Metabotropic Glutamate Receptor 2/3 Activation Improves Motor Performance and Reduces Pathology in Heterozygous zQ175 Huntington Disease Mice

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

“…There is growing evidence that sex may influence HD phenotype and neuropathology in HD rodent models and patients (Dorner et al, 2007;Bode et al, 2008;Zielonka et al, 2013). We recently showed that activation of mGluR2/3 in male and female HD mice led to differential regulation of cell signaling pathways and there are sex-specific differences in cell signaling mechanisms contributing to the pathogenesis of HD (Li et al, 2021). More importantly, we have also reported sex-specific signaling of mGluR5 in AD mice (Abd-Elrahman et al, 2020a;Abd-Elrahman and Ferguson, 2022).…”

“…We have previously reported a similar reduction in apoptotic neuronal loss and mHtt aggregates in male zQ175 mice that was attributed to reactivation of a ZBTB16-dependent autophagy pathway that facilitates the clearance of mHtt aggregates from the striatum (Abd-Elrahman et al, 2017). However, ZBTB16 autophagic pathway is regulated in a sex-specific manner in zQ175 and AD mice and therefore it is likely that the mechanisms underling such reduction in mHtt load and neuronal loss after mGluR5 antagonism are different between both sexes (Abd-Elrahman et al, 2020a;Li et al, 2021). Further investigation in the mechanism(s) underlying such reduction in mHtt pathology in CTEP-treated female zQ175 mice is required in the future.…”

“…We have previously shown that male heterozygous zQ175 mice at 12 months of age have significant deficits in both motor and cognitive functions that can be reversed by 12-week treatment with CTEP (Abd-Elrahman et al, 2017;Li et al, 2021). Here, we find that both male and female heterozygous zQ175 mice present with significant and comparable impairments in their grip strength and motor coordination that are consistent with previous findings by our group and others using the same mouse model (Menalled et al, 2012;Smith et al, 2014;Abd-Elrahman et al, 2017;Li et al, 2021). We also show that the short (4 weeks) and the long (12 weeks) treatment paradigms are to a great extent equally effective in reversing impairments in grip force and motor coordination of male zQ175 mice during rotarod test.…”

“…Slide were scanned using a Leica Aperio Slide scanner at 20× and the number of EM positive aggregates, NeuN or Iba1 positive cells were counted in representative 300 × 300 µm 2 areas of the striatum. Experimenters were blinded to analysis and six sections per mouse were analyzed and for each section two ROIs in the striatum were quantified using the cell counter tool in ImageJ (Abd-Elrahman et al, 2017, 2020b, 2021aLi et al, 2021).…”

G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

“… 313 In the mouse model, activating mGluR2 and mGluR3 could enhance limb coordination by attenuating the generation of huntingtin aggregate. 316 mGluR2 and mGluR3 demonstrate protective effects on the nigrostriatal system, which restores functional deficits in Parkinson’s disease rat model. 317 , 318 Overexpression of mGluR2 in the neocortical layers, cerebellum, striatum, hippocampus, and thalamus/hypothalamus could build up glutamate-mediated excitotoxicity and promote Huntington’s disease progression.…”