Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia

Abstract

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.

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

“…Our data presented here provide evidence that APDs are unlikely to account for the reduced SV2A binding in SCZ patients as observed by PET 19 . More broadly, the lack of change in either SV2A, NLGN or synaptic (overlapping SV2A/NLGN) cluster density suggests APD treatment may be unrelated to changes in other synaptic markers found in human post mortem SCZ tissue, such as reduced SYN levels 8,64 . Whether SV2A protein levels are reduced in BD and SCZ post-mortem brain tissue has yet to be investigated, but could be expected to reflect the same changes as those observed with SYN.…”

Creation of a myosin Va‐TAP‐tagged mouse and identification of potential myosin Va‐interacting proteins in the cerebellum

“…This is noteworthy, as defects in the expression and trafficking of the AMPA receptor subunit glutamate receptor 1 (GluR1), which is highly expressed in PNs (Lambolez, Audinat, Bochet, Crepel, & Rossier, 1992), are known to contribute to the etiology of schizophrenia (Hammond, McCullumsmith, Funk, Haroutunian, & Meador-Woodruff, 2010;Wiedholz et al, 2008). In addition, mutations in Stxbp1/Munc18-1, another potential myosin Va-binding partner and schizophrenia biomarker (Behan, Byrne, Dunn, Cagney, & Cotter, 2009) identified in this study, lead to vesicle docking defects (Egbujo, Sinclair, & Hahn, 2016;Hamdan et al, 2009;Waites & Garner, 2011;Weimer et al, 2003) and a disruption of Stxbp1's interaction with syntaxin 1A (Gil-Pisa et al, 2012;Rizo & Sudhof, 2012). Syntaxin 1A is a known myosin Va-binding protein (Watanabe et al, 2005), and its reduced expression has been linked to schizophrenic symptoms (Wong et al, 2004).…”

Genetics of Aggression in Alzheimer’s Disease (AD)

“…As previously mentioned, five of these six genes (AR, BDNF, COMT, DBH, NOS1) identified to be dysregulated in this study in AD and aggression have been implicated in the development, onset and/or propagation of schizophrenia. Interestingly both “ dopaminergic and serotoninergic hypotheses for schizophrenia ”, involving an elevated genetically-based capacity for striatal increased L-phenylalanine- and/or L-tyrosine-derived DA biosynthesis, altered DA release and defects in the tryptophan-derived serotonin (5-HT) and the serotonin receptor, transporter and synaptic vesicle trafficking systems have been implicated in several of the longest held pathoetiologic- and pathogenic-hypotheses for schizophrenia (Zhang et al, 2014; Baou et al, 2016; Cocchi et al, 2016; Egbujo et al, 2016; Garay et al, 2016; Howes et al, 2017). The overlapping participation of dopaminergic and serotoninergic pathways, especially with DA-metabolizing COMT pathways and serotonin (5-HT) reuptake inhibitors (SSRIs; Zoloft, Paxil, Prozac and other antidepressants) and blockage of serotonin transporter activities are remarkable.…”