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Citation
Tags
HERO ID
1501412
Reference Type
Journal Article
Title
Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in cocultured striatal and cortical neurons
Author(s)
Kaufman, AM; Milnerwood, AJ; Sepers, MD; Coquinco, A; She, K; Wang, L; Lee, H; Craig, AM; Cynader, M; Raymond, LA
Year
2012
Is Peer Reviewed?
Yes
Journal
Journal of Neuroscience
ISSN:
0270-6474
EISSN:
1529-2401
Volume
32
Issue
12
Page Numbers
3992-4003
Language
English
PMID
22442066
DOI
10.1523/JNEUROSCI.4129-11.2012
Web of Science Id
WOS:000302119800005
Abstract
The NMDAR plays a unique and vital role in subcellular signaling. Calcium influx initiates signaling cascades important for both 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 stimulate cell survival pathways, while extrasynaptic receptors signal for cell death. Thus far, this interplay between synaptic and extrasynaptic NMDARs has been studied exclusively in cortical (CTX) and hippocampal neurons. It was unknown whether other cell types, such as GABAergic medium-sized spiny projection neurons of the striatum (MSNs), which bear the brunt of neurodegeneration in Huntington's disease, follow the same pattern. Here we report synaptic versus extrasynaptic NMDAR signaling in striatal MSNs and resultant activation of cAMP response element binding protein (CREB), in rat primary corticostriatal cocultures. Similarly to CTX, we found in striatal MSNs that synaptic NMDARs activate CREB, whereas extrasynaptic NMDARs dominantly oppose CREB activation. However, MSNs are much less susceptible to NMDA-mediated toxicity than CTX cells and show differences in subcellular GluN2B distribution. Blocking NMDARs with memantine (30 μm) or GluN2B-containing receptors with ifenprodil (3 μm) prevents CREB shutoff effectively in CTX and MSNs, and also rescues both neuronal types from NMDA-mediated toxicity. This work may provide cell and NMDAR subtype-specific targets for treatment of diseases with putative NMDAR involvement, including neurodegenerative disorders and ischemia.
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