Glutamate Hypothesis of Schizophrenia and Approach for Possible Therapeutic Drugs

L-Glutamic acid (glutamate) is a major excitatory amino acid in the nervous system, and it is known that glutamate plays a major role in brain development, affecting neuronal migration, neuronal differentiation, axon genesis, and neuronal survival. Several lines of evidence suggest that a dysfunction in glutamatergic neurotransmission via the Nmethyl- D-aspartate (NMDA) subtype of glutamate receptors might be involved in the pathophysiology of schizophrenia. In this review, we discuss the NMDA receptor hypofunction hypothesis of schizophrenia and the role of glutamate in the action of atypical antipsychotic drugs such as clozapine. In addition, as novel targets for therapeutic drugs for the treatment of schizophrenia, we focus on the glycine sites on NMDA receptors, metabotropic glutamate (mGlu) receptors, and AMPA receptors. This review covers known information about agonists for the glycine site on NMDA receptors, the glycine transporter inhibitors, the mGlu II receptor agonists, and the allosteric modulators of AMPA receptors.