Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice.
N-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.
Milnerwood
Austen J
AJ
Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Gladding
Clare M
CM
Pouladi
Mahmoud A
MA
Kaufman
Alexandra M
AM
Hines
Rochelle M
RM
Boyd
Jamie D
JD
Ko
Rebecca W Y
RW
Vasuta
Oana C
OC
Graham
Rona K
RK
Hayden
Michael R
MR
Murphy
Timothy H
TH
Raymond
Lynn A
LA
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics; D013997:Time Factors
D016194:Receptors, N-Methyl-D-Aspartate