Review: NMDA Receptor Hypofunction and Its Involvement in Excitotoxicity in Schizophrenia

Abstract

Schizophrenia is a severely debilitating psychiatric condition that has long been associated with altered neurotransmission in the brain, especially in dopaminergic transmission. The dopamine hypothesis of schizophrenia, while it has been the main focus of research in the past decades, fails to explain the underlying pathogenesis. A more recent hypothesis dealing with altered central glutamate signaling in schizophrenia may help to ameliorate the deficit in understanding. Blockade of the glutamatergic NMDA receptors produces schizophrenic behaviours and phenotypes almost indistinguishable from the disease itself in animal and human models. It has been elucidated that hypofunction of NMDA receptors on the parvalbumin-­‐containing interneurons in the cortex and subcortical regions leads to a downstream increase in cortical glutamate release, which may be causing functional connectivity issues through mechanisms of excitotoxicity. A number of studies have pointed to the hypofunction of these NMDA receptors leading to excitotoxicity and cellular degeneration, which may be implicated in the disease pathology. This review will evaluate and highlight this forthcoming evidence.