Metabotropic Glutamate Receptor 5 Antagonism Reduces Pathology and Differentially Improves Symptoms in Male and Female Heterozygous zQ175 Huntington’s Mice

Abstract

Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder that leads to progressive motor and cognitive impairment. There are currently no available disease modifying treatments for HD patients. We have previously shown that pharmacological blockade of metabotropic glutamate receptor 5 (mGluR5) signaling rescues motor deficits, improves cognitive impairments and mitigates HD neuropathology in male zQ175 HD mice. Mounting evidence indicates that sex may influence HD progression and we have recently reported a sex-specific pathological mGluR5 signaling in Alzheimer’s disease (AD) mice. Here, we compared the outcomes of treatment with the mGluR5 negative allosteric modulator CTEP (2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4-yl]ethynyl]pyridine) in both male and female symptomatic zQ175 mice. We found that female zQ175 mice required a longer treatment duration with CTEP than male mice to show improvement in their rotarod performance. Unlike males, chronic CTEP treatment did not improve the grip strength nor reverse the cognitive decline of female zQ175 mice. However, CTEP reduced the number of huntingtin aggregates, improved neuronal survival and decreased microglia activation in the striatum of both male and female zQ175 mice. Together, our results indicate that mGluR5 antagonism can reduce HD neuropathology in both male and female zQ175 HD mice, but sex has a clear impact on the efficacy of the treatment and must be taken into consideration for future HD drug development.

Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling

“… 86 , 87 Further, activation of upstream complement cascade components as well as aberrant mGlu 5 R signaling have been identified as central to the pathology of Huntington’s disease, Parkinson’s disease, and multiple sclerosis. 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 Therefore, it will be critical for future studies to elucidate whether the pathological mGlu 5 R-NMDAR-C5aR1 signaling axis identified in our study underlies synapse deterioration in multiple brain disorders.…”

Amyloid-β1–42oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C3aR/C5aR signaling

“…Further, studies from in vitro and mouse models of these diseases have demonstrated the necessity of C3 and/or C5 for their pathology (Woodruff, et al, 2008; McGeer, Lee, & McGeer, 2017; Wang, Lee, Lee, Woodruff, & Noakes, 2017; Hammond, et al, 2020; Bourel, et al, 2021; Chen, Hu, Ding, Du, & Hu, 2021; Gregersen, et al, 2021; Lopez-Sanchez, et al, 2022). Interestingly, mGlu 5 R has separately been identified as an emerging therapeutic target in these complement-associated neurodegenerative diseases (Geurts, et al, 2003; Abd-Elrahman, et al, 2017; Bonifacino, et al, 2017; Doria, et al, 2018; Bonifacino, et al, 2019; Farmer, et al, 2020; Su, Wang, Han, & Shen, 2021; Zhang, et al, 2021; Azam, et al, 2022; Li, Colson, Abd-Elrahman, & Ferguson, 2022). We therefore speculate that the mGlu 5 R-NMDAR-C3aR/C5aR signaling axis identified in our study may be a common feature of many brain disorders.…”

Targeting the Type 5 Metabotropic Glutamate Receptor: A Potential Therapeutic Strategy for Neurodegenerative Diseases?

“…As in AD, the effects of mGlu 5 antagonism on HD pathology have been studied predominantly in male HD mice. Recent work compared the response of male and female zQ 175 mice to chronic treatment with CTEP ( Li et al, 2022 ). This study showed that improvements in motor and cognitive skills differed between the sexes.…”