Altered membrane properties and firing patterns of external globus pallidus neurons in the R6/2 mouse model of Huntington's disease

Abstract

In mouse models of Huntington’s disease (HD), striatal neuron properties are significantly altered. These alterations predict changes in striatal output regions. However, little is known about alterations in those regions. In the present study we examined changes in passive and active membrane properties of neurons in the external globus pallidus (GPe), the first relay station of the indirect pathway, in the R6/2 mouse model of juvenile HD at pre- (1 mo) and symptomatic (2 mo) stages. In GPe, two principal types of neurons can be distinguished based on firing properties and the presence (type A) or absence (type B) of Ih currents. In symptomatic animals (2 mo), cell membrane capacitance and input resistance of type A neurons were increased compared to controls. In addition, action potential after-hyperpolarization amplitude was reduced. Although the spontaneous firing rate of GPe neurons was not different between control and R6/2 mice, the number of spikes evoked by depolarizing current pulses was significantly reduced in symptomatic R6/2 animals. In addition, these changes were accompanied by altered firing patterns evidenced by increased inter-spike interval variation and increased number of bursts. Blockade of GABAA receptors facilitated bursting activity in R6/2 mice but not in control littermates. Thus, alterations in firing patterns could be caused by changes in intrinsic membrane conductances and modulated by synaptic inputs.

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease

“…Another possible explanation for the discrepancy is that the 2 groups were sampled from different populations of GPe neuron. GPe neurons can be roughly divided into prototypical and arkypallidal classes, which can be distinguished on anatomical and physiological criteria . In particular, prototypical neurons constitute the largest class of GPe neuron and can be distinguished by (1) their innervation of the STN, GPi, SNr, and thalamus; (2) expression of PV or Lim homeobox protein 6 (Lhx6); (3) a high autonomous discharge rate; and (4) the absence of a prominent voltage sag with hyperpolarizing current injection from near −60 mV.…”

“…GPe neurons can be roughly divided into prototypical and arkypallidal classes, which can be distinguished on anatomical and physiological criteria. 28,34,36,37,[52][53][54] In particular, prototypical neurons constitute the largest class of GPe neuron and can be distinguished by (1) their innervation of the STN, GPi, SNr, and thalamus; (2) expression of PV or Lim homeobox protein 6 (Lhx6); (3) a high autonomous discharge rate; and (4) the absence of a prominent voltage sag with hyperpolarizing current injection from near −60 mV. In contrast, arkypallidal GPe neurons constitute about 30% of the GPe population and can be distinguished by (1) their innervation of the striatum, (2) the expression of neuronal PAS domain protein 1 (Npas1) or forkhead box P2 (FoxP2) and not PV, (3) a low autonomous spike rate, and (4) the presence of a voltage sag with hyperpolarizing current injection.…”

Alteration of GABAergic neurotransmission in Huntington's disease

“…In humans, the GPe is overactive in HD, and GPe deep brain stimulation has been shown to alleviate motor and cognitive dysfunctions in both human patients and a rat model of HD . Ex vivo, the firing pattern of GPe neurons is altered in R6/2 mice where blockade of GABA A Rs facilitates bursting activity . It is then reasonable to anticipate that the HD mutation has an impact on GABAergic neurotransmission in this brain structure.…”

“…[16][17][18]20 Ex vivo, the firing pattern of GPe neurons is altered in R6/2 mice where blockade of GABA A Rs facilitates bursting activity. 100 It is then reasonable to anticipate that the HD mutation has an impact on GABAergic neurotransmission in this brain structure.…”

Progress in developing transgenic monkey model for Huntington’s disease

“…The N171-82Q mice also showed significant atrophy of the neocortex, hippocampus, piriform cortex and amygdala by the end of the disease at five to six months of age (Aggarwal et al 2012). Furthermore, changes in neural activity of the GPe and decreased connectivity of the MSNs of the indirect pathway in R6/2 mice were also observed (Akopian et al 2016; Cepeda et al 2013).…”