Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington’s disease

Abstract

The psychomotor symptoms of Huntington’s disease (HD) are linked to degeneration of the basal ganglia indirect pathway. To determine how this pathway is perturbed prior to cell loss, optogenetic- and reporter-guided electrophysiological interrogation approaches were applied to early symptomatic 6-month-old Q175 HD mice. Although cortical activity was unaffected, indirect pathway striatal projection neurons were hypoactive in vivo, consistent with reduced cortical input strength and dendritic excitability. Downstream parvalbumin-expressing prototypic external globus pallidus (GPe) neurons were hyperactive in vivo and exhibited elevated autonomous firing ex vivo. Optogenetic inhibition of prototypic GPe neurons ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative arkypallidal neurons in vivo. In contrast to STN neurons, autonomous arkypallidal activity was unimpaired ex vivo. Together with previous studies, these findings demonstrate that basal ganglia indirect pathway neurons are highly dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic properties 6-12 months before cell loss.

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

“…Additionally, Barry, Akopian, Cepeda, and Levine (2018) showed reduced GABA release in SNr by dSPNs in R6/2 mice, and they attributed this effect to reduced activity of dSPNs. Similarly, in heterozygous Q175 mice at 6 months of age, Bevan and coworkers have shown that iSPNs show decreased responses to cortical activation (Callahan & Bevan, 2019). Thus, the presently observed increase in ENK+ striato‐GPe terminals and SP+ striato‐GPi/SN terminals in Q175 mice may, at least in part, reflect reduced neuronal firing of SPNs, and as a result, reduced neurotransmitter release by their terminals in GPe and GPi/SNr.…”

Synaptic pathology in Huntington's disease: Beyond the corticostriatal pathway

“…In contrast, arkypallidal GPe neurons and STN neurons were hypoactive. Notably, the hypoactivity of STN and arkypallidal GPe neurons was partially alleviated by optogenetic inhibition of prototypic GPe neurons ( Callahan et al, 2021 ). Another recent study identified a subnetwork of direct pathway MSNs specifically targeting arkypallidal Npas-positive neurons in the GPe ( Cui et al, 2021 ).…”