Abstract
N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed.
Highlights
N-methyl-d-aspartate receptors (NMDARs) are ligand-gated ionotropic receptors that play important roles in synaptic plasticity within the central nervous system (CNS)
NMDAR function is involved in CNS activity including cognitive function, behavior, and memory[12,13]
A number of studies have shown that NMDAR antagonists cause psychotic symptoms that are diagnostically difficult to differentiate from SCZ14
Summary
N-methyl-d-aspartate receptors (NMDARs) are ligand-gated ionotropic receptors that play important roles in synaptic plasticity within the central nervous system (CNS). NMDAR function is involved in CNS activity including cognitive function, behavior, and memory[12,13]. These functions are often impaired in psychiatric diseases such as SCZ and ASD. Mice with reduced expression of NR1 subunits display abnormal SCZ-like behavior that is ameliorated by treatment with antipsychotic drugs[18]. Shank[2] is a scaffolding protein in the PSD and interconnects receptors at the PSD including NMDARs. Shank2−/−mice have reduced NMDAR activity and exhibit ASD-like behaviors that are corrected by normalizing NMDAR functions[22]. In contrast to Shank2−/−mice, IRSp53−/−mice have enhanced NMDAR activity in the hippocampus, and show impaired social interaction These ASD-like behaviors are rescued by memantine. NMDAR dysregulation in the CNS may contribute to development of ASD23
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