Presynaptic Glutamatergic Mechanisms

Glutamate synapses are specialized for rapid vesicle fusion/neurotransmitter release. Fusion is initiated by SNARE proteins such as syntaxin-1, synaptobrevin-2, and SNAP-25 (see Chapter 2.4 this volume). Presynaptic gene expression, in general, is widely disturbed in schizophrenia (Mimics et al., 2000 Mimics et al., 2001 Hemby et al., 2002), including reduced expression of SNAP-25 RNA(Hemby et al., 2002) and 

Schematic model of the glutamate synapse. Gly glycine o-Ser D-serine DAAO D-amino acid oxidase DAOA D-amino acid oxidase activator (aka, G72) 

Other presynaptic elements, such as complexins, that dock presynaptic vesicles (Brose, 2008) or syanptotagmin, which may couple Ca2+ entry to rapid vesicle fusion, permitting synchronous presynaptic glutamate release (Maximov and Sudhof, 2005), have not been heavily investigated in schizophrenia. One study has suggested an abnormal interaction between complexin-2 and synapsin-2 in schizophrenia, illustrating the complexity of the potential dysfunctional mechanisms (Lee et al., 2005). 

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The increased levels of quinolinic acid—as NMDA receptor agonist—lead to increased levels of glutamate. Quinolinic acid was shown to cause an overrelease of glutamate in the striatum and in the cortex, presumably by presynaptic mechanisms (Fedele and Foster 1993 Chen et al., 1999). The quinolinic pathway might be the mechanism involved in the increased glutamatergic neurotransmission in MD (Sanacora et al., 2004a). 

Shupliakov O, Pieribone VA, Gad H, Brodin L (1996) Presynaptic mechanisms in central synaptic transmission biochemistry of an intact glutamatergic synapse. Acta Physiol Scand 757 369-379. 

Abstract The CBi cannabinoid receptor is widely distributed in the central and peripheral nervous system. Within the neuron, the CBi receptor is often localised in axon terminals, and its activation leads to inhibition of transmitter release. The consequence is inhibition of neurotransmission via a presynaptic mechanism. Inhibition of glutamatergic, GABAergic, glycinergic, cholinergic, noradrenergic and serotonergic neurotransmission has been observed in many regions... 

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