Plasma Membrane Citrate Transporter (SLC13A5) Mutations Produce Heterogeneous Epileptiform Profiles in the Mouse Model
Abstract number :
3.021
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2022
Submission ID :
2205153
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:28 AM
Authors :
Kelvin De Leon, BA – Brown University;
Rationale: Mutations in the SLC13A5 gene, which encodes a plasma membrane citrate transporter, result_x000D_
in a newly diagnosed form of genetic epilepsy termed early infantile epileptic encephalopathy. Neonates with mutations suffer multi-focal seizures, and subsequently develop cognitive and behavioral deficits. Human genetics has identified commonly occurring missense mutations which greatly outnumber deletion mutations, which suggests heterogeneity in pathogenicity of the mutations; but it is not known how distinct genetic mutations affect disease presentation and seizure severity.
Methods: We are addressing this question by characterizing an array of SLC13A5 mutant mouse models carrying: (1) ablation of its endogenous murine Slc13a5 gene (knockout), (2) the most common patient mutation, the G222R point mutation (equivalent to the human mutation G219R), and (3) the second most common patient mutation, the T230M (equivalent to the human mutation T227M).
Results: Our preliminary data indicate that homozygous Slc13a5 knockout mouse shows abnormal epileptiform electroencephalogram (EEG) profiles, while G222R and T230M show significantly more severe epileptiform activity. The G222R heterozygous mice uniquely show electrographic seizures. Preliminary histopathology reveals differential interneuron reduction in the cortex and hippocampus between the knockout and G222R, with the G222R additionally showing oligodendroglia loss and astroglial reactivity. The knockout has shown reduced excitatory and inhibitory postsynaptic activity, suggestive of reduced neurotransmitter levels. Hippocampal neurons in the knockout also show a reduced rheobase which leads to an increased ability to fire action potentials.
Conclusions: These results are consistent with our interpretation that SLC13A5 loss of function causes epilepsy via altered neurotransmitter levels, and that specific missense mutations are associated with increased pathogenicity which exacerbate neuronal hyperexcitability.
Funding: This work is supported by 3R01NS104428-03S2 (KDL, JSL) and a Carney Institute for Brain Science Innovator award (JSL, SLH).
Basic Mechanisms