Metabotropic glutamate receptor 5 in schizophrenia: emerging evidence for the development of antipsychotic drugs

Metabotropic glutamate receptor 5 (mGluR5) is an exciting novel drug target for the treatment of several psychiatric disorders, including schizophrenia. mGluR5 is a seven transmembrane spanning, G protein-coupled receptor that modulates glutamatergic signaling, especially in association with the NMDA receptor (NMDAR). The NMDAR is well documented to play a critical role in schizophrenia pathophysiology, especially the associated cognitive dysfunctions [1,2]. Therapeutics that target the NMDAR directly are problematic because the NMDAR is an ionotropic receptor; its activation allows calcium entry into the neuron, which at high levels activates an excitotoxic cascade, ultimately leading to neuronal death. Researchers have been trying to overcome this and target the NMDAR via a 'back door' approach for many years. The NMDAR shares a structural connection with mGluR5, via one or a combination of various scaffolding proteins (e.g., Homer, Shank, GKAP and PSD-95); through this link, mGluR5 activation enhances NMDAR activity, thereby forming the basis of mGluR5 as a novel drug target for the treatment of schizophrenia.