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J Neurochem. 2009 Nov;111(4):891-900. doi: 10.1111/j.1471-4159.2009.06325.x. Epub 2009 Aug 4.

Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications.

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  • 1Clínica Psiquiátrica Universitaria, Hospital Clínico de la Universidad de Chile, Casilla, Santiago, Chile. pgaspar@neuro.med.uchile.cl

Abstract

Early models for the etiology of schizophrenia focused on dopamine neurotransmission because of the powerful anti-psychotic action of dopamine antagonists. Nevertheless, recent evidence increasingly supports a primarily glutamatergic dysfunction in this condition, where dopaminergic disbalance is a secondary effect. A current model for the pathophysiology of schizophrenia involves a dysfunctional mechanism by which the NMDA receptor (NMDAR) hypofunction leads to a dysregulation of GABA fast- spiking interneurons, consequently disinhibiting pyramidal glutamatergic output and disturbing the signal-to-noise ratio. This mechanism might explain better than other models some cognitive deficits observed in this disease, as well as the dopaminergic alterations and therapeutic effect of anti-psychotics. Although the modulation of glutamate activity has, in principle, great therapeutic potential, a side effect of NMDAR overactivation is neurotoxicity, which accelerates neuropathological alterations in this illness. We propose that metabotropic glutamate receptors can have a modulatory effect over the NMDAR and regulate excitotoxity mechanisms. Therefore, in our view metabotropic glutamate receptors constitute a highly promising target for future drug treatment in this disease.

PMID:
19686383
[PubMed - indexed for MEDLINE]
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