Impaired synaptic plasticity in mice carrying the Huntington's disease mutation.
Cognitive impairment is an early symptom of Huntington's disease (HD). Mice engineered to carry the HD mutation in the endogenous huntingtin gene showed a significant reduction in long-term potentiation (LTP), a measure of synaptic plasticity often thought to be involved in memory. However, LTP could be induced in mutant slices by an 'enhanced' tetanic stimulus, implying that the LTP-producing mechanism is intact in mutant mice, but that their synapses are less able to reach the threshold for LTP induction. Mutant mice showed less post-tetanic potentiation than wild-type animals, and also showed decreased paired pulse facilitation, suggesting that excitatory synapses in HD mutant mice are impaired in their ability to sustain transmission during repetitive stimulation. We show that mutants, while normal in their ability to transmit at low frequencies, released significantly less glutamate during higher frequency synaptic activation. Thus, a reduced ability of Huntington synapses to respond to repetitive synaptic demand of even moderate frequency could result not only in a functional impairment of LTP induction, but could also serve as a substrate for the cognitive symptoms that comprise the early-stage pathology of HD.
Usdin
M T
MT
Department of Genetics, B111 Beckman Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
Shelbourne
P F
PF
Myers
R M
RM
Madison
D V
DV
D000818:Animals; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D013569:Synapses / Q000235:genetics* / Q000473:pathology*
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins