Investigating Behavioral Changes Associated with Recombinant Adeno- Associated Virus - Mediated Gene Delivery in the Nervous System

Abstract

Recombinant adeno-associated viruses (rAAVs) have revolutionized neuroscience research and are the basis of approved human nervous system gene therapies. AAV is well-suited as a vector for gene delivery, in part due to its ease of transduction into CNS cell types and relatively low immunogenicity. However, a growing body of research suggests that rAAV can cause unwanted side effects in the nervous system, including cell death, loss of dendritic length and complexity, and changes in synaptic transmission. Preliminary data suggests that the AAV genome itself, not the encoded transgene, is sufficient to cause both dendritic loss and synaptic changes, raising the possibility that most if not all rAAVs could impact circuits. Given the widespread use of AAV in research, and its expanding role in the clinic, it is important to understand if AAV-induced circuit changes are associated with changes in perception, cognition, or behavior. In my thesis research, I investigated if AAV-mediated gene delivery was sufficient to cause behavioral changes in a rodent model. In the novel object recognition task, uninjected animals demonstrated preference for the novel object, indicating that they remembered encountering the other object. In contrast, the AAV-injected animals did not demonstrate a significant preference for the novel object. These differences between AAV-injected and uninjected animals were present when the task was performed in the dark or in the light, suggesting that it is not due to a specific sensory deficit, but rather that a fundamental lack of memory formation or recall may be to blame. The potential for behavioral effects of AAV are important to consider when performing behavioral research using AAV-mediated genetic manipulations, and when evaluating the side effects of nervous system-targeting gene therapies.