The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia

• Published in: Schizophrenia research Vol. 167; no. 1-3; pp. 98 - 107
• Main Authors: Cohen, Samuel M., Tsien, Richard W., Goff, Donald C., Halassa, Michael M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2015
• Subjects: Animals; Brain - metabolism; Brain - pathology; GABA; GABAergic Neurons - metabolism; Humans; Inhibitory interneuron; NMDA receptor; Psychiatry; Receptors, N-Methyl-D-Aspartate - metabolism; Schizophrenia; Schizophrenia - pathology; Schizophrenia - physiopathology; CaMK; DMN; Inhibitory interneuron; PV; Schizophrenia; LTP; GAD67; PFC; CaM; MRS; DAN; TRN; IPSC; GABA; BOLD; EPSC; NMDA receptor; LTD; prefrontal cortex; magnetic resonance spectroscopy; calmodulin; blood-oxygen-level dependent; dorsal attentional network; excitatory postsynaptic current; long term potentiation; Ca 2 + /CaM dependent protein kinase; inhibitory postsynaptic current; glutamic acid decarboxylase 67; long term depression; parvalbumin; thalamic reticular nucleus; default mode network
• ISSN: 0920-9964; 1573-2509; 1573-2509
• DOI: 10.1016/j.schres.2014.12.026

While the dopamine hypothesis has dominated schizophrenia research for several decades, more recent studies have highlighted the role of fast synaptic transmitters and their receptors in schizophrenia etiology. Here we review evidence that schizophrenia is associated with a reduction in N-methyl-d-aspartate receptor (NMDAR) function. By highlighting postmortem, neuroimaging and electrophysiological studies, we provide evidence for preferential disruption of GABAergic circuits in the context of NMDAR hypo-activity states. The functional relationship between NMDARs and GABAergic neurons is realized at the molecular, cellular, microcircuit and systems levels. A synthesis of findings across these levels explains how NMDA-mediated inhibitory dysfunction may lead to aberrant interactions among brain regions, accounting for key clinical features of schizophrenia. This synthesis of schizophrenia unifies observations from diverse fields and may help chart pathways for developing novel diagnostics and therapeutics.