Translational in vitro and in vivo Neurobiological and Behavioral Outcomes in Preclinical Models of Neurodevelopmental Disorders
eScholarship, University of California, 2023
Online
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Neurodevelopmental disorders (NDDs) are a large group of profound, debilitating, andlifelong conditions that impact the normal development of the central nervous system. Autismspectrum disorders, developmental delay, intellectual disability, and seizure disorders are amongthe clinical presentations of NDDs. Although a large population of patients live with thedevastating symptoms of NDDs, no corrective therapies are currently available, stemming fromthe complexity of etiologies and broad range of conditions. To broaden our understanding of themechanisms that contribute to NDDs and advance the discovery and development oftherapeutics, we used preclinical mouse models to establish clinically relevant outcome measuresand identify potential drug candidates. Chapter 1 introduces several strategies that address thechallenges of developing therapeutics for NDDs and provides rationale for studies detailed insubsequent chapters. Chapters 2 and 3 investigate one approach proposed in the introduction:drug repurposing. Following earlier successes of repurposed drugs for other NDDs, thesechapters focus on preclinical evaluation of several potential small molecule therapeutics fortreating Angelman Syndrome (AS); a disorder caused by the absence of the protein UBE3A inthe brain. We performed comprehensive behavioral pharmacology batteries, tailored to AS, usingan AS mouse model and wildtype littermates. We treated both genotypes with one of threeseparate compounds, paxilline, LB-100, and lovastatin, compared to vehicle. We found thatpaxilline and LB-100 did not exert positive rescue effects in the motor or cognitive behavioraldomains. However, lovastatin treatment of AS mice exhibited an improvement to motor abilitywhen we assessed gait using an automated treadmill system, providing promising evidence thatthis treatment could have potential in the clinic. Chapter 4 examines in vitro and in vivotechniques for assessing potential drug candidates for the treatment of AS. We utilized the highlyiiiobjective and translational touchscreen operant chamber task for assessing cognition and thewhole-body plethysmography (WBP) task for assessing pulmonary physiology and applied thesemethods to the AS mouse model, compared to WT, sex-matched littermates. To better informour future behavioral pharmacology experiments, we established two in vitro assays to assess thestructure and electrophysiological properties of primary neurons derived from the AS mousemodel. Chapter 5 applies the lessons we learned from our research in Angelman Syndrome toanother NDD, SYNGAP1-related intellectual disability (SYNGAP1-ID). SYNGAP1-ID is adisorder caused by the reduction of SynGAP1 protein in the brain, resulting in symptoms such asintellectual disability, hyperactivity, and epilepsy. We performed comprehensive behavioralcharacterization of a Syngap1 mutant mouse model to understand the clinically relevantphenotypes and to identify translational biomarkers. Hyperactivity, increasedelectroencephalographic (EEG) signal and disruptions to sleep were observed in the mutantmouse, offering clinically relevant targets for future preclinical therapeutic testing. In addition,we utilized the in vitro electrophysiological assay of primary neurons established in Chapter 4 toconfirm similar hyperexcitability in both cultured neurons and recordings directly from thesurface of the brain of the Syngap1 mouse model, bridging the gap between in vitro and in vivoassays of neuronal function. Taken together, this body of research increases our understanding ofthe complex nature of NDDs and highlights the progress toward improving preclinicalbiomarkers to aid in the discovery and development of therapeutics for NDDs.
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Translational in vitro and in vivo Neurobiological and Behavioral Outcomes in Preclinical Models of Neurodevelopmental Disorders
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Autor/in / Beteiligte Person: | Fenton, Timothy Allen |
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Veröffentlichung: | eScholarship, University of California, 2023 |
Medientyp: | unknown |
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