The hippocampus is one of the most extensively studied brain regions and plays a critical rolein emotional regulation, spatial reasoning, and learning and memory. This structure is involved in a number of neuropsychiatric disorders including mood disorders, schizophrenia, epilepsy, and Alzheimer’s disease. Gene expression alterations in the hippocampus are frequently observed in the context of these disorders as either causal or consequential to the diseased state making the hippocampus a potentially desirable target for gene-therapy interventions. In this thesis, mechanisms to modify gene expression in the hippocampus are explored with the goal of informing gene therapy development. Short hairpin RNAs are used to elucidate the role of Homer1b/c in learning and memory and the prevention of age-associated cognitive decline. Single nuclei RNA sequencing (snRNA-seq) methods are next employed to characterize the impacts of App editing in a mouse model of Alzheimer’s disease. Finally, the delivery of gene editing machinery to hippocampus are profiled using snRNA-seq with a CRISPR-Cas9 nanocapsule. These studies thoroughly characterize cell-type specific responses to this novel nanocapsule delivery system for gene editing in the hippocampus. Altogether, the data presented here contribute to the understanding of disease etiology within the hippocampus and advance the field of gene-therapy-based therapeutics by informing best practices for safety and efficacy evaluation.