Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice.
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.
Simmons
Danielle A
DA
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92617-4291, USA. danielle.a.simmons@gmail.com.
Rex
Christopher S
CS
Palmer
Linda
L
Pandyarajan
Vijay
V
Fedulov
Vadim
V
Gall
Christine M
CM
Lynch
Gary
G
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*
D000199:Actins; D019208:Brain-Derived Neurotrophic Factor