UC San Diego

Prion diseases are a group of fatal neurodegenerative disorders characterized by the accumulation of misfolded and aggregated prion protein in the central nervous system. Inhibitory interneuron and synapse loss have been shown to drive hyperexcitability in Alzheimer's disease, epilepsy, schizophrenia, autism, and Rett syndrome. The role of inhibitory interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs) in prion diseases remains unclear. This thesis aims to elucidate the role that inhibitory interneurons play in prion disease. Quantification of immunolabeled PV- and SST-INs in a novel knock-in model of prion disease reveals that loss of PV- and SST-INs within the hippocampus and motor cortex is variable and occurs only at terminal disease. Although inhibitory neurons are preserved in a genetic model of prion disease, hippocampal inhibitory synapse perturbations were detectable around post-natal day 20 (P20), in which there is a significant increase in inhibitory VGAT+ synapses. Overall, this study suggests that inhibitory interneuron loss occurs late in disease and is not likely an early driver, but is secondary to earlier changes like neuroinflammation, synapse loss, or other upstream changes in cellular prion protein (PrPC) signaling. Therefore, a comprehensive understanding of the intricate interplay between prion pathology and inhibitory interneuron dysfunction may hold promise for developing targeted therapeutic approaches to dampen aberrant excitatory circuitry and slow the progression of prion disease.