A critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy

Zane R. Lybrand, Sonal Goswami, Jingfei Zhu, Veronica Jarzabek, Nikolas Merlock, Mahafuza Aktar, Courtney Smith, Ling Zhang, Parul Varma, Kyung-Ok Cho, Shaoyu Ge and Jenny Hsieh ()
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Zane R. Lybrand: The University of Texas at San Antonio
Sonal Goswami: The University of Texas at San Antonio
Jingfei Zhu: UT Southwestern Medical Center
Veronica Jarzabek: The University of Texas at San Antonio
Nikolas Merlock: The University of Texas at San Antonio
Mahafuza Aktar: UT Southwestern Medical Center
Courtney Smith: The University of Texas at San Antonio
Ling Zhang: UT Southwestern Medical Center
Parul Varma: The University of Texas at San Antonio
Kyung-Ok Cho: The Catholic University of Korea
Shaoyu Ge: Stony Brook University
Jenny Hsieh: The University of Texas at San Antonio

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.

Date: 2021
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DOI: 10.1038/s41467-021-21649-8

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