ORCID
0000-0002-2246-0636
Date of Award
2025
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Pharmacology
First Advisor
Jeremy Barry
Abstract
Mutations in the KCNT1 gene result in GOF effects, resulting in various forms of developmental encephalopathies and in some cases cognitive deficits. This GOF has been elucidated in the animal model from the gene, cell and synapse levels in relation to seizure outcomes, strongly indicating that Kcnt1 mutation primarily effects circuit networks as a form of interneuronopaty most strongly affecting somatostatin positive (SST+) interneurons. We hypothesized that cognitive deficits in this model are hippocampal in origin. We first trained animals (WT, YH-HET, YH-HOM) on the active avoidance task on a rotating arena as a test of hippocampal-dependent spatial cognition. In these same animals we used high-density laminar silicon probes (H3, Cambridge Neurotech) to investigate the coordination of cortico-hippocampal activity along the CA1 and DG somatodendritc axis. We further hypothesized that both cognitive deficits and pathological oscillations in YH animals would stem from interneuronopathy and dysregulation of these cortico-hippocampal inputs. In comparison to WT, we found cognitive deficits in YH-HOM and YH-HET mice, where the YH-HOM mice in particular showed no improvement in performance by day, receiving the same number of shocks and spending equal time in the shock zone on days 1 and 2. We also measured hippocampal theta and gamma properties as a function of cell layers and cortico-hippocampal synaptic inputs as an indicator of the efficacy of synaptic regulation by hippocampal interneurons. In YH-HOM mice we show consistent decreases in mean theta (4-12Hz), mean slow gamma (30-50), mean medium gamma (70-90) frequencies, and shifts in the amount of current source density (CSD) and voltage amplitude as a function of depth relative to both WT and YH-HET. Lastly, in YH-HOM mice we showed several examples of interictal epileptiform discharges (IEDs) where we used CSD measures to indicate hilar origins of these epochs of cortico-hippocampal hypersynchrony. Mirroring this result, we recorded an instance of generalized tonic-clonic seizure where a hilar IED progressed to a cortico-hippocampal seizure. Taken together, all results support our hypothesis that pathological signal discoordination and resultant hypersynchrony in the Kcnt1 GOF model are a result of synaptic dysregulation by hilar SST+ interneurons.
Language
en
Number of Pages
54 p.
Recommended Citation
Marchand, Dylan Harrison, "Characterization Of Network Inhibition And Cognitive Deficit In The Kcnt1 Gain Of Function Model Of Developmental Epileptic Encephalopathy" (2025). Graduate College Dissertations and Theses. 2145.
https://scholarworks.uvm.edu/graddis/2145