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. The present study examines 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 presymptomatic (1 month) and symptomatic (2 month) 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 I_h currents. In symptomatic animals (2 month), cell membrane capacitance and input resistance of type A neurons were increased compared with controls. In addition, action potential afterhyperpolarization 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 interspike interval variation and increased number of bursts. Blockade of GABA_A 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. © 2016 Wiley Periodicals, Inc.

Keywords: Huntington's disease; electrophysiology; globus pallidus; mouse model.

Fig. 1

Traces show typical I-V relationships (500 ms current pulses starting at −300 pA, with 50 pA increments) of GPe neurons in WT and R6/2 mice. Based on the presence or absence of hyperpolarization-activated cation currents (I_h or sag), GPe neurons from both WT and R6/2 mice could be divided into two main groups, one (A) with prominent I_h (type A) and one (B) without prominent I_h (type B). Images on top of the traces show examples of biocytin-filled type A and type B cells in WT and R6/2 mice (2 mo). Notice decreased firing regularity in cells from R6/2 animals.

Fig. 2

A. Spontaneous firing patterns of type A and type B GPe neurons in presymptomatic (1 mo) R6/2 mice and age-matched WT mice. B. Graphs illustrate average firing rates and burst numbers between WT and R6/2 mice. Compared to WTs, R6/2 mice showed a significant increase in burst numbers when both cell types were pooled. C. Coefficients of variation (CV) of inter-spike intervals also were significantly increased due to more firing irregularity of R6/2 neurons.

Fig. 3

A. Spontaneous firing patterns of type A and type B GPe neurons in symptomatic (2 mo) R6/2 mice and age-matched WT mice. B. At 2 mo the burst numbers were increased, similar to presymptomatic animals. Spontaneous firing rates were not different. C. The average CVs were not different between WT and R62 mice. This was due to the fact that two populations of cells could be distinguished in R6/2 mice, some with low CV values and some with high CV values. Proportionately, more R6/2 neurons had high CV values. In addition, about 20% of neurons displayed membrane oscillations consisting of rhythmic depolarizations and bursts followed by hyperpolarizations. This unique firing pattern was not observed in cells from WT mice.

Fig. 4

GPe neurons in R6/2 and WT mice respond differently to small, prolonged depolarizing current injections. The traces show responses of GPe neurons to 25 pA depolarizing current steps of 1500 ms duration in 1 mo (A) and 2 mo (B) mice. (C) Bar graphs summarize the number of spikes per step and the CV (D) of inter-spike intervals in R6/2 mice and age-matched WTs. Asterisks above the bars indicate p<0.05.

Fig. 5

GPe neurons in slices from symptomatic R6/2 and WT mice respond differently to BIC (20 μM). Panels in A show the recorded cells filled with biocytin. B. Spontaneous firing of WT and R6/2 neurons during control (ACSF) conditions. C. In the WT cell BIC reduced the firing frequency of the GPe neuron. In contrast, in the cell from the R6/2 mouse BIC induced rhythmic bursts of APs.