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Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in co-cultured striatal and cortical neurons Kaufman, Alexandra

Abstract

The N-methyl-d-aspartate receptor- type glutamate receptor (NMDAR) plays a unique and vital role in subcellular signaling. Ca²⁺ influx initiates signaling cascades important for synaptic plasticity and survival. However, overactivation of the receptor leads to toxicity and cell death. This dichotomy is partially explained by the subcellular location of the receptor. NMDARs located at the synapse have been shown to signal for cell survival, while extrasynaptic receptors signal for cell death. Thus far, the interplay between synaptic and extrasynaptic NMDARs has been studied exclusively in cortical (CTX) and hippocampal neurons; it is unknown whether medium spiny neurons of the striatum (MSNs), which bear the brunt of neurodegeneration in Huntington disease, follow the same pattern. There is evidence to suggest that signaling pathways may be different in CTX compared with MSNs. Here we study, for the first time, synaptic versus extrasynaptic signaling in striatal MSNs, focusing on activation of cAMP response element binding protein (CREB). Synaptic NMDARs activate CREB in striatal MSNs, although this pathway is slightly less efficacious compared with CTX. Similarly to CTX, extrasynaptic NMDARs shut off CREB in MSNs. MSNs are less susceptible to NMDA-mediated toxicity compared with CTX. Blocking extrasynaptic receptors with memantine (30 µM) and GluN2B-containing receptors with ifenprodil (3 µM) prevents CREB shutoff and rescues neurons from NMDA-mediated toxicity. This work may provide cell- and NMDAR subtype-specific targets for treatment of diseases with putative NMDAR involvement, including neurodegenerative diseases and ischemia.

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