title: Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in cocultured striatal and cortical neurons.
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.
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Kaufman
authors.forename: Austen J
authors.initials: AJ
authors.lastname: Milnerwood
authors.forename: Marja D
authors.initials: MD
authors.lastname: Sepers
authors.forename: Ainsley
authors.initials: A
authors.lastname: Coquinco
authors.forename: Kevin
authors.initials: K
authors.lastname: She
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Hwan
authors.initials: H
authors.lastname: Lee
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Craig
authors.forename: Max
authors.initials: M
authors.lastname: Cynader
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000166:cytology*; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018684:Glycine Agents / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D046210:Microfluidic Analytical Techniques / Q000379:methods; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013331:Strychnine / Q000494:pharmacology; D013569:Synapses / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D018683:Excitatory Amino Acid Agents; D058787:GABA-A Receptor Antagonists; D018684:Glycine Agents; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D050598:Vesicular Glutamate Transport Protein 1; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D015761:4-Aminopyridine; D050882:CREB-Binding Protein; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D013331:Strychnine; D009543:Nifedipine; D001640:Bicuculline