Reversible synaptic adaptations in a subpopulation of murine hippocampal neurons following early-life seizures
Bo Xing, Aaron J. Barbour, Joseph Vithayathil, Xiaofan Li, Sierra Dutko, Jessica Fawcett-Patel, Eunjoo Lancaster, Delia M. Talos, Frances E. Jensen
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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Research Article Neuroscience

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

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 7

Diminished LTP and LTD in ELS-TRAPed CA1 neurons at P28–P35.

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Diminished LTP and LTD in ELS-TRAPed CA1 neurons at P28–P35. (A and B) L...
(A and B) LTP paradigm, showing example traces and plots of evoked AMPA currents before and after paired LTP stimulation protocol (0.3 ms, 100 Hz, separated by 20 seconds) from Sal-treated mice, and tdT– and tdT+ neurons from ELS-treated mice. Sal and tdT– neurons exhibited a long-lasting increase in EPSC following tetanus (arrow), while tdT+ neurons did not show an increase in EPSC amplitude after stimulation. (C) Summary of LTP experiments showing significantly less LTP in tdT+ neurons compared with neurons from Sal-treated mice, or tdT– neurons from ELS-treated mice (Sal, n = 10 neurons/4 mice; tdT–, n = 11 neurons/6 mice; tdT+, n = 11 neurons/6 mice). *P < 0.05 by Kruskal-Wallis test followed by Dunn’s test. (D and E) LTD paradigm, showing example traces and plots of evoked AMPA currents before and after long-frequency (5 Hz, 900 pulses) LTD stimulation (LFS) from Sal, tdT–, and tdT+ neurons. Sal and tdT– neurons showed a long-lasting reduction in EPSC, but tdT+ neurons exhibited comparable EPSC amplitudes before and after long-frequency stimulation. (F) Summary of LTD experiments showing significantly less LTD in tdT+ neurons compared with tdT– neurons from ELS mice or neurons from Sal-treated (no seizure) mice (Sal, n = 9 neurons/4 mice; tdT–, n = 8 neurons/5 mice; tdT+, n = 7 neurons/5 mice). **P < 0.01, ***P < 0.001 by 1-way ANOVA followed by Tukey’s test. Data expressed as mean ± SEM.