Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington's disease.
Asymptomatic Huntington's disease (HD) patients exhibit memory and cognition deficits that generally worsen with age. Similarly, long-term potentiation (LTP), a form of synaptic plasticity involved in memory encoding, is impaired in HD mouse models well before motor disturbances occur. The reasons why LTP deteriorates are unknown. Here we show that LTP is impaired in hippocampal slices from presymptomatic Hdh(Q92) and Hdh(Q111) knock-in mice, describe two factors contributing to this deficit, and establish that potentiation can be rescued with brain-derived neurotrophic factor (BDNF). Baseline physiological measures were unaffected by the HD mutation, but LTP induction and, to a greater degree, consolidation were both defective. The facilitation of burst responses that normally occurs during a theta stimulation train was reduced in HD knock-in mice, as was theta-induced actin polymerization in dendritic spines. The decrease in actin polymerization and deficits in LTP stabilization were reversed by BDNF, concentrations of which were substantially reduced in hippocampus of both Hdh(Q92) and Hdh(Q111) mice. These results suggest that the HD mutation discretely disrupts processes needed to both induce and stabilize LTP, with the latter effect likely arising from reduced BDNF expression. That BDNF rescues LTP in HD knock-in mice suggests the possibility of treating cognitive deficits in asymptomatic HD gene carriers by upregulating production of the neurotrophin.
Lynch
Gary
G
Department of Psychiatry and Human Behavior, University of California, Irvine, California 92617-4291, USA.
Kramar
Eniko A
EA
Rex
Christopher S
CS
Jia
Yousheng
Y
Chappas
Danielle
D
Gall
Christine M
CM
Simmons
Danielle A
DA
D000199:Actins / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000503:physiopathology; D006816:Huntington Disease / Q000235:genetics*; D017774:Long-Term Potentiation / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000235:genetics*; D013569:Synapses / Q000378:metabolism; D013826:Theta Rhythm
D000199:Actins; D019208:Brain-Derived Neurotrophic Factor