Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia

Abstract

The N-methyl-d-aspartate receptor hypofunction is one of the most prevalent models of schizophrenia. For example, healthy subjects treated with uncompetitive N-methyl-d-aspartate receptor antagonists elicit positive, negative, and cognitive-like symptoms of schizophrenia. Patients with anti-N-methyl-d-aspartate receptor encephalitis, which is likely caused by autoantibody-mediated down-regulation of cell surface N-methyl-d-aspartate receptors, often experience psychiatric symptoms similar to schizophrenia initially. However, where and when N-methyl-d-aspartate receptor hypofunction occurs in the brain of schizophrenic patients is poorly understood. Here we review the findings from N-methyl-d-aspartate receptor antagonist and autoantibody models, postmortem studies on N-methyl-d-aspartate receptor subunits, as well as the global and cell-type-specific knockout mouse models of subunit GluN1. We compare various conditional GluN1 knockout mouse strains, focusing on the onset of N-methyl-d-aspartate receptor deletion and on the cortical cell-types. Based on these results, we hypothesize that N-methyl-d-aspartate receptor hypofunction initially occurs in cortical GABAergic neurons during early postnatal development. The resulting GABA neuron maturation deficit may cause reduction of intrinsic excitability and GABA release, leading to disinhibition of pyramidal neurons. The cortical disinhibition in turn could elicit glutamate spillover and subsequent homeostatic down regulation of N-methyl-d-aspartate receptor function in pyramidal neurons in prodromal stage. These two temporally-distinct N-methyl-d-aspartate receptor hypofunctions may be complimentary, as neither alone may not be able to fully explain the entire schizophrenia pathophysiology. Potential underlying mechanisms for N-methyl-d-aspartate receptor hypofunction in cortical GABA neurons are also discussed, based on studies of naturally-occurring N-methyl-d-aspartate receptor antagonists, neuregulin/ErbB4 signaling pathway, and theoretical analysis of excitatory/inhibitory balance.

Mice lacking a functional NMDA receptor exhibit social subordination in a group‐housed environment

“…Several studies have shown that Grin1 mutant mice exhibit reduced social interactions under nongroup‐housed conditions []. Some Grin1 mutant mice (hypomorph, region‐specific knockout and cell‐specific knockout mice) showed the reduced time spent sniffing, grooming and following to unfamiliar mice [].…”

“…Therefore, a competitively subordinate phenotype might be due to greater anxiety in Grin1 Rgsc174/+ mice. Several studies have shown that Grin1 mutant mice exhibit reduced social interactions under nongrouphoused conditions [15][16][17]19,20,[25][26][27][28][29][30][31][32]. Some Grin1 mutant mice (hypomorph, region-specific knockout and cell-specific knockout mice) showed the reduced time spent sniffing, grooming and following to unfamiliar mice [15][16][17]19,29,30,32].…”

“…Grin1 mutant mice might serve as an appropriate animal model of psychiatric disorders. Indeed, Grin1 mutant mice exhibit psychiatric disorder‐like phenotypes, such as hyperactivity , increased exploratory behaviour , abnormal anxiety and impaired social interactions .…”

“…Grin1 mutant mice might serve as an appropriate animal model of psychiatric disorders. Indeed, Grin1 mutant mice exhibit psychiatric disorder-like phenotypes, such as hyperactivity [14][15][16][17][18][19][20][21][22][23], increased exploratory behaviour [17,[22][23][24], abnormal anxiety [15][16][17][18]22,23,25] and impaired social interactions [15][16][17]19,22,23,[25][26][27][28][29][30][31][32].…”

NMDA-receptor antibodies alter cortical microcircuit dynamics

“…NMDAR-Ab directly affect glutamate transmission through reversible loss of NMDARs, resulting in a reduction of miniature excitatory post synaptic currents (mEPSCs) in brain slices 10,11 . NMDAR hypofunction is also a hallmark of psychiatric conditions, such as schizophrenia and acute psychosis 12,13 -whose clinical features resemble the neuropsychiatric and behavioural symptoms also seen in NMDAR-Ab encephalitis.…”