Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of Huntington's disease.
Predictive genetic testing for Huntington's disease (HD) has revealed early cognitive deficits in asymptomatic gene carriers, such as altered working memory, executive function and impaired recognition memory. The perirhinal cortex processes aspects of recognition memory and the underlying mechanism is believed to be long-term depression (LTD) of excitatory neurotransmission, the converse of long-term potentiation (LTP). We have used the R6/1 mouse model of HD to assess synaptic plasticity in the perirhinal cortex. We report here a progressive derailment of both LTD and short-term plasticity at perirhinal synapses. Layer II/III neurones gradually lose their ability to support LTD, show early nuclear localization of mutant huntingtin and display a progressive loss of membrane integrity (depolarization and loss of cell capacitance) accompanied by a reduction in the expression of D1 and D2 dopamine receptors visualized in layer I of the perirhinal cortex. Importantly, abnormalities in both short-term and long-term plasticity can be reversed by the introduction of a D2 dopamine receptor agonist (Quinpirole), suggesting that alterations in dopaminergic signalling may underlie early cognitive dysfunction in HD.
Cummings
Damian M
DM
Huntington's Disease Research Forum, Department of Biological Sciences, Open University, Milton Keynes, UK.
Milnerwood
Austen J
AJ
Dallérac
Glenn M
GM
Waights
Verina
V
Brown
Jacki Y
JY
Vatsavayai
Sarat C
SC
Hirst
Mark C
MC
Murphy
Kerry P S J
KP
D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009473:Neuronal Plasticity / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D011954:Receptors, Dopamine / Q000378:metabolism; D009435:Synaptic Transmission
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011954:Receptors, Dopamine; D004298:Dopamine