Effect of Extracellular Citrate on Neuronal Excitability in SLC13A5 Epilepsy
Abstract number :
3.018
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2024
Submission ID :
583
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Alice Lin, BS – Brown University
Kelvin De Leon, PhD – Brown University
Haruki Higashimori, PhD – Brown University
Alex Zeng, HS – Brown University
Isabella Yoo, HS – Brown University
Daniel Cheong, HS – Brown University
Elena Kurov, HS – Brown University
Stephanie Torres, BS – Brown University
Li-Jin Chew, PhD – Brown University
Judy Liu, MD, PhD – Rhode Island Hospital
Rationale: SLC13A5 epilepsy, or developmental epileptic encephalopathy 25 (DEE25), is caused by mutations in SLC13A5, a sodium-citrate transporter. Neonates with mutations in SLC13A5 are affected by multi-focal seizures and subsequently develop cognitive and motor impairments. SLC13A5 regulates intracellular citrate levels and is known to be expressed in the brain, but the exact relationship between citrate levels, as regulated by SLC13A5, and epileptiform activity is unclear.
Methods: To investigate the effect of SLC13A5 loss of function, which may lead to chronic systemic increases of citrate levels, we performed 72-hour video EEG recording in wild-type (WT), full-body endogenous murine SLC13A5 knockout (KO), liver-specific endogenous murine SLC13A5 knockout (Albumin-Cre; SLC13A5) mice, and brain-specific endogenous murine SLC13A5 knockout (Nestin-Cre; SLC13A5) mice. To study how acute increases in citrate levels affect neuronal activity, we performed whole-cell patch clamp electrophysiology in layer II/III of the somatosensory cortex of wild-type mice while varying extracellular citrate concentrations.
Results: We saw increased interictal spiking by video EEG of both full-body SLC13A5 knockout and liver-specific SLC13A5 knockout mice (Figure 1). Our preliminary data shows that increased extracellular citrate levels lead to increased excitability in excitatory cells of wild-type SLC13A5 knockout mice (Figure 2).
Conclusions: Overall, we found circuit-level changes after increasing citrate levels, both acutely and chronically, in mice with varying expression patterns of SLC13A5. These results are consistent with our hypothesis that increased citrate levels lead to neuronal hyperexcitability. This work explores one potential mechanism by which SLC13A5 dysfunction may lead to epilepsy.
Funding: This work was supported by 1R01NS131865-01.
Basic Mechanisms