Vermudez, S. A. D. | Search bioRxiv

bioRxiv2025

Profiling metabotropic glutamate receptor 7 expression in Rett syndrome: consequences for pharmacotherapy

We have reported that levels of metabotropic glutamate receptor 7 (mGlu7) are dramatically decreased in brain samples from Rett syndrome patients carrying truncation mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene. Additionally, we identified decreases in mGlu7 levels in Mecp2+/- female mice and demonstrated that administration of a positive allosteric modulator (PAM) with activity at mGlu7 corrected deficits in cognitive, social, and respiratory domains. Here, we expanded our studies to a larger cohort of RTT samples covering a range of mutations and evaluated expression of the three widely expressed group III mGlu receptors (mGlu4,7 and 8). We found significant decreases in mGlu7, but not mGlu4 or mGlu8, mRNA expression across this larger cohort; additionally, we identified a previously unknown and robust correlation in the expression of mGlu4 and mGlu8 in control individuals. Stratification of RTT patients into individuals with mutations that are clinically correlated with severe versus mild disease revealed statistically significant decreases in mGlu7 expression only in patients with mutations that induce more severe symptoms. We then administered the PAM VU0422288 to mice modeling the mild R306C mutation (Mecp2R306C/+) and found a significant reduction in apneas induced by VU0422888 administration despite no decreases in mGlu7 expression in the brainstem or cortex. These results provide the first evidence of potentially broad utility for mGlu7 PAMs in reducing apneas in RTT patients.

neuroscience↗

bioRxiv2023

Sex differences in seizure presentation in Dravet syndrome model mice, Scn1a+/-

Dravet syndrome (DS) is an epileptic encephalopathy mostly due to haploinsufficiency of the SCN1A voltagegated sodium channel subunit. Disease presentation (i.e., severe seizures and early life mortality) is highly recapitulated in mice haploinsufficient in Scn1a (Scn1a+/-). However, phenotypic characterization in Scn1a+/- mice in a sex and temporal manner is limited. Given the reliance of mouse models for studying disease pathophysiology and for the development of novel treatments, we tested whether mortality and seizure morbidity differed among young and adult male and female Scn1a+/- animals in the F1 hybrid C57x129S6 background. We found increased mortality in female Scn1a+/- mice regardless of age compared to their male counterparts (n = 120-125 mice/sex; p < 0.05). Interestingly, long-term video EEG recordings revealed the opposite for morbidity as seizure frequency and severity were escalated in adult male Scn1a+/- animals (n = 21-30 mice/sex; p < 0.05 or p < 0.01). Adult female Scn1a+/- mice, however, are more hyperactive (p < 0.05), which could be related to sleep impairment and contribute to the increased mortality despite decreased seizure morbidity. Overall, the phenotypic presentation of Scn1a+/- mice is sex-dependent and may have translational implications for therapeutic drug discovery and basic biology understanding in DS. Short SummarySex differences in mortality and seizure morbidity are discovered in Scn1a haploinsufficient mice, Scn1a+/-, which faithfully model the epileptic encephalopathy disorder, Dravet syndrome (DS). Female Scn1a+/- mice die more across all ages, whereas adult male Scn1a+/- mice have more seizures that are of greater severity. Hyperactivity, as a proxy for sleep disruption, may contribute to the increased mortality in female Scn1a+/- mice despite decreased seizure incidence and severity. These sex-specific findings may have considerable impact in therapeutic discovery and development for DS and other SCN1A-related disorders.

neuroscience↗