|About GSBS | FAQ | Job Opportunities | Search UMDNJ|
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.
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 Â-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 ChC¨GC 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.