Thalamocortical Projections Are Significantly Impaired in the R6/2 Mouse Model of Huntington's Disease

S M Holley,K D Oikonomou, C M Swift, L Mohan, B Matthews, O Vega, G Mkrtchyan,C Cepeda,M S Levine

ENEURO(2022)

Cited 2|Views13
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Abstract
As Huntington's disease (HD) progresses, there is a significant loss of neurons in the striatum in addition to a distinct thinning of the cerebral cortex. Despite an early presence of sensorimotor deficits in patients with HD, electrophysiological studies designed to assess the integrity of thalamocortical circuits are sparse. Using the R6/2 mouse model of HD, we provide evidence of reduced connectivity between thalamic cells and their targeted cortical regions. Whole-cell patch clamp recordings from ventral anterolateral nucleus (VAL; motor) and ventral posteromedial nucleus (VPM; somatosensory) thalamic neurons in ex vivo brain slices of R6/2 and wild-type (WT) mice revealed that cells in both thalamic nuclei of R6/2 mice exhibited significant differences in passive and active cell membrane properties (smaller cell membrane capacitances, faster decay time constants and increased input resistances) compared with WT cells. Although only cells in the VPM of symptomatic R6/2 mice had more depolarized resting membrane potentials compared with WTs, cells in both nuclei displayed increased excitability in symptomatic, but not presymptomatic, R6/2 mice. Optical activation of VAL and VPM terminals elicited smaller magnitude current responses in cortical pyramidal neurons (CPNs) in both motor cortex (M1CTX) and somatosensory barrel cortex (BCTX) of symptomatic R6/2 mice compared with CPNs in WT mice. Furthermore, we observed a decrease in the frequency of thalamocortical excitatory quantal events in R6/2 BCTX CPNs, with no genotype-dependent differences in AMPA:NMDA response amplitude ratios. These data suggest there is a decrease in the transmission of thalamocortical information that is likely because of impaired neurotransmitter release.
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Key words
animal models, electrophysiology, Huntington's disease, thalamocortical
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