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Reversible synaptic adaptations in a subpopulation of murine hippocampal neurons following early-life seizures
Bo Xing, … , Delia M. Talos, Frances E. Jensen
Bo Xing, … , Delia M. Talos, Frances E. Jensen
Published January 16, 2024
Citation Information: J Clin Invest. 2024;134(5):e175167. https://doi.org/10.1172/JCI175167.
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Research Article Neuroscience Article has an altmetric score of 82

Reversible synaptic adaptations in a subpopulation of murine hippocampal neurons following early-life seizures

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Abstract

Early-life seizures (ELSs) can cause permanent cognitive deficits and network hyperexcitability, but it is unclear whether ELSs induce persistent changes in specific neuronal populations and whether these changes can be targeted to mitigate network dysfunction. We used the targeted recombination of activated populations (TRAP) approach to genetically label neurons activated by kainate-induced ELSs in immature mice. The ELS-TRAPed neurons were mainly found in hippocampal CA1, remained uniquely susceptible to reactivation by later-life seizures, and displayed sustained enhancement in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–mediated (AMPAR-mediated) excitatory synaptic transmission and inward rectification. ELS-TRAPed neurons, but not non-TRAPed surrounding neurons, exhibited enduring decreases in Gria2 mRNA, responsible for encoding the GluA2 subunit of the AMPARs. This was paralleled by decreased synaptic GluA2 protein expression and heightened phosphorylated GluA2 at Ser880 in dendrites, indicative of GluA2 internalization. Consistent with increased GluA2-lacking AMPARs, ELS-TRAPed neurons showed premature silent synapse depletion, impaired long-term potentiation, and impaired long-term depression. In vivo postseizure treatment with IEM-1460, an inhibitor of GluA2-lacking AMPARs, markedly mitigated ELS-induced changes in TRAPed neurons. These findings show that enduring modifications of AMPARs occur in a subpopulation of ELS-activated neurons, contributing to synaptic dysplasticity and network hyperexcitability, but are reversible with early IEM-1460 intervention.

Authors

Bo Xing, Aaron J. Barbour, Joseph Vithayathil, Xiaofan Li, Sierra Dutko, Jessica Fawcett-Patel, Eunjoo Lancaster, Delia M. Talos, Frances E. Jensen

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Figure 1

FosTRAP permanently and selectively labels ELS-activated cells.

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FosTRAP permanently and selectively labels ELS-activated cells.
(A) Sche...
(A) Schematic of experimental paradigm and TRAPing of neurons active during ELSs by paring 4-OHT and KA (2 mg/kg, i.p.). (B) Representative images of sagittal sections from FosTRAP mice injected with saline (Sal controls, upper) and KA (tonic-clonic seizures, lower). TRAPed cells expressing tdTomao (tdT, red) are enriched in the hippocampus. Scale bars: 500 μm. (C–F) Light-sheet fluorescence microscopy (LSFM) of ELS-TRAPed mouse brain (see Supplemental Video 1). (C) LSFM images of sagittal maximum intensity projection across 10 planes (top) and 3D reconstruction of KA-treated TRAPed hemisphere (bottom). Scale bar: 1 mm. (D) Results from the brain mapping pipeline displaying cell counts from Sal- and KA-treated mice broken down into broad regions according to the Allen Brain Atlas hierarchy. (E) Cell counts from hippocampal subregions. (F) 3D reconstruction of all detected CA1 cells from a KA-treated TRAP hemisphere (top left). Cellular distribution along the dorsal-ventral (right) and medial-lateral axes (bottom) from KA-treated TRAP mice. CA1 tdT+ locations were quantified along the dorsal/ventral and lateral/medial axes. *P < 0.05, **P < 0.01 by linear regression (n = 4 Sal and 4 KA). (G) Representative confocal images of hippocampal CA1 region immunolabeled for NeuN showing ELS-TRAPed neurons. Images in G are shown again in Supplemental Figure 4A. Scale bars: 100 μm (top row and bottom left) and 50 μm (bottom right). (H) Quantitative confocal imaging analysis showed a higher density of TRAPed (tdT+) cells in the CA1 region from KA-treated mice compared with Sal controls. ***P < 0.001 by Mann-Whitney U test (n = 6 Sal and 11 KA). (I) Linear regression of tonic-clonic seizures duration and density of TRAPed cells (n = 10 mice) in CA1 region. The dashed lines define the 95% confidence interval. R2 = 0.6419, **P < 0.01. Data expressed as mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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