UCLA

Huntington’s disease (HD) is a fatal, autosomal dominant, genetic disorder characterized by cell death of medium-sized spiny neurons (MSNs) in the striatum. Striatal cell death has been traditionally attributed to excessive excitatory inputs, or more recently to disrupted balance of excitatory, inhibitory, and modulatory signaling. Therefore, understanding of altered synaptic signaling at striatal inputs is essential for the development and design of HD treatments. MSNs receive excitatory glutamatergic projections from the cortex and thalamus. HD induced functional changes in corticostriatal projections have been studied extensively in mouse models. However, although thalamic atrophy is correlated with cognitive impairments in HD patients and the centromedian-parafascicular (CMPf) nuclear complex (the primary origin of thalamostriatal projections) undergoes a 55% neuronal loss in HD patients, functional alterations of thalamostriatal projections have not been electrophysiology investigated. An adeno-associated virus (AAV) expressing channelrhodopsin-2 (ChR2) under the calcium/calmodulin-dependent protein kinase type II alpha subunit (CaMKIIa) promoter was injected into the CMPf or the sensorimotor cortex of HD model mice to allow for selective activation of thalamostriatal or corticostriatal projections respectively. Pharmacological and holding potential manipulations were used to isolate AMPA and NMDA receptor-mediated currents. In the symptomatic R6/2 fragment mouse model, thalamostriatal synapses displayed increased decay times of both AMPA and NMDA receptor-mediated currents, alterations in glutamate reuptake, and increased probability of glutamate release. These findings suggest functional evidence consistent with early degeneration of thalamostriatal projections observed in the Q140 mouse model previously published. These effects were more prominent at synapses between thalamic inputs and direct pathway projecting MSNs rather than indirect pathway projecting MSNs. Corticostriatal synapses showed much more discrete changes than thalamostriatal. The differences in kinetics of AMPA and NMDA receptor-mediated currents were contrasting, changes in glutamate reuptake were smaller than those at thalamostriatal projections, and no change in the probability of glutamate release was detected. No significant changes were observed in presymptomatic or symptomatic YAC128 full length mouse models. Perhaps, a more severe and later disease state should be examined in this slowly progressing HD model.