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 postsynaptic 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 messenger RNA (mRNA) and protein expression of presynaptic neurotransmitter release molecules in schizophrenia and other neuropsychiatric conditions. In this review article, we present recent evidence from schizophrenia human postmortem studies that key proteins involved in the presynaptic release mechanism are dysregulated in the disorder. We also discuss the potential impact of dysfunctional presynaptic neurotransmitter release on the various neurotransmitter systems implicated in schizophrenia.

Keywords: Complexin; Munc18; Neurotransmitter; Presynaptic; SNAP-25 (synaptosomal-associated protein 25); SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor); Schizophrenia; Synapsin; Synaptobrevin; Synaptophysin; Syntaxin.

Figure 1. Presynaptic Terminal

Schematic diagram of a presynaptic terminal with synaptic vesicles (SV), showing steps involved vesicle formation, fusion, neurotransmitter release and vesicle recycling via endocytosis at the active zone. Ca2+-channels and other pre and post-synaptic receptors along with the postsynaptic density (PSD) are also shown.

Figure 2. Synaptic Vesicle

Schematic diagram of a synaptic vesicle showing the SNARE and other key proteins involved in vesicular formation, targeting and membrane fusion and recycling at the presynaptic terminals. The arrows indicate the relative expression levels of each protein in schizophrenia when compared to matched controls.