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.
Highlights
Memantine (3,5-dimethyl-1-adamantanamine) is an approved drug in the treatment of moderate-to-severe Alzheimer’s disease (AD)
Enhanced cholinergic signaling following donepezil treatment [21] and activation of dopamine signals by L-Dopa [21,22] had no significant effect on behavior in both normal and mutant mice (Table 1). These results suggest that, in addition to the ataxic phenotype, the mutant mice were characterized by enhanced memantine susceptibility, which was probably due to impaired NMDA receptor functions
We examined whether Grid2Htake/Htake mice possessed memantine-sensitive NMDA receptors on cerebellar granule cells, using granule cell-enriched (Purkinje cell-free) primary cultures from P2 mice
Summary
Memantine (3,5-dimethyl-1-adamantanamine) is an approved drug in the treatment of moderate-to-severe Alzheimer’s disease (AD). In addition to the known phenotypes in mice, new phenotypes presumably involving NMDA receptor dysfunction or memantine effects, such as nystagmus (in frogs) [10], oculomotor apraxia (in cats) [11,12], dementia (in humans) [13,14], have been observed in human patients with GRID2 gene deletions [15,16,17,18]. Only a small population of cultured granule cells isolated from the mutant mice showed memantine-sensitive NMDA-induced currents. These phenomena were mimicked in wild-type (WT) mice following co-treatment with memantine and AMPA
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