INVESTIGATING STRUCTURAL PLASTICITY AND PERINEURONAL NETS IN THE HIPPOCAMPUS AND DORSAL STRIATUM

Abstract

My dissertation work investigates dentate gyrus and dorsal striatum-dependent plasticity, specifically to better understand inhibitory neurons and perineuronal nets (PNNs), specialized extracellular matrix structures. These structures have been studied extensively within the developing visual cortex and are typically thought of as molecular restraints on structural and synaptic plasticity, but it is unknown what role, if any, PNNs play in regions exhibiting high degrees of experience-dependent plasticity throughout adulthood.

In the dentate gyrus, we investigated adult-born granule cell (abGC) projections onto GABAergic inhibitory parvalbumin (PV+) interneurons, many of which are enwrapped in PNNs, and discovered that abGC mossy fibers and boutons are more often associated with PV+PNN+ interneurons. These results, while unexpected, suggest a more complex region-specific role for PNNs in the adult mammalian brain.

To further investigate this possibility, we turned to the dorsal striatum, a region we have demonstrated exhibits experience-dependent structural plasticity in medium spiny neurons (MSNs). To understand how PNNs influence inhibitory signaling and linked behaviors, we examined PNN-expression in the dorsomedial striatum (DMS) of four mouse strains known to lack behavioral flexibility and exhibit robust phenotypes for excessive repetitive behavior. Across all strains, we observed consistent over-expression of PNNs surrounding PV+ interneurons, further implicating PNNs involvement in mechanisms of inhibitory plasticity. Furthermore, we found that reducing PNN-expression subsequently reduces excessive repetitive behaviors. To characterize the effects of increased PNNs on inhibitory signaling, we investigated various electrophysiological and structural properties of DMS MSNs. Mice with increased PNNs showed decreased MSN dendritic spines and altered inhibitory signaling compared to healthy controls, and while reduction of DMS PNNs altered inhibitory signaling, it did not “normalize” it. These findings additionally suggest that an overabundance of PNNs in the DMS prevent adaptive disengagement from repetitive behaviors, potentially through abnormal inhibitory signaling, but further studies are required to identify the mechanisms in which PNNs might gate this behavior.

These studies taken together demonstrate that PNNs play complex roles that differ depending on brain region; hippocampal PNNs participate in structural plasticity via connectivity from abGCs, and conversely, DMS PNNs are related to mechanisms of behavioral rigidity in mouse models of excessive repetitive behaviors.