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 show ed a significant reduction in long-term potentiation (LTP), a measure of sy naptic plasticity often thought to be involved in memory, However, LTP coul d be induced in mutant slices by an 'enhanced' tetanic stimulus, implying t hat the LTP-producing mechanism is intact in mutant mice, but that their sy napses are less able to reach the threshold for LTP induction, Mutant mice showed less post-tetanic potentiation than wild-type animals, and also st-s owed decreased paired pulse facilitation, suggesting that excitatory synaps es 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 glutama te during higher frequency synaptic activation. Thus, a reduced ability of Huntington synapses to respond to repetitive synaptic demand of even modera te frequency could result not only in a functional impairment of LTP induct ion, but could also serve as a substrate for the cognitive symptoms that co mprise the early-stage pathology of HD.