Growth-associated protein 43 (GAP-43) and synaptophysin alterations in the dentate gyrus of patients with schizophrenia

Chambers, Jessie S.; Thomas, D.N.; Saland, L.C.; Neve, Rachael L.; Perrone‐Bizzozero, Nora I.

doi:10.1016/j.pnpbp.2004.11.013

Cited by 55 publications

(25 citation statements)

References 64 publications

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“…Reductions in synaptophysin expression in schizophrenia have also been reported in different brain regions by various groups including, in the left thalamus using radioimmunoassay by [34] and in the medial temporal lobe using immunoradiography [35]. Furthermore synaptophysin immunoreactivity was significantly reduced in both the inner and outer molecular layers of the dentate gyrus [36] and also in the glomeruli of the olfactory bulb [37••]…”

Section: Introduction/backgroundmentioning

confidence: 82%

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia

Egbujo

Sinclair

Hahn

2016

Curr Psychiatry Rep

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Schizophrenia is a serious psychiatric illness which is experienced by about 1% of individuals worldwide and has a debilitating impact on perception, cognition and social function. Over the years, several models/hypotheses have been developed which link schizophrenia to dysregulations of the dopamine, glutamate and serotonin receptor pathways. An important segment of these pathways that have been extensively studied for the pathophysiology of schizophrenia is the presynaptic neurotransmitter release mechanism. This set of molecular events is an evolutionarily well-conserved process that involves vesicle recruitment, docking, membrane fusion and recycling, leading to efficient neurotransmitter delivery at the synapse. Accumulated evidence indicate dysregulation of this mechanism impacting post-synaptic signal transduction via different neurotransmitters in key brain regions implicated in schizophrenia. In recent years, after ground-breaking work that elucidated the operations of this mechanism, research efforts have focused on the alterations in the mRNA and protein expression of pre-synaptic neurotransmitter release molecules in schizophrenia and other neuropsychiatric conditions. In this review article, we present recent evidence from schizophrenia human post-mortem studies that key proteins involved in the pre-synaptic release mechanism are dysregulated in the disorder. We also discuss the potential impact of dysfunctional pre-synaptic neurotransmitter release on the various neurotransmitter systems implicated in schizophrenia.

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Section: Introduction/backgroundmentioning

confidence: 82%

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia

Egbujo

Sinclair

Hahn

2016

Curr Psychiatry Rep

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“…It is worth noting that previous expression studies in SCZ and BPD generally reported a tendency towards a reduced expression in SCZ and BPD, 76,77 with increases in some synaptic-associated proteins, such as SNAP-25 60 and conflicting reports regarding other such as GAP-43 and synaptophysin. 37,[78][79][80][81][82] A strength of the current investigation is the use of two complementary proteomic approaches, 2D DIGE and GeLC-MS/MS to identify candidate diseaseassociated proteins within the MM proteome in SCZ and BPD. The use of these methods has allowed us to identify and then to proceed to validate important new disease-associated proteins within a functionally important but low-abundance proteome.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

et al. 2008

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The dorsolateral prefrontal cortex (dlpfc) is strongly implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BPD) and, within this region, abnormalities in glutamatergic neurotransmission and synaptic function have been described. Proteins associated with these functions are enriched in membrane microdomains (MM). In the current study, we used two complementary proteomic methods, two-dimensional difference gel electrophoresis and one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis followed by reverse phase-liquid chromatography-tandem mass spectrometry (RP-LC-MS/MS) (gel separation liquid chromatography-tandem mass spectrometry (GeLC-MS/MS)) to assess protein expression in MM in pooled samples of dlpfc from SCZ, BPD and control cases (n = 10 per group) from the Stanley Foundation Brain series. We identified 16 proteins altered in one/both disorders using proteomic methods. We selected three proteins with roles in synaptic function (syntaxin-binding protein 1 (STXBP1), brain abundant membrane-attached signal protein 1 (BASP1) and limbic system-associated membrane protein (LAMP)) for validation by western blotting. This revealed significantly increased expression of these proteins in SCZ (STXBP1 (24% difference; P < 0.001), BASP1 (40% difference; P < 0.05) and LAMP (22% difference; P < 0.01)) and BPD (STXBP1 (31% difference; P < 0.001), BASP1 (23% difference; P < 0.01) and LAMP (20% difference; P < 0.01)) in the Stanley brain series (n = 20 per group). Further validation in dlpfc from the Harvard brain subseries (n = 10 per group) confirmed increased protein expression in SCZ of STXBP1 (18% difference; P < 0.0001), BASP1 (14% difference; P < 0.0001) but not LAMP (20% difference; P = 0.14). No significant differences in STXBP1, BASP1 or LAMP protein expression in BPD dlpfc were observed. This study, through proteomic assessments of MM in dlpfc and validation in two brain series, strongly implicates LAMP, STXBP1 and BASP1 in SCZ and supports the view of a neuritic and synaptic dysfunction in the neuropathology of SCZ.

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“…Alterations in the overall level of CaM have been implicated in heart failure [3], schizophrenia [4], and Parkinson's disease [5–7]. Outright CaM mutations in Drosophila have been associated with muscle malfunction [8].…”

Section: Introductionmentioning

confidence: 99%

Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca2+ currents and promote proarrhythmic behavior in ventricular myocytes

Limpitikul

Dick

Joshi-Mukherjee

et al. 2014

Journal of Molecular and Cellular Cardiology

152

225

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Recent work has identified missense mutations in calmodulin (CaM) that are associated with severe early-onset long-QT syndrome (LQTS), leading to the proposition that altered CaM function may contribute to the molecular etiology of this subset of LQTS. To date, however, no experimental evidence has established these mutations as directly causative of LQTS substrates, nor have the molecular targets of CaM mutants been identified. Here, therefore, we test whether expression of CaM mutants in adult guinea-pig ventricular myocytes (aGPVM) induces action-potential prolongation, and whether affiliated alterations in the Ca2+ regulation of L-type Ca2+ channels (LTCC) might contribute to such prolongation. In particular, we first overexpressed CaM mutants in aGPVMs, and observed both increased action potential duration (APD) and heightened Ca2+ transients. Next, we demonstrated that all LQTS CaM mutants have the potential to strongly suppress Ca2+/CaM-dependent inactivation (CDI) of LTCCs, whether channels were heterologously expressed in HEK293 cells, or present in native form within myocytes. This attenuation of CDI is predicted to promote action-potential prolongation and boost Ca2+ influx. Finally, we demonstrated how a small fraction of LQTS CaM mutants (as in heterozygous patients) would nonetheless suffice to substantially diminish CDI, and derange electrical and Ca2+ profiles. In all, these results highlight LTCCs as a molecular locus for understanding and treating CaM-related LQTS in this group of patients.

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Growth-associated protein 43 (GAP-43) and synaptophysin alterations in the dentate gyrus of patients with schizophrenia

Cited by 55 publications

References 64 publications

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca2+ currents and promote proarrhythmic behavior in ventricular myocytes

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