DISC1 Dynamically Regulates Synaptic N-Methyl-D-Aspartate Responses in Excitatory Neurons

Abstract

Schizophrenia and related mood disorders are complex psychiatric disorders that affect � 2% of the population (1,2). The fortuitous finding of chlorpromazine and other phenothiazines in the early 1950s and subsequent development of clozapine and related antipsychotic drugs ameliorated a subset of syndromes of psychosis and resulted in deinstitutionalization of many patients with psychiatric disorders. The drugs seem to benefit patients by modulating dopaminergic or serotoninergic function, or both. The exact mechanisms of action of the drugs are unknown. There are still no good answers 50 years after the discovery of these drugs as to why the medications fail to treat the negative symptoms and cognitive deficits, and this lack of answers has hampered the development of more effective medications (1,2). A comprehensive understanding of the etiopathology of psychiatric disorders is urgently needed for developing improved medications. Accumulating research findings have fostered a hypothesis that aberrant glutamatergic transmission, particularly aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated glutamate transmission, may be responsible for schizophrenia and related psychiatric disorders (1–4). The initial evidence has emerged from administration of NMDAR antagonists, including phencyclidine and ketamine, which elicit psychotic symptoms and cognitive dysfunction similar to those of schizophrenia and related psychiatric disorders and aggravate the psychotic symptoms in patients with the disorders. The effects of NMDAR antagonists persist in the absence of activity of monoamines. Additionally, genetically reducing NMDAR expression in interneurons produces schizophrenia-like phenotypes. Finally, more recent genetic studies have linked numerous genes, including the disrupted in schizophrenia 1 gene (DISC1), with the disorders, and many of those molecules have been implicated in regulation of glutamatergic transmission (3,4). Together, these findings have led to the prevailing hypothesis that hypofunction of NMDARs, particularly hypofunction of NMDARs in interneurons, causes progression and symptoms of schizophrenia and related psychiatric disorders.