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Coupling extrasynaptic NMDA receptors to aberrant intracellular signaling in Huntington disease Dau, Alejandro

Abstract

N-methyl-D-aspartate glutamate receptors (NMDARs) play dichotomous roles on neuronal survival, depending on their surface localization: while synaptic NMDARs promote pro-survival pathways, those expressed at extrasynaptic sites (Ex-NMDARs) trigger pro-death cascades. In the YAC128 transgenic mouse model of Huntington disease (HD), elevated Ex-NMDAR expression contributes to the onset of cognitive dysfunction and striatal death. A shift in the balance of synaptic-extrasynaptic NMDAR signaling and localization is paralleled by dysregulation of intracellular calcium signaling pathways that couple to pro-death cascades. However, whether aberrant calcium signaling is a consequence of elevated Ex-NMDAR expression in HD is unknown. Here, we examined calcium-dependent pathways downstream of Ex-NMDARs in HD. Chronic (2-month) treatment of YAC128 and WT mice with memantine (1 and 10mg/kg/d), which at a low dose selectively blocks Ex-NDMARs, reduced striatal Ex-NMDAR expression in YAC128 mice without altering synaptic NMDAR levels. In contrast, calpain activity was not affected by memantine treatment, and was elevated in untreated YAC128 mice at 1.5 months but not 4 months of age. In YAC128 mice, memantine at 1mg/kg/d rescued CREB shut-off, while both doses suppressed p38 MAPK activation to WT levels. In contrast, extrasynaptic PSD-95 expression was not affected by memantine in YAC128 mice but was increased by memantine at 10mg/kg/d in WT littermates. Hence, Ex-NMDAR activity drives increased extrasynaptic receptor expression as well as dysregulated p38 MAPK and CREB signaling in HD. Elucidation of the pathways centered around Ex-NMDARs in HD could help provide novel therapeutic targets for this disease.

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