Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications

Authors

  • Pablo A. Gaspar,

    1. Clínica Psiquiátrica Universitaria, Hospital Clínico de la Universidad de Chile, Casilla, Santiago, Chile
    2. Laboratorio de Neurociencias Cognitivas, Departamento de Psiquiatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile
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  • M. Leonor Bustamante,

    1. Clínica Psiquiátrica Universitaria, Hospital Clínico de la Universidad de Chile, Casilla, Santiago, Chile
    2. Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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  • Hernán Silva,

    1. Clínica Psiquiátrica Universitaria, Hospital Clínico de la Universidad de Chile, Casilla, Santiago, Chile
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  • Francisco Aboitiz

    1. Laboratorio de Neurociencias Cognitivas, Departamento de Psiquiatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile
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Address correspondence and reprint requests to Pablo A. Gaspar, Clínica Psiquiátrica Universitaria, Hospital Clínico de la Universidad de Chile Av. La Paz 1003-Recoleta, Casilla 70014, Chile. E-mail: 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.

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