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"Selective plasticity of dentate parvalbumin-expressing interneurons in a model of experimental epilepsy: Implications for network excitability and rhythms"

Archana Proddutur
Biomedical Engineering Program
B.Tech 2008, Joginpally B.R. Engineering College, JNTU, India
M.S. 2010, New Jersey Institute of Technology, Newark, NJ

Thesis Advisor: Viji Santhakumar, M.D., Ph.D.
Associate Professor
Department of Pharmacology, Physiology and Neuroscience

Friday, December 8, 2017
10:00 A.M., MSB H609b


Temporal lobe epilepsy (TLE) is a disorder characterized by an abnormal increase in network excitability and alterations in oscillatory rhythms. Inhibitory dysfunction has been proposed to play a role in both these phenomena. Synaptically interconnected microcircuits of parvalbumin-positive interneurons that include fast-spiking basket cells (FS-BCs) and chandelier cells (ChCs) regulate dentate output and synchrony. This thesis examined how chemoconvulsive status epilepticus (SE) in a model of experimental epilepsy alter the functional characteristics of parvalbumin-expressing interneurons. In collaborative studies, morphologically identified BCs, were shown to have enhanced tonic GABA currents and depolarizing shift in GABA reversal following SE. Immunohistochemical analysis revealed post-SE increases GABAAR -subunit expression and a decrease in membrane expression of KCC2 transporters in FS-BC demonstrating the molecular basis for the physiological changes. Computational studies detailed in the thesis examined the network effects of post-SE changes in FS-BC tonic GABA currents, reversal potential and cell-specific reduction in reliability of synapses to FS-BCs. Specifically, effects of the physiological changes on dentate network excitability and rhythms were simulated using biophysically realistic large-scale dentate network models rigorously constrained by experimental data. The simulations predicted that, while individual changes may perturb excitability, the combination of post-SE modifications in FS-BCs appears to restore dentate network excitability. However, the alteration consistently compromised network rhythms known to be crucial for memory processing. Targeted examination of parvalbumin-expressing dentate cell types identified that PV-ChCs are morphologically and physiologically distinct from PV-BCs. PV-ChCs exhibit reduced intrinsic excitability as well as spontaneous excitatory and inhibitory synaptic drive after seizures. While reliability at ChCGC synapses are preserved, the above changes in intrinsic and synaptic physiology could reduce ChC recruitment during network activity and compromise ChC-dependent feed-forward inhibition of dentate output neurons after seizures. Together, the studies show that parvalbumin interneurons undergo cell-specific modifications following SE and could contribute to compromised network oscillations and contribute to memory and cognitive co-morbidities in epilepsy.

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