A Ketogenic Diet Mitigates Hippocampal Astrogliosis in Epileptic Brain
Abstract number :
2.004
Submission category :
10. Dietary Therapies (Ketogenic, Atkins, etc.)
Year :
2025
Submission ID :
385
Source :
www.aesnet.org
Presentation date :
12/7/2025 12:00:00 AM
Published date :
Authors :
Jae Hyouk Choi, PhD – University of California San Diego
Hugo Kim, PhD – University of California San Diego
Shuhe Wang, BS – University of California San Diego
Yueyang Cai, BS – University of California San Diego
Ananya Achanta, Undergraduate – University of California San Diego
Srija Pamujula, BS – University of California San Diego
Hamza Thange, Undergraduate – University of California San Diego
Matthew Shtrahman, MD, PhD – University of California San Diego
Presenting Author: Jong Rho, MD – Yale University School of Medicine
Rationale: While prior mechanistic investigations have examined the effects of the ketogenic diet (KD) and its metabolic substrates (such as beta-hydroxybutyrate or BHB) on synaptic transmission, few studies have explored a potential connection between astrocytic ion channels and seizure genesis. Moreover, it is unknown whether the KD can affect astrogliosis, a neuropathological finding in epileptic tissues derived from both humans and animal models. One essential function of astrocytes is spatial potassium buffering which influences passive potassium conductance (PPC), and when impaired, can result in neuronal hyperexcitability. Here, we asked whether the KD can influence astrogliosis and modulate astrocytic PPC in an established murine model of epilepsy.
Methods: We employed the clinically relevant Kcna1-null (KO) mouse model of developmental epilepsy utilizing a combination of immunohistochemical, molecular, and cellular electrophysiological techniques.
Results: We observed a significant increase in GFAP expression in KO mice fed a control diet compared to wild-type (WT) mice, and that the KD prevented this change. Furthermore, we noted a reduction in hippocampal astrocytic PPC in epileptic mice, whereas KD-treated KO animals exhibited nearly normal passive conductance levels. In this regard, we found that while Kir4.1, TREK-1 and TWIK-1 RNA expression levels were not significantly altered by KD treatment in either WT or KO mice, BHB appeared to only minimally affect Kir4.1-mediated currents in transfected HEK cells. Furthermore, bulk RNA-seq analysis of the various treatment groups revealed KD-induced down-regulation of factors linked to hippocampal astrogliosis.
Conclusions: In the present study, we demonstrate that the KD can mitigate hippocampal astrogliosis in the Kcna1-null (KO) mouse model of developmental epilepsy, and that the KD can protect against epilepsy-associated astrocytic PPC changes, underscoring a novel mechanism of action implicating extracellular potassium in its anti-seizure effects.
Funding: University of California San Diego
Dietary Therapies (Ketogenic, Atkins, etc.)