Complexins And Schizophrenia

4.1. Presynaptic Localization of Complexins

The Cxs (also previously known as synaphins) are small, neuronal cytosolic proteins that are found at highest concentrations in the presynaptic nerve terminals, where they interact with the soluble NSF-attachment protein receptor (SNARE)

complex17. Complexins interact directly with SNAREs, which form a thermo-

dynamically stable complex that is hypothesized to drive fusion of vesicular and presynaptic membranes. Molecular studies have confirmed that Cxs are the only neuronal proteins known to bind tightly to the SNARE complex, in a 1:1

stoichiometry along the groove between the transmembrane regions of syntaxin and synaptobrevin (VAMP), possibly facilitating the interaction between these two proteins18. Complexins are necessary for Ca2+-dependent neurotransmission, and in this manner act as positive regulators of synaptic vesicle exocytosis.

4.2. Expression of Complexins in the Brain

The precise regional localization of Cxs in the brain continues to be a matter of debate. A number of studies have published in situ hybridization data showing that Cx I is predominantly expressed in inhibitory interneurons, whereas Cx II is expressed mainly in glutamatergic neurons19. By contrast, other groups have reported that both glutamatergic and GABAergic neurons express high levels of Cx II, and that the differential expression of Cx isoforms is unrelated to the identity of the neurotransmitter; rather, it is hypothesized that isoform expression is more closely related to anatomical circuitry20. A possible resolution to this conundrum may be obtained by investigating the localization of Cxs at the level of the synapse. An initial electron microscopic study determined that Cx I was most prominent in the axon terminals of axosomatic synapses, whereas Cx II exhibited greater immunoreactivity in the axon terminals of axospinous and axodendritic synapses21. These results indicate that Cx I is more common at inhibitory synapses, while Cx II is more common at excitatory synapses, regardless of whether the different isoforms are expressed by different types of cell. We have recently provided additional evidence to support this generalization. Our quantitative immunohistochemistry studies of the hippocampus in both rats and humans clearly demonstrate that at a macroarchitectural level, Cx I is more strongly localized with markers of inhibitory terminals, such as the GABA transporter, while Cx II is more strongly localized with markers of excitatory terminals, such as the glutamate

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