Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice
| Autor: | Mahmoud A. Pouladi, Timothy H. Murphy, Michael R. Hayden, Rona K. Graham, Jamie D. Boyd, Rochelle M. Hines, Oana Cristina Vasuta, Lynn A. Raymond, Clare M. Gladding, Alexandra M. Kaufman, Rebecca W.Y. Ko, Austen J. Milnerwood |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Huntingtin
Neuroscience(all) Excitotoxicity Biology medicine.disease_cause CREB Neuroprotection Pathogenesis 03 medical and health sciences 0302 clinical medicine Huntington's disease mental disorders medicine humdisease 030304 developmental biology 0303 health sciences musculoskeletal neural and ocular physiology General Neuroscience Memantine medicine.disease 3. Good health nervous system molneuro biology.protein NMDA receptor signaling Neuroscience 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Neuron. (3):436 |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2010.01.031 |
| Popis: | SummaryN-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative disease. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|