title: Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in HD mice.
abstract: Huntington's disease (HD) is caused by an expanded polyglutamine repeat in huntingtin protein that disrupts synaptic function in specific neuronal populations and results in characteristic motor, cognitive and affective deficits. Histopathological hallmarks observed in both HD patients and genetic mouse models include the reduced expression of synaptic proteins, reduced medium spiny neuron (MSN) dendritic spine density and decreased frequency of spontaneous excitatory post-synaptic currents (sEPSCs). Early down-regulation of cannabinoid CB1 receptor expression on MSN (CB1(MSN)) is thought to participate in HD pathogenesis. Here we present a cell-specific genetic rescue of CB1(MSN) in R6/2 mice and report that treatment prevents the reduction of excitatory synaptic markers in the striatum (synaptophysin, vGLUT1 and vGLUT2), of dendritic spine density on MSNs and of MSN sEPSCs, but does not prevent motor impairment. We conclude that loss of excitatory striatal synapses in HD mice is controlled by CB1(MSN) and can be uncoupled from the motor phenotype.
authors.affiliation: Medical Scientist Training Program, University of Washington, Seattle, WA USA; Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, WA USA.
authors.forename: Alipi V
authors.initials: AV
authors.lastname: Naydenov
authors.affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Marja D
authors.initials: MD
authors.lastname: Sepers
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Swinney
authors.affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, WA USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA USA. Electronic address: nstella@uw.edu.
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D003342:Corpus Striatum / Q000473:pathology*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D053580:Muscle Strength / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D016622:Silver Staining; D013569:Synapses / Q000502:physiology*; D013997:Time Factors
chemical_list: C578453:CNR1 protein, mouse; C485998:Gpr88 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D043884:Receptor, Cannabinoid, CB1; D043562:Receptors, G-Protein-Coupled; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: CB1; Dendritic spines; Endocannabinoids; Huntington's disease; R6/2 mice; Synaptic loss