title: Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice.
abstract: Cognitive problems occur in asymptomatic gene carriers of Huntington's disease (HD), and mouse models of the disease exhibit impaired learning and substantial deficits in the cytoskeletal changes that stabilize long-term potentiation (LTP). The latter effects may be related to the decreased production of brain-derived neurotrophic factor (BDNF) associated with the HD mutation. This study asked whether up-regulating endogenous BDNF levels with an ampakine, a positive modulator of AMPA-type glutamate receptors, rescues plasticity and reduces learning problems in HD (CAG140) mice. Twice-daily injections of a short half-life ampakine normalized BDNF levels, activity-driven actin polymerization in dendritic spines, and LTP stabilization in 8-week-old mutants. Comparable results were obtained in 16-week-old HD mice with more severe LTP deficits. Ampakine treatments had no measurable effect on the decreased locomotor activity observed in the mutants but offset their impairments in long-term memory. Given that ampakines are well tolerated in clinical trials and were effective in this study after brief exposures, these results suggest a novel strategy for chronic treatment of the cognitive difficulties that occur in the early stages of HD.
authors.affiliation: Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92617-4291, USA. danielle.a.simmons@gmail.com.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Simmons
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Rex
authors.forename: Linda
authors.initials: L
authors.lastname: Palmer
authors.forename: Vijay
authors.initials: V
authors.lastname: Pandyarajan
authors.forename: Vadim
authors.initials: V
authors.lastname: Fedulov
authors.forename: Christine M
authors.initials: CM
authors.lastname: Gall
authors.forename: Gary
authors.initials: G
authors.lastname: Lynch
mesh_terms: D000199:Actins / Q000378:metabolism; D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000150:complications / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000150:complications; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000199:Actins; D019208:Brain-Derived Neurotrophic Factor