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

Abstract

Huntington’s disease (HD) is a heritable neurological disorder that affects cognitive and motor performance in patients carrying the mutated huntingtin (HTT) gene. In mouse models of HD, previous reports showed a significant increase in spontaneous GABA A receptor-mediated synaptic activity in striatal spiny projection neurons (SPNs). In this study, using optogenetics and slice electrophysiology, we examined the contribution of γ-aminobutyric acid (GABA)-ergic parvalbumin (PV)- and somatostatin (SOM)-expressing interneurons to the increase in GABA neurotransmission using the Q175 (heterozygote) mouse model of HD. Patch clamp recordings in voltage-clamp mode were performed on SPNs from brain slices of presymptomatic (2 months) and symptomatic (8 and 12 months) Q175 mice and wildtype (WT) littermates. While inhibitory postsynaptic currents (IPSCs) evoked in SPNs following optical activation of PV- and SOM-expressing interneurons differed in amplitude, no genotype-dependent differences were observed at all ages from both interneuron types; however, responses evoked by either type were found to have faster kinetics in symptomatic mice. Since SOM-expressing interneurons are constitutively active in striatal brain slices, we then examined the effects of acutely silencing these neurons in symptomatic mice with enhanced Natronomonas pharaonis halorhodopsin (eNpHR). Optically silencing SOM-expressing interneurons resulted in a greater decrease in the frequency of spontaneous IPSCs (sIPSCs) in a subset of SPNs from Q175 mice compared to WTs, suggesting that SOM-expressing interneurons are the main contributors to the overall increased GABA synaptic activity in HD SPNs. Additionally, the effects of activating GABA B and cannabinoid (CB1) receptors were investigated to determine whether these receptors were involved in modulating interneuron-specific GABA synaptic transmission and if this modulation differed in HD mice. When selectively activating PV- and SOM-expressing interneurons in the presence of the CB1 receptor agonist WIN-55,212, the magnitudes of the evoked IPSCs in SPNs decreased for both interneuron types although this change was less prominent in symptomatic Q175 SPNs during SOM-expressing interneuron activation. Overall, these findings show that dysfunction of SOM-expressing interneurons contributes to the increased GABA synaptic activity found in HD mouse models and that dysregulation of the endocannabinoid system may contribute to this effect.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…In addition, CB1 is downregulated in Huntington's [180,181]. GAT229 (10 mg/kg/day), a CB1 PAM, positively affected motor functions and gene expression, as well as delayed the onset of symptoms in the mice model of Huntington's disease [182].…”

Cortical and Striatal Circuits in Huntington’s Disease

“…Even though unchanged in numbers, other types of interneurons are also likely to be functionally affected in HD (Reiner and Deng, 2018). Recent studies started tackling the contributions of different interneuron types using genetic targeting and circuit manipulation tools (Cepeda et al, 2013;Holley et al, 2015Holley et al, , 2019bTanimura et al, 2016). Thus, optogenetic silencing of SST-positive interneurons [also referred to as low-threshold spiking (LTS) interneurons] in brain slices suggested a major contribution of this cell type to the increased GABAergic inhibition in symptomatic zQ175 and R6/2 mice (Holley et al, 2019b).…”

“…Recent studies started tackling the contributions of different interneuron types using genetic targeting and circuit manipulation tools (Cepeda et al, 2013;Holley et al, 2015Holley et al, , 2019bTanimura et al, 2016). Thus, optogenetic silencing of SST-positive interneurons [also referred to as low-threshold spiking (LTS) interneurons] in brain slices suggested a major contribution of this cell type to the increased GABAergic inhibition in symptomatic zQ175 and R6/2 mice (Holley et al, 2019b). In addition, the feedback inhibitory connections between SPNs are also partially severed, and their pattern is altered in HD mice, with a substantial number of abnormal bidirectional connections between SPN pairs (Cepeda et al, 2013).…”

Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

“…This sub-family of GABA A Rs seems to be implicated in several neurological diseases [47] and may affect seizure susceptibility [48] thus making them an interesting target for new pharmacological compounds. Indeed, GABA A Rs dysfunction is involved in epileptic disorders [49], drug addiction [50], Huntington disease [51], chronic stress, and anxiety [52]. More specifically, GABA A Rs undergo structural and functional alterations due to a significant change in subunit composition both in animal models of temporal lobe epilepsy (TLE) [53] and in pharmaco-resistant TLE patients, partially explaining the increased cerebral network excitability [54].…”