Effect of Extracellular Citrate on Neuronal Excitability in Mouse Models of SLC13A5 Deficiency (DEE 25)
Abstract number :
2.487
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2023
Submission ID :
1376
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Alice Lin, BS – Brown University
Kelvin De Leon, BS – Brown University; Haruki Higashimori, PhD – Brown University; Sihan Chen, HS – University of Toronto; Alexander Zeng, HS – Brown University; Judy Liu, MD, PhD – Brown University
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), and liver-specific endogenous murine SLC13A5 knockout (Alb-Cre; SLC13A5) mice. To study how acute increases in citrate levels affect neuronal activity, we recorded local field potentials (LFPs) in region CA1 of the hippocampi of wild-type mice and full-body SLC13A5 knockout 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 an increased number of spikes in wild-type and, more profoundly, in full-body 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