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 1

Inhibition of hippocampal DGCs suppresses SRS.

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Inhibition of hippocampal DGCs suppresses SRS. (A) hM4Di and YFP are exp...
(A) hM4Di and YFP are expressed in hippocampal DGCs in POMC-Cre;hM4Difl/+;YFPfl/+ mice. (B) CRE is expressed in the DG, and YFP, which is an indicator of hM4Di, is expressed in all DGCs in POMC-Cre;hM4Difl/+;YFPfl/+ mice. (C) Representative EEG traces in the absence and presence of CNO in POMC-Cre;hM4Difl/+ mice during pilocarpine-induced epilepsy. (D and E) On days 1–3, vehicle treatment did not significantly change epileptic spikes or SRS in either control or POMC-Cre;hM4Difl/+ mice. On days 4–6, CNO-mediated suppression of hippocampal DGCs significantly reduced epileptic spikes (SPKs ) (n = 19) as well as SRS (n = 11) in POMC-Cre;hM4Difl/+ mice in an inducible and reversible manner, as determined by 2-way RM ANOVA with a Bonferroni’s multiple comparison post test. On days 7–9, epileptic spikes and SRS returned to basal levels in POMC-Cre;hM4Difl/+, showing CNO-dependent transient and reversible suppression of DGC activity. Note that epilepsy spikes and SRS were quantified during the 24 hours after vehicle (days 1–3, blue circles), CNO (days 4-6, red circles), and recovery without treatment (days 7-9, green circles). Two-way RM ANOVA with Bonferroni’s multiple comparison tests were used for D and E. Asterisks indicate that CNO treatment resulted in a significant reduction in epileptic spikes and SRS compared with vehicle treatment, which returned to basal levels during the recovery period. ***P < 0.001.