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The role of astrocytic CD44 protein in epileptogenesis : PhD thesis
Creator: Contributor:Dzwonek, Joanna (1971- ) : Supervisor
Publisher:Nencki Institute of Experimental Biology PAS
Place of publishing: Date issued/created: Description:118 pages : illustrations ; 30 cm ; Bibliography ; Summary in Polish
Degree name: Degree discipline : Degree grantor:Nencki Institute of Experimental Biology PAS ; degree obtained: 10.10.2025
Type of object: Subject and Keywords:Astrocytes ; Epilepsy ; CD44 ; Seizure ; Synapses ; TLE
Abstract:
Epilepsy is a widespread neurological disorder affecting millions worldwide, with temporal lobe epilepsy (TLE) being its most common drug-resistant form. Current treatments primarily target neuronal excitability, neglecting the significant contributions of glial cells, particularly astrocytes, in epilepsy progression. CD44, a cell-surface glycoprotein involved in cell adhesion, neuroinflammation, and synaptic plasticity, is highly upregulated in epilepsy models. This thesis investigates the role of astrocytic CD44 in epileptogenesis, aiming to elucidate its involvement in seizure development, hippocampal structural remodeling, and synaptic alterations. The central research question addresses whether astrocytic CD44 contributes to TLEʹs pathophysiological changes and whether its modulation could influence disease progression. To explore this question, an astrocyte-specific CD44 knockout mouse model was generated using the Cre-loxP system. The kainate (KA) model of temporal lobe epilepsy was employed to induce status epilepticus, replicating TLE-like pathologies. Advanced methodologies were applied, including immunohistochemistry for assessing reactive astrogliosis, mossy fiber sprouting and granule cell dispersion, Western blot analysis for protein expression, and serial block-face electron microscopy (SBEM) for high-resolution examination of synaptic ultrastructure. Electroencephalographic (EEG) recordings further characterized seizure patterns and severity in CD44-depleted mice compared to controls. This comprehensive approach enabled the assessment of astrocytic CD44ʹs role across molecular, cellular, and systemic levels in epileptogenesis. The thesis findings demonstrate that astrocytic CD44 deletion influences both seizure patterns and hippocampal remodeling in a KA-induced model of TLE. Specifically, CD44- deficient mice showed a reduction in the frequency of behavioral seizures but an increase in electrographic non-convulsive episodes detectable only via EEG. While CD44 deletion did not significantly affect the latency to the first spontaneous seizure or the severity of convulsive seizures, it reduced hallmark structural changes of epileptogenesis, including reactive astrogliosis, mossy fiber sprouting, and granule cell dispersion. SBEM analyses showed increased dendritic spine number, reduced postsynaptic density size, and decreased astrocytic ensheathment in the CD44-depleted epileptic brain compared to controls. These findings underscore the essential role of astrocytic CD44 in preserving synaptic integrity and stability during epileptic insults. These results suggest that astrocytic CD44 plays a pivotal role in hippocampal remodeling and seizure propagation. By attenuating pathological astrocyte responses, CD44 deletion may mitigate some of the structural changes associated with TLE, positioning CD44 as a potential therapeutic target. This work underscores the importance of astrocyte-driven mechanisms in epilepsy and advocates for a broader perspective in designing future treatments, integrating neuronal and glial contributions to disease progression.
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Copyright holder:Publication made available with the written permission of the author
Digitizing institution:Nencki Institute of Experimental Biology of the Polish Academy of Sciences
Original in:Library of the Nencki Institute of Experimental Biology PAS
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