Elucidating the mechanisms of altered cortical sensory processing in a mouse model of Huntington disease

Deficits in sensory perception characterize Huntington disease (HD), alongside motor and cognitive impairments. This study investigates altered cortical network connectivity in HD, focusing on sensory spread, where sensory stimulation provokes more extensive cortical activity in HD model mice compared to wild-type (WT) controls.In vivo, we utilized widefield, mesoscale calcium imaging in the awake, head-fixed zQ175 mouse model of HD, crossed with Thy1-GCaMP mice, expressing GCaMP in cortical pyramidal neurons. In vivo, LED flashes induced visual responses imaged through an intact-skull cranial window. Ex vivo, we conducted electrophysiological recordings and calcium imaging in acute brain slices, evoking cortical activity by stimulating the visual cortex. A subset of mice underwent long-term oral treatment with low-dose memantine, known to block extrasynaptic NMDARs, to investigate the pharmacological modulation of sensory spread.Our findings reveal that at early motor manifest ages (7-9 months), zQ175 mice exhibited an enhanced and prolonged activity spread compared to WT, both in vivo and ex vivo. This was in line with elevated excitatory/inhibitory balance in cortical sensory areas. This aberrant spread was attenuated by NMDAR inhibition ex vivo, indicating a reliance on NMDAR activation. Preliminary findings suggest that memantine treatment reduces sensory response spread across genotypes in vivo. These findings underscore the role of extrasynaptic NMDA receptors, as well as altered inhibition in the aberrant observed sensory spread, contributing to our understanding of sensory perception deficits in HD. Funding provided by Canadian Institutes of Health Research PJT-178043 to LAR and Hereditary Disease Foundation Fellowship to JM.