A quantitative review of the postmortem evidence for decreased cortical N-methyl-d-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?

Abstract

Evidence suggests that anomalous mismatch negativity (MMN) in schizophrenia is related to glutamatergic abnormalities, possibly involving N-methyl-D-aspartate (NMDA) receptors. Decreased cortical expressions of NMDA receptor subunits have been observed in schizophrenia, though not consistently. To aid with integration and interpretation of previous work, we performed a meta-analysis of effect sizes of mRNA or protein levels of the obligatory NR1 subunit in prefrontal cortex from people with schizophrenia. In schizophrenia compared to unaffected controls the pooled effect size was -0.64 (95% confidence interval: -1.08 to -0.20) for NR1 mRNA reduction and -0.44 (95% confidence interval: -0.80 to -0.07) for NR1 protein reduction. These results represent the first step to a deeper understanding of the region-specific, cell-specific, and stage-specific NMDA receptor hypofunction in schizophrenia, which could be linked to mismatch negativity deficits via transgenic and pharmacological animal models.

Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders

“…Computational modeling studies have also demonstrated that elevating E/I balance in a microcircuit capable of working memory computations results in a specific pattern of behavioral errors(2). This hypothesized ‘disinhibited’ behavioral and neural regime was confirmed experimentally following NMDAR antagonism(138,153). Finally, a computational perturbation simulating disinhibition in a large-scale functional connectivity model predicted neural activity patterns confirmed in resting state scans from SCZ patients.…”

“…This finding is consistent with arterial spin labeling studies on this topic(137). It may have important implications for identifying drug targets related to altered NMDAR signaling in SCZ, which likely contribute to E/I imbalance(138). While pharmacological models of SCZ in healthy controls have provided important tests of mechanistic predictions for explaining the SCZ disease state, as yet, no parallel model exists for ASD.…”

Neurophysiology and Regulation of the Balance Between Excitation and Inhibition in Neocortical Circuits

“…Even in properly connected circuits, neuronal and local circuit excitability can be altered due to: inappropriate differentiation of neuronal phenotypes (115), improper regulation of neurotransmitter release (116), impaired expression of excitatory (117) or inhibitory postsynaptic receptors (118) and/or their scaffolding proteins (119, 120). As our understanding of the mechanisms for homeostatic plasticity is still limited, most experimental work on disease models focused on identifying changes in synaptic transmission within circuits, but has not yet delved deeply into investigating possible defects in compensatory mechanisms.…”

Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1 PAM VU6004256

“…5–7 Post-mortem studies have also revealed reductions in the mRNA and protein expression of the NR1 subunit of the NMDAR in the prefrontal cortex (PFC) of individuals with schizophrenia. 8 Moreover, animal studies with cell-specific deletion or global knockdown (KD) of the GluN1 subunit of the NMDAR have reported abnormalities in various physiologic measures, including changes in gamma band oscillations, and impairments in social and cognitive performance that are considered endophenotypes of schizophrenia symptoms. 9–14 Taken together, targeting abnormalities in NMDAR function represents a critical strategy for the treatment of the complex symptoms associated with schizophrenia.…”