Neurodevelopmental disorders (NDDs) are a broad group of conditions characterized by abnormal development of the nervous system that includes intellectual disability and autism spectrum disorders. NDDs are pervasive, lifelong, and increasing in prevalence, yet neither targeted pharmacological nor precision medicine therapies are currently available. This unmet need is in large part due to the complex and relatively unknown etiology of many NDDs. Multiple genetic loci, in combination with exposure to environmental risk factors during critical periods of development, contribute to both NDD susceptibility and symptom severity. In an effort to improve our understanding of NDD etiology, as well as help develop effective treatments, we used Sprague Dawley rats to examine the effects of two environmental risk factors and one causal genetic mutation on behaviors and neurobiological outcomes relevant to NDDs. While the mouse has predominated in recent decades as the species of choice for modeling NDDs, we sought to take advantage of the broader and more nuanced social communication repertoire of the rat. Therefore, we measured effects on a variety of behavioral domains including motor and cognition and gave particular focus to social and communication behaviors. Chapter 1 serves as an introduction to the study of social communication in rodent models of NDDs and provides detailed rationales behind many of the assays utilized in subsequent chapters. Chapters 2 and 3 investigate environmental factors that have been associated with increased risk for NDDs: air pollution and pesticides, respectively. Our findings support the hypothesis that developmental exposure to heavily trafficked roadways, or to the commonly used pesticide chlorpyrifos, increases NDD risk. Then, Chapters 4 and 5 characterize a novel genetic rat model of the NDD Angelman Syndrome, which is caused by dysfunction of the gene UBE3A (ubiquitin protein ligase E3A). We discovered that the Ube3a deletion rat model of Angelman Syndrome recapitulated many of the core behavioral and neurobiological phenotypes of the disorder, including elevated expression of positive affect signals, and thereby utilized the rat model in Chapter 6 to test the efficacy of a candidate therapeutic, insulin-like growth factor 2. Although treatment with insulin-like growth factor 2 failed to rescue the model’s deficits, the outcome measures used were robust and reproducible, indicating that the Ube3a deletion rat offers a strong preclinical model of Angelman Syndrome. Finally, Chapter 7 investigates a leading-edge “gene therapy-like” antisense oligonucleotide treatment in the rat model of Angelman Syndrome. Multiple clinical trials are currently evaluating antisense oligonucleotide therapies in humans with Angelman Syndrome and, while they have demonstrated remarkable efficacy, serious adverse reactions have been observed. By identifying an antisense oligonucleotide with molecular efficacy in the rat and delivering it via the brain, the cisterna magna, and lumbar puncture, we established a paradigm through which to elucidate the pathophysiology underlying the adverse clinical reactions. Taken together, this research advances our understanding of the complex etiology of NDDs, represents significant progress in modeling NDDs preclinically, and provides insights with direct implications to the ongoing pursuit of pharmacological treatments targeted to NDDs.