title: Chronic blockade of extrasynaptic NMDA receptors ameliorates synaptic dysfunction and pro-death signaling in Huntington disease transgenic mice.
abstract: In the YAC128 mouse model of Huntington disease (HD), elevated extrasynaptic NMDA receptor (Ex-NMDAR) expression contributes to the onset of striatal dysfunction and atrophy. A shift in the balance of synaptic-extrasynaptic NMDAR signaling and localization is paralleled by early stage dysregulation of intracellular calcium signaling pathways, including calpain and p38 MAPK activation, that couple to pro-death cascades. However, whether aberrant calcium signaling is a consequence of elevated Ex-NMDAR expression in HD is unknown. Here, we aimed to identify calcium-dependent pathways downstream of Ex-NMDARs in HD. Chronic (2-month) treatment of YAC128 and WT mice with memantine (1 and 10mg/kg/day), which at a low dose selectively blocks Ex-NMDARs, reduced striatal Ex-NMDAR expression and current in 4-month old YAC128 mice without altering synaptic NMDAR levels. In contrast, calpain activity was not affected by memantine treatment, and was elevated in untreated YAC128 mice at 1.5months but not 4months of age. In YAC128 mice, memantine at 1mg/kg/day rescued CREB shut-off, while both doses suppressed p38 MAPK activation to WT levels. Taken together, our results indicate that Ex-NMDAR activity perpetuates increased extrasynaptic NMDAR expression and drives dysregulated p38 MAPK and CREB signaling in YAC128 mice. Elucidation of the pathways downstream of Ex-NMDARs in HD could help provide novel therapeutic targets for this disease.
authors.affiliation: Department of Psychiatry, Division of Neuroscience, Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: adau@alumni.ubc.ca.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Dau
authors.affiliation: Department of Psychiatry, Division of Neuroscience, Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: cgladding@cdrd.ca.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Gladding
authors.affiliation: Department of Psychiatry, Division of Neuroscience, Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: marjasepers@gmail.com.
authors.forename: Marja D
authors.initials: MD
authors.lastname: Sepers
authors.affiliation: Department of Psychiatry, Division of Neuroscience, Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: lynn.raymond@ubc.ca.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D020013:Calcium Signaling; D002154:Calpain / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D002154:Calpain; D008559:Memantine
keywords: Calcium signaling; Calpain; Extrasynaptic; GluN2B; Huntington disease; Memantine; NMDA receptor; Striatum; p38; pCREB