Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits
Qi-Gang Zhou, … , Imad M. Najm, Hoonkyo Suh
Qi-Gang Zhou, … , Imad M. Najm, Hoonkyo Suh
Published December 3, 2018
Citation Information: J Clin Invest. 2019;129(1):310-323. https://doi.org/10.1172/JCI95731.
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Research Article Neuroscience

Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits

Abstract

We investigated how pathological changes in newborn hippocampal dentate granule cells (DGCs) lead to epilepsy. Using a rabies virus–mediated retrograde tracing system and a designer receptors exclusively activated by designer drugs (DREADD) chemogenetic method, we demonstrated that newborn hippocampal DGCs are required for the formation of epileptic neural circuits and the induction of spontaneous recurrent seizures (SRS). A rabies virus–mediated mapping study revealed that aberrant circuit integration of hippocampal newborn DGCs formed excessive de novo excitatory connections as well as recurrent excitatory loops, allowing the hippocampus to produce, amplify, and propagate excessive recurrent excitatory signals. In epileptic mice, DREADD-mediated–specific suppression of hippocampal newborn DGCs dramatically reduced epileptic spikes and SRS in an inducible and reversible manner. Conversely, specific activation of hippocampal newborn DGCs increased both epileptic spikes and SRS. Our study reveals an essential role for hippocampal newborn DGCs in the formation and function of epileptic neural circuits, providing critical insights into DGCs as a potential therapeutic target for treating epilepsy.

Authors

Qi-Gang Zhou, Ashley D. Nemes, Daehoon Lee, Eun Jeoung Ro, Jing Zhang, Amy S. Nowacki, Susan M. Dymecki, Imad M. Najm, Hoonkyo Suh

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Figure 4

The essential role of hippocampal DGCs in the production of seizures during epilepsy.

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The essential role of hippocampal DGCs in the production of seizures dur...
(A and B) Experimental schematics showing the strategy to selectively suppress the neuronal activity of hippocampal newborn DGCs in NCE;hM4Difl/+ or NCE;hM4Difl/+;YFPfl/+ mice. (C) Representative EEG recordings show that CNO treatment suppressed epileptic spikes as well as SRS in NCE;hM4Difl/+mice, but not in hM4Difl/+ control mice. (D and E) Epileptic spikes and SRS were quantified during 24 hours of vehicle (days 1–3, blue circles), CNO (days 4–6 and 10, red circles), and recovery without treatment (days 7–9 and 11, green circles). Quantitative results show that CNO treatment effectively reduced the frequency of epileptic spikes (n = 17) and SRS (n = 9) only in NCE;hM4Difl/+ mice during epilepsy. ***P < 0.001. (F and G) Percentage of inhibition of epileptic spikes was proportional to the total number of hM4Di-expressing YFP-positive cells, as well as aberrant hM4Di-expressing YFP-positive cells, in the dentate gyrus. Asterisks in D and E indicate that CNO treatment resulted in a significant reduction in epileptic spikes and SRS compared with vehicle treatment, which returned to basal levels during each recovery period. Two-way RM ANOVA with Bonferroni’s multiple comparison tests (D, E) or Pearson’s correlation (F, G) were used.