Neurodevelopmental disorders (NDDs) are a large group of profound, debilitating, andlifelong conditions that impact the normal development of the central nervous system. Autism spectrum disorders, developmental delay, intellectual disability, and seizure disorders are among the clinical presentations of NDDs. Although a large population of patients live with the devastating symptoms of NDDs, no corrective therapies are currently available, stemming from the complexity of etiologies and broad range of conditions. To broaden our understanding of the mechanisms that contribute to NDDs and advance the discovery and development of therapeutics, we used preclinical mouse models to establish clinically relevant outcome measures and identify potential drug candidates. Chapter 1 introduces several strategies that address the challenges of developing therapeutics for NDDs and provides rationale for studies detailed in subsequent chapters. Chapters 2 and 3 investigate one approach proposed in the introduction: drug repurposing. Following earlier successes of repurposed drugs for other NDDs, these chapters focus on preclinical evaluation of several potential small molecule therapeutics for treating Angelman Syndrome (AS); a disorder caused by the absence of the protein UBE3A in the brain. We performed comprehensive behavioral pharmacology batteries, tailored to AS, using an AS mouse model and wildtype littermates. We treated both genotypes with one of three separate compounds, paxilline, LB-100, and lovastatin, compared to vehicle. We found that paxilline and LB-100 did not exert positive rescue effects in the motor or cognitive behavioral domains. However, lovastatin treatment of AS mice exhibited an improvement to motor ability when we assessed gait using an automated treadmill system, providing promising evidence that this treatment could have potential in the clinic. Chapter 4 examines in vitro and in vivo techniques for assessing potential drug candidates for the treatment of AS. We utilized the highlyiii objective and translational touchscreen operant chamber task for assessing cognition and the whole-body plethysmography (WBP) task for assessing pulmonary physiology and applied these methods to the AS mouse model, compared to WT, sex-matched littermates. To better inform our future behavioral pharmacology experiments, we established two in vitro assays to assess the structure and electrophysiological properties of primary neurons derived from the AS mouse model. Chapter 5 applies the lessons we learned from our research in Angelman Syndrome to another NDD, SYNGAP1-related intellectual disability (SYNGAP1-ID). SYNGAP1-ID is a disorder caused by the reduction of SynGAP1 protein in the brain, resulting in symptoms such as intellectual disability, hyperactivity, and epilepsy. We performed comprehensive behavioral characterization of a Syngap1 mutant mouse model to understand the clinically relevant phenotypes and to identify translational biomarkers. Hyperactivity, increased electroencephalographic (EEG) signal and disruptions to sleep were observed in the mutant mouse, 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 to confirm similar hyperexcitability in both cultured neurons and recordings directly from the surface of the brain of the Syngap1 mouse model, bridging the gap between in vitro and in vivo assays of neuronal function. Taken together, this body of research increases our understanding of the complex nature of NDDs and highlights the progress toward improving preclinical biomarkers to aid in the discovery and development of therapeutics for NDDs.