Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line

Abstract

Memantine is a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR) and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds.

The plasma peptides of Alzheimer’s disease

“…Variants in the splicing regulatory elements of EXOC3L4 were associated with Alzheimer’s disease [ 99 ]. GRID2 is important for the function of the NMDA receptor that plays a key role in synaptogenesis, synaptic plasticity, and motor coordination and that is a therapeutic target in AD [ 100 ]. Glutaredoxin And Cysteine Rich Domain Containing 1 (GRXCR1) that may function in cell survival was observed in the plasma of AD patients and Glutaredoxin was released to the cerebrospinal fluid in the early stages of AD [ 101 ].…”

Association of Gene Variations in Ionotropic Glutamate Receptor and Attention-Deficit/Hyperactivity Disorder in the Chinese Population: A Two-Stage Case–Control Study

“…As members of the iGluRs family, NMDAR and AMPAR dysfunction might be one of the potential causes of ADHD pathogenesis (J. P. Chang et al, 2014;Cheng et al, 2017;Fan et al, 2018;Medin et al, 2019), and GRID2 is critical for correcting NMDAR function and maintaining proper transmission of AMPAR signals (Kumagai et al, 2014;Yamasaki et al, 2011). In addition, dysfunction in GluRD2 is associated with a host of psychiatric phenotypes, including ASD, which shares 50%-70% of its contributing genetic factors with ADHD (Kalkan et al, 2016;Pinto et al, 2014;Rommelse et al, 2010), obsessive-compulsive disorder (OCD) (Khramtsova et al, 2019), and schizophrenia endophenotypes (Greenwood et al, 2016).…”

Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes

“… 6 New evidence linking GRID2 deletion with altered response to the NMDA receptor antagonist memantine further supports the importance of intact GluD2 function for optimal glutamate signaling. 67 …”