Calcium Dysregulation and Compensation in Cortical Pyramidal Neurons of the R6/2 Mouse Model of Huntington’s Disease

J Neurophysiol. 2021 Sep 1. doi: 10.1152/jn.00181.2021. Online ahead of print.

ABSTRACT

Huntington’s disease (HD) is a fatal, hereditary neurodegenerative disorder that predominantly affects striatal medium-sized spiny neurons and cortical pyramidal neurons (CPNs). It has been proposed that perturbations in Ca²⁺ homeostasis could play a role in CPN alterations. To test this hypothesis, we used the R6/2 mouse model of juvenile HD at different stages of disease progression; presymptomatic, early symptomatic, and late symptomatic. We combined whole-cell patch clamp recordings of layer 2/3 CPNs with two-photon laser scanning microscopy to image somatic and dendritic Ca²⁺ transients associated with evoked action potentials (APs). We found that the amplitude of AP-induced Ca²⁺ transients recorded at the somata of CPNs was significantly reduced in presymptomatic and late symptomatic R6/2 mice compared to wildtype (WT) littermates. However, reduced amplitudes were compensated by increases in decay times, so that Ca²⁺ transient areas were similar between genotypes. AP-induced Ca²⁺ transients in CPN proximal dendrites were variable and differences did not reach statistical significance, except for reduced areas in the late symptomatic group. In late symptomatic mice, a specific store-operated Ca²⁺ channel antagonist, EVP4593, reduced somatic Ca²⁺ transient amplitude similarly in WT and R6/2 CPNs. In contrast, dantrolene, a ryanodine receptor (RyR) antagonist, and nifedipine, an L-type Ca²⁺ channel blocker, significantly reduced both somatic Ca²⁺ transient amplitude and area in R6/2 but not WT CPNs. These findings demonstrate that perturbations of Ca²⁺ homeostasis and compensation occur in CPNs before and after the onset of overt symptoms, and suggest RyRs and L-type Ca²⁺ channels as potential targets for therapeutic intervention.

PMID:34469694 | DOI:10.1152/jn.00181.2021