Biology subjects

Rotenberg, A.

Publications and source records attributed to Rotenberg, A..

3 recordsLinked to original sources

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↗

bioRxiv2021

Mosaic and non-mosaic pcdh19 mutation leads to neuronal hyperexcitability in zebrafish

Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called carrier males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. Evaluating zebrafish larvae for electrophysiological abnormalities, we observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/- and pcdh19-/- mutant larvae. Thus, we demonstrate that the key feature of epilepsy--network hyperexcitability--can be modeled effectively in zebrafish, even though overt spontaneous seizure-like swim patterns were not observed. Further, zebrafish with non-mosaic pcdh19 mutation displayed reduced numbers of inhibitory interneurons suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes.

neuroscience↗

bioRxiv2020

Novel genetic tools to model functional enzyme restoration in succinic semialdehyde dehydrogenase deficiency (SSADHD)

SSADHD is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the aldh5a1 gene), an enzyme essential for breaking down the inhibitory neurotransmitter{gamma} -aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA results in broad spectrum encephalopathy including developmental delay, ataxia, seizures and a risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy (ERT) or aldh5a1 gene transfer increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable cure for SSADHD. However, before testing SSADH restoration therapy in patients, we must consider its safety and feasibility in context of the unique SSADHD pathophysiology. Specifically, a profound use-dependent down-regulation of GABAA receptors in SSADHD indicates a risk that sudden SSADH restoration might diminish GABAergic tone and provoke seizures. Such risk may be mitigated by gradual, rather than abrupt, SSADH restoration, or by restoration that is confined to critical cell types and brain regions. We therefore describe early work to construct a novel SSADHD mouse model that allows on-demand SSADH restoration for the systematic investigation of the rate, timing and cell-specific parameters of SSADH-restoring therapies. We aim to understand the clinical readiness of specific SSADH restoration protocols on brain physiology for purposes of accelerating the bench to bed-side development of ERT or gene therapy for SSADHD patients.

neuroscience↗