All ETDs from UAB

Advisory Committee Chair

Lucas Pozzo-Miller

Advisory Committee Members

Linda Overstreet-Wadiche

Kazutoshi Nakazawa

Lawrence Sincich

Patricio O'Donnell

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Both the ventral hippocampus (vHIP) and medial prefrontal cortex (mPFC) are active participants in the neural circuitry activated by social interaction, and are both necessary for certain aspects of social behavior. Additionally, synaptic projections from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC) are implicated in several neuropsychiatric disorders. Using the Mecp2 knockout (KO) mouse model of Rett syndrome, an autism-associated disorder with network level deficits in the vHIP and mPFC as well as aberrant social behavior, we strove to determine the role of vHIP-mPFC in social behavior. Here, we show that the vHIP-mPFC projection is hyperactive in Mecp2 KO mice. Long-term excitation of mPFC-projecting vHIP neurons in wild-type mice impaired social memory, whereas their long-term inhibition in Mecp2 KO mice rescued social memory deficits. The extent of social memory improvement was negatively correlated with vHIP-evoked responses in mPFC slices, on a mouse-per-mouse basis. Acute manipulations of the vHIP-mPFC projection affected social memory in a region and behavior selective manner, suggesting that proper vHIP-mPFC signaling is necessary to recall social memories. In addition, we identified an altered pattern of vHIP innervation of mPFC neurons, and increased synaptic strength of vHIP inputs onto layer 5 pyramidal neurons as contributing factors of aberrant vHIP-mPFC signaling in Mecp2 KO mice. In summary, we demonstrate that the vHIP-mPFC projection regulates social memory in WT mice, and that its dysfunction causes social memory deficits in Mecp2 KO mice. Defining the synaptic bases of social behaviors provides insight and potential targets for therapies in psychiatric disorders associated with vHIP-mPFC dysfunction, such as autism and schizophrenia.

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