Striatal GABAergic interneuron dysfunction in the Q175 mouse model of Huntington's disease

Abstract

The pathological hallmark of Huntington's disease (HD) is the massive loss of striatal and cortical neurons. Until recently, it was believed that striatal interneurons were spared from degeneration. This view has changed after the demonstration that parvalbumin (PV)‐expressing interneurons also are vulnerable in humans. Here we compared morphological and functional changes of striatal fast‐spiking interneurons (FSIs) and low‐threshold spiking (LTS) interneurons in the Q175 mouse model of HD at presymptomatic (2 months) and symptomatic (12 months) stages of the disease. Electrophysiological intrinsic and synaptic properties of FSIs were significantly altered in symptomatic mice compared to wild‐type (WT) littermates. Overall, FSIs became more excitable with disease progression. Sholl analysis also revealed a significant loss of dendritic complexity and excitatory synaptic inputs. The basic membrane and synaptic properties of LTS interneurons were similar in Q175 and WT mice regardless of disease stage. The resilience of LTS interneurons could be related to their sparsity of excitatory synaptic inputs compared with FSIs. However, in symptomatic mice, a subpopulation of LTS interneurons displayed an increase in action potential firing within oscillating bursts. Thus, we conclude that while both FSI and LTS interneurons demonstrate increases in excitability, the HD mutation differentially affects their membrane and synaptic properties as well as their ability to respond to compensatory challenges presented during the late stage of the disease. Alterations in GABAergic interneuron intrinsic activity and responsiveness to incoming signals may significantly affect SPN output thus contributing to abnormal motor movements in patients afflicted with HD.

Major Contribution of Somatostatin-Expressing Interneurons and Cannabinoid Receptors to Increased GABA Synaptic Activity in the Striatum of Huntington’s Disease Mice

“…ChR2 was selectively expressed in striatal PV- and SOM-expressing interneurons by stereotactically injecting a Cre-dependent AAV-ChR2-eYFP into WT and Q175 mice crossed with PV- and SOM-Cre mice, respectively (Figures 1A,C). Recordings from eYFP positive cells in PV-Cre (Figure 1B1) and SOM-Cre (Figure 1D1) mice showed distinct electrophysiological properties as previously reported (Tepper et al, 2010; Holley et al, 2019). Compared with SOM-expressing interneurons, PV-expressing interneurons were more hyperpolarized at rest, and displayed suprathreshold firing frequencies of 50–100 Hz.…”

“…There is growing evidence that GABA neurotransmission is abnormal in animal models of HD (Cepeda et al, 2004, 2010; Centonze et al, 2005; Andre et al, 2011; Dvorzhak et al, 2013; Indersmitten et al, 2015; Hsu et al, 2018). Further studies from our laboratory demonstrated alterations in intrinsic and synaptic properties in both FSIs and LTS interneurons which may contribute to the increased striatal GABA transmission (Cepeda et al, 2013; Holley et al, 2019). While there are multiple sources of GABA inhibition in the striatum of HD model mice, the underlying mechanisms are not well understood.…”

“…In symptomatic HD patients and mouse models, the number of GABAergic parvalbumin (PV)-expressing interneurons is decreased and their dendritic arborization is greatly diminished (Reiner et al, 2013; Simmons et al, 2013; Paldino et al, 2017; Holley et al, 2019). Furthermore, while large cholinergic and GABAergic somatostatin (SOM)-expressing interneurons appear to be spared in HD, both types of interneurons display altered physiology in symptomatic HD mice (Holley et al, 2015, 2019; Tanimura et al, 2016). These disease-related dysfunctions in individual cell populations add stress on striatal microcircuits leading to altered striatal output generally associated with abnormal movements.…”

“…There are three main types, low-threshold spiking (LTS) interneurons, which are SOM-, neuropeptide Y (NPY)-, and nitric oxide synthase (NOS)-expressing, fast-spiking (FS) PV-expressing interneurons and calretinin-expressing interneurons. All but the latter have been characterized in brains of healthy and HD mice (Tepper et al, 2010; Cepeda et al, 2013; Holley et al, 2019). Fast-spiking interneurons (FSIs) display fast-firing properties and mediate feed-forward inhibition, while the LTS interneurons fire spontaneously at lower frequencies and, in addition to GABA, they release neuromodulators that may have neuroprotective attributes (Kumar, 2008; Rajput et al, 2011).…”

Cortical and Striatal Circuits in Huntington’s Disease

“…In contrast to SPNs, most local interneurons are relatively spared in HD, with the exception of PV interneurons, which are reduced in numbers in human patients and R6/2 mice (Giampà et al, 2009;Reiner et al, 2013;Reiner and Deng, 2018). A detailed analysis of PV cells in the zQ175 mouse model furthermore uncovered changes in morphology, physiological properties, and connectivity (Holley et al, 2019a). A recent study combining activity manipulation of PV interneurons with simultaneous calcium imaging of PV cells and SPNs in freely moving mice pointed to the function of PV cells in facilitating execution of movement (Gritton et al, 2019); it is therefore tempting to speculate that dysfunction and loss of striatal PV interneurons may play a causal role in HD-related akinesia, a hypothesis still to be tested in HD model animals.…”