Abstract: Angelman syndrome (AS) is a genetic disorder occurring approximately one in every 15,000 births. It is characterized by severe intellectual disability, seizures, difficulty speaking and ataxia. The gene responsible for AS was identified as UBE3A and encodes for E6AP, an E3 ubiquitin ligase. A unique feature of this gene is that it undergoes maternal gene imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal allele. Currently, the specific molecular mechanisms of E6AP action that lead to cognitive disruption in AS is not defined and this has likely contributed to lack of therapeutics. It has been shown in AS patients and the AS mouse, that the extracellular matrix protein Reelin (which modulates nearly all of the molecular components listed above) is significantly reduced. More important to this study, Reelin supplementation can recover the phenotype of AS mice from a single intracerebroventricular (ICV) protein injection. However, due to a lack of small molecule agonists for Reelin signaling, there is an absence of studies exploring effects of long-term increased Reelin signaling as a potential therapeutic for AS. In order to address this, we generated a novel small active Reelin construct that can be packaged into an adeno-associated virus (AAV) vector to achieve long-term elevated Reelin signaling within the brain. We demonstrate that this fragment exhibits the same biological effects as full-length Reelin, as exhibited by behavioral rescue in a mouse model of Fragile X syndrome (FXS) using both protein and AAV delivery approaches. We previously shown that a rAAV Ube3a gene replacement therapy was successful in rescuing some cognitive impairments in AS mice but did not fully recover long-term potentiation (LTP) deficits or improve motor deficits. With current viral vectors it is not feasible in humans or even animal models to transduce all neurons within the brain, which may limit the effectiveness of gene therapy with cellular proteins such as E6AP. Our new approach offers the distinct advantage of using the secreted Reelin construct, which can diffuse from a subset of transduced cells to achieve a broader distribution within the brain. We hypothesize this Reelin gene therapy approach will rescue synaptic plasticity and cognitive deficits in the AS rat. We will test our hypothesis with the following aims. Aim 1: rAAV9-R36 rescues cognitive deficits in AS rats. Aim 2: rAAV9-R36 improves electrophysiology deficits in AS rats. With therapeutic interventions currently lacking for AS, our unique Reelin analog offers a novel therapeutic perspective to improve cognition in AS.