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Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications
Author(s) -
Gaspar Pablo A.,
Bustamante M. Leonor,
Silva Hernán,
Aboitiz Francisco
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06325.x
Subject(s) - glutamatergic , neuroscience , dopamine hypothesis of schizophrenia , metabotropic glutamate receptor , dopaminergic , dopamine , schizophrenia (object oriented programming) , glutamate receptor , nmda receptor , metabotropic receptor , mechanism (biology) , medicine , psychology , receptor , psychiatry , philosophy , epistemology
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.