Metabolic Underpinnings of SLC13A5 Epilepsy
Abstract number :
1.017
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2025
Submission ID :
927
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Alice Lin, BS – Brown University
Li-Jin Chew, PhD – Brown University
Alex Zeng, BS – Brown University
Elizabeth Nolan, BS – Brown University
Kirsten Whitley, BS – Brown University
Isaac Jin, HS – Brown University
Haruki Higashimori, PhD – Brown University
Judy Liu, MD, PhD – Department of Neurology, University of Texas Southwestern Medical Center, Dallas TX
Rationale: SLC13A5 Citrate Transporter Disorder (DEE25) is caused by mutations in SLC13A5, a sodium-citrate co-transporter. Neonates with mutations in SLC13A5 present with severe multi-focal seizures and subsequently develop cognitive and motor impairments. In humans, SLC13A5 is highly expressed in both the brain and the liver, and functions to regulate intracellular citrate levels. Currently, the effect of citrate on neuronal hyperexcitability, epileptogenesis, and disease progression in SLC13A5 Citrate Transporter Disorder is unclear.
Methods: To study the effect of SLC13A5 loss of function on epileptogenesis, we performed 72-hour video EEG recording in wild-type (WT), full-body SLC13A5 knockout (KO), liver-specific SLC13A5 knockout mice, and brain-specific SLC13A5 knockout mice. To understand the effect of SLC13A5 loss of function in varying tissues on citrate levels, we performed targeted metabolomics to measure citrate levels in the cerebrospinal fluid and plasma of WT, KO, liver-specific SLC13A5 knockout and brain-specific SLC13A5 knockout mice. To investigate how acute increases in citrate levels affect intrinsic neuronal hyperexcitability, we performed whole-cell patch clamp electrophysiology on regular-spiking cells in layer II/III of the somatosensory cortex of WT and KO mice with varying extracellular citrate concentrations.
Results: Our video-EEG results demonstrate that only liver-specific SLC13A5 knockout mice had increased seizure frequency (Figure 1). Our targeted metabolomics analysis revealed that citrate levels in the cerebrospinal fluid are elevated in full-body SLC13A5 knockout mice and brain-specific SLC13A5 knockout mice but are normal in liver-specific SLC13A5 knockout mice (Figure 1). Similarly, our whole-cell patch clamp data reveals no change in intrinsic properties in excitatory cells of WT and full-body SLC13A5 knockout animals upon administration of citrate (Figure 2).
Conclusions: Overall, we found neuronal hyperexcitability in SLC13A5-deficient animals to be correlated with liver-specific knockout of SLC13A5 rather than increased citrate levels in the cerebrospinal fluid. These results suggest that increased extracellular citrate levels do not cause the neurological symptoms seen in patients with SLC13A5 Citrate Transporter Disorder. Future directions include performing untargeted metabolomics to identify alternative metabolites that may be dysregulated, leading to neuronal hyperexcitability, as well as studying neuronal hyperexcitability in mice with SLC13A5 expression rescued in the liver. This work explores multiple mechanisms by which SLC13A5 deficiency may lead to epilepsy.
Funding: NIH Grant R01NS131865, NIH Grant F30NS141502, Blavatnik Family Foundation Fellowship, Sidney E. Frank Fellowship
Basic Mechanisms