Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.