeremy S. Lum,Martin Engel,Jessica L. Andrews,Nils C. Gassen,Klaus V. Wagner,Mathias V. Schmidt,Kelly A. Newell +9 more
- Vol. 2, Iss: 1, pp 16022-16022
TLDR
A quantitative immunoblot experiment supports the presence of extensive molecular abnormalities to PSD95 and several of its associated proteins in the CA1 region in schizophrenia, offering a small but significant step toward understanding how protein levels in the PSD are altered in the schizophrenia brain, and their relevance to overall hippocampal and cognitive dysfunction in the illness.Abstract:
Alterations of postsynaptic density (PSD)95-complex proteins in schizophrenia ostensibly induce deficits in synaptic plasticity, the molecular process underlying cognitive functions. Although some PSD95-complex proteins have been previously examined in the hippocampus in schizophrenia, the status of other equally important molecules is unclear. This is especially true in the cornu ammonis (CA)1 hippocampal subfield, a region that is critically involved in the pathophysiology of the illness. We thus performed a quantitative immunoblot experiment to examine PSD95 and several of its associated proteins in the CA1 region, using post mortem brain samples derived from schizophrenia subjects with age-, sex-, and post mortem interval-matched controls (n=20/group). Our results indicate a substantial reduction in PSD95 protein expression (-61.8%). Further analysis showed additional alterations to the scaffold protein Homer1 (Homer1a: +42.9%, Homer1b/c: -24.6%), with a twofold reduction in the ratio of Homer1b/c:Homer1a isoforms (P=0.011). Metabotropic glutamate receptor 1 (mGluR1) protein levels were significantly reduced (-32.7%), and Preso, a protein that supports interactions between Homer1 or PSD95 with mGluR1, was elevated (+83.3%). Significant reduction in synaptophysin (-27.8%) was also detected, which is a validated marker of synaptic density. These findings support the presence of extensive molecular abnormalities to PSD95 and several of its associated proteins in the CA1 region in schizophrenia, offering a small but significant step toward understanding how proteins in the PSD are altered in the schizophrenia brain, and their relevance to overall hippocampal and cognitive dysfunction in the illness.read more
Citations
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Journal ArticleDOI
Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures.
TL;DR: Findings of moderate–large reductions in synaptophysin in hippocampus and frontal cortical regions, and a tendency for reductions in other pre- and postsynaptic proteins in the hippocampus are consistent with models that implicate synaptic loss in schizophrenia, but they also identify potential differences between regions and proteins, suggesting synaptic loss is not uniform in nature or extent.
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Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.
Ellis Chika Onwordi,Els F. Halff,Thomas Whitehurst,Thomas Whitehurst,Thomas Whitehurst,Ayla Mansur,Marie-Caroline Cotel,Lisa Wells,Hannah Creeney,David R. Bonsall,Maria Rogdaki,Ekaterina Shatalina,Ekaterina Shatalina,Tiago Reis Marques,Tiago Reis Marques,Tiago Reis Marques,Eugenii A. Rabiner,Roger N. Gunn,Sridhar Natesan,Sridhar Natesan,Anthony C. Vernon,Oliver D. Howes +21 more
TL;DR: It is shown for the first time in vivo that levels of the synaptic marker protein SV2A are reduced in schizophrenia and unaffected by antipsychotic treatment in a rat model, indicating that there are lower synaptic terminal protein levels in schizophrenia in vivo and that antipsychotics exposure is unlikely to account for them.
Journal ArticleDOI
Synapse Pathology in Schizophrenia : A Meta-analysis of Postsynaptic Elements in Postmortem Brain Studies
Amber Berdenis van Berlekom,Cita H Muflihah,Cita H Muflihah,G. Snijders,Harold D. MacGillavry,Jinte Middeldorp,Elly M. Hol,René S. Kahn,René S. Kahn,René S. Kahn,Lot D. de Witte,Lot D. de Witte,Lot D. de Witte +12 more
TL;DR: This meta-analysis shows a region-specific decrease in the density of postsynaptic elements in SCZ, which provides an important cellular hallmark for future preclinical and neuropathological research in order to increase the understanding of brain dysconnectivity inSCZ.
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Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development.
TL;DR: A state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for in-human imaging, shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others.
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Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system.
Luisa Di Menna,Max E. Joffe,Luisa Iacovelli,Rosamaria Orlando,Craig W. Lindsley,Jérôme Mairesse,Pierre Gressens,Pierre Gressens,Milena Cannella,Filippo Caraci,Agata Copani,Valeria Bruno,Giuseppe Battaglia,P. Jeffrey Conn,Ferdinando Nicoletti +14 more
TL;DR: MGlu3 receptors, which are traditionally linked to the control of neurotransmitter release, support mGlu5 receptor signaling in neurons and largely contribute to the robust mGLU5 receptor‐mediated polyphosphoinositide hydrolysis in the early postnatal life.
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