Alterations in Hippocampal Inhibitory Synaptic Transmission in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a genetic neurodegenerative disorder of the central nervous system characterized by choreatic movements, behavioral and psychiatric disturbances and cognitive impairments. Deficits in learning and memory are often the first signs of disease onset in both HD patients and mouse models of HD and are in part regulated by the hippocampus. In the R6/2 mouse model of HD, GABAergic transmission can be excitatory in the hippocampus and restoring inhibition can rescue the associated memory deficits. In the present study we determine that hippocampal GABAergic neurotransmission in the R6/2 mouse is disrupted as early as 4 weeks of age and is accompanied by alterations in the expression of key inhibitory proteins. Specifically, spontaneous inhibitory postsynaptic currents were initially increased in frequency at 4 postnatal weeks and subsequently decreased after the mice displayed the typical R612 behavioral phenotype at 10 weeks of age. Symptomatic mice also exhibited a change in the probability of GABA release and changes in the basic membrane properties including neuronal excitability and input resistance. These electrophysiological changes in presymptomatic and symptomatic R612 mice were further accompanied by alterations in the protein expression level of pre- and postsynaptic inhibitory markers. Taken together, the present findings demonstrate profound alterations in the inhibitory neurotransmission in the hippocampus across the lifespan of the disease, including prior to neuronal degeneration, which suggests that the inhibitory hippocampal synapses may prove useful as a target for future therapeutic design. Crown Copyright (C) 2019 Published by Elsevier Ltd on behalf of IBRO. All rights reserved.