Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications.
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.
Gaspar
Pablo A
PA
Clínica Psiquiátrica Universitaria, Hospital Clínico de la Universidad de Chile, Casilla, Santiago, Chile. pgaspar@neuro.med.uchile.cl
Bustamante
M Leonor
ML
Silva
Hernán
H
Aboitiz
Francisco
F
D000818:Animals; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007395:Interneurons / Q000378:metabolism; D008959:Models, Neurological; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012559:Schizophrenia / Q000378:metabolism* / Q000503:physiopathology* / Q000628:therapy; D015398:Signal Transduction / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid