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Activity of hippocampal adult-born neurons regulates alcohol withdrawal seizures
Daehoon Lee, … , Yu-Na Jung, Hoonkyo Suh
Daehoon Lee, … , Yu-Na Jung, Hoonkyo Suh
Published October 3, 2019
Citation Information: JCI Insight. 2019;4(19):e128770. https://doi.org/10.1172/jci.insight.128770.
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Research Article Neuroscience

Activity of hippocampal adult-born neurons regulates alcohol withdrawal seizures

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Abstract

Alcohol withdrawal (AW) after chronic alcohol exposure produces a series of symptoms, with AW-associated seizures being among the most serious and dangerous. However, the mechanism underlying AW seizures has yet to be established. In our mouse model, a sudden AW produced 2 waves of seizures: the first wave includes a surge of multiple seizures that occurs within hours to days of AW, and the second wave consists of sustained expression of epileptiform spikes and wave discharges (SWDs) during a protracted period of abstinence. We revealed that the structural and functional adaptations in newborn dentate granule cells (DGCs) in the hippocampus underlie the second wave of seizures but not the first wave. While the general morphology of newborn DGCs remained unchanged, AW increased the dendritic spine density of newborn DGCs, suggesting that AW induced synaptic connectivity of newborn DGCs with excitatory afferent neurons and enhanced excitability of newborn DGCs. Indeed, specific activation and suppression of newborn DGCs by the chemogenetic DREADD method increased and decreased the expression of epileptiform SWDs, respectively, during abstinence. Thus, our study unveiled that the pathological plasticity of hippocampal newborn DGCs underlies AW seizures during a protracted period of abstinence, providing critical insight into hippocampal neural circuits as a foundation to understand and treat AW seizures.

Authors

Daehoon Lee, Balu Krishnan, Hai Zhang, Hee Ra Park, Eun Jeoung Ro, Yu-Na Jung, Hoonkyo Suh

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Figure 1

Alcohol withdrawal produces epileptic seizures.

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Alcohol withdrawal produces epileptic seizures.
(A) Experimental timelin...
(A) Experimental timeline describing the alcohol feeding and electroencephalogram (EEG) recording schedule. (B) Representative EEG traces of control diet–fed (upper) and alcohol-fed (lower) mice upon alcohol withdrawal (AW). (C) Quantification of seizure frequency induced by AW (2.33 ± 1.86, n = 6). (D) Distribution of seizure events within 24 hours of AW. (E) Average AW seizure duration (31.79 ± 5.45 seconds, n = 14). Seizure activities were absent in control mice. (F) Quantification of epileptic spikes within 24 hours of AW (P < 0.01, alcohol-fed mice, 1442 ± 687, n = 6; pair-fed mice, 25.0 ± 10.17, n = 4). (G and H) No correlation between alcohol consumption and frequencies of AW seizures and spikes was observed. **P < 0.01 as determined by 2-tailed unpaired t tests. Data are represented as mean ± SD. Ref, reference; LC, left cortex; RC, right cortex; LH, left hippocampus; RH, right hippocampus.

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