Universität zu Köln

Bas, Timucin (2025). KCNT1-Associated Epileptic Encephalopathies in Mouse Models: Phenotypic Characterization and Targeted Therapeutic Interventions. PhD thesis, Universität zu Köln.

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Abstract

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by refractory seizures, cognitive deficits, and behavioral abnormalities. Among these, KCNT1-associated DEE are caused by gain-of-function (GoF) mutations in the KCNT1 gene, encoding the sodium-gated potassium channel KNa1.1 (Slack). These mutations disrupt neuronal excitability, leading to profound impairments in brain development and function. Despite the severity of these disorders, treatment options remain extremely limited, and there are no approved therapies specifically targeting KCNT1 mutations. This thesis investigates the pathophysiological mechanisms underlying KCNT1-associated epilepsy and evaluates potential therapeutic interventions using two novel knock-in mouse models harboring patient-derived KCNT1 mutations, p.I335N (KCNIN) and p.R950Q (KCNRQ), which exhibit distinct GoF properties. Comprehensive phenotypic characterization of these models revealed spontaneous generalized seizures, significant hippocampal pathology, and pronounced behavioral abnormalities. Histological analyses demonstrated reactive astrogliosis, enhanced perineuronal net density in the dentate gyrus, and elevated neuropeptide Y expression in the hippocampal mossy fibers, indicative of extensive hippocampal network remodeling. Behavioral experiments revealed increased locomotion, reduced anxiety-related behavior, and impaired memory performance. Electrocorticography (ECoG) recordings uncovered significant disruptions in sleep architecture and interictal network activity, including reductions in cortical theta power during both sleep and wakefulness. Together, these findings establish the face and construct validity of these mouse models for KCNT1-associated epileptic encephalopathies. To address the limited efficacy of existing treatment options, brain-permeable KCNT1 channel blockers were identified through high-throughput screening of FDA-approved compounds and validated on KCNT1 channels in vitro. Chronic treatment with these blockers in adult mice failed to ameliorate seizure phenotypes, highlighting the importance of targeting earlier developmental periods. Notably, treatment administered during the neonatal period increased the proportion of seizure-free animals but did not prevent the alterations in interictal network activity, emphasizing the need for therapeutic interventions that address the early stages of epileptogenesis. This study provides a detailed characterization of KCNT1-associated epilepsy models, elucidates their underlying pathophysiology, and highlights important challenges of developing therapies for these disorders. These findings underscore the urgent need for precision medicine approaches targeting developmental windows to address the unmet clinical need for effective treatments.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Bas, Timucin timucin.bas46@gmail.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-780703
Date:	2025
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Sonstiges > Experimentelle Neurophysiologie
Subjects:	Natural sciences and mathematics Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Epilepsy English Ion Channelopathies English Mouse Models English
Date of oral exam:	31 March 2025
Referee:	Name Academic Title Korotkova, Tatiana Prof. Dr. Bergami, Matteo Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/78070