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

Zane R Lybrand,Jenny Hsieh,Shaoyu Ge,Veronica Jarzabek,Parul Varma,Nikolas Merlock,Courtney Smith,Mahafuza Aktar,Kyung-Ok Cho,Ling Zhang,Sonal Goswami,Jingfei Zhu

doi:10.1038/s41467-021-21649-8

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.

Highlights

In the mammalian hippocampus, adult-born granule cells contribute to the function of the dentate gyrus (DG)
Blocking GABAA receptors had the largest effect on suppressing the enhanced intracellular calcium baseline. Together these results suggest that aberrant neurogenesis is characterized by an enhanced baseline of intracellular calcium that is dependent on GABAA receptor activation
Pathological changes during epileptogenesis are thought to increase the excitability of the hippocampus circuitry by abnormal adult-born granule cells (abGCs) migration, formation of hilar basal dendrites, mossy fiber sprouting, interneuron cell loss, and accelerated aberrant neurogenesis[11,14,16,36,37]

Summary

Introduction

Adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Circuitry of the dentate gyrus (DG), the principle gating structure of the hippocampus, establishes an inhibitory feedback circuit comprised of interneuron microcircuits that suppress the firing of dentate granule cells (GCs) Unique to this circuit is the continuous production and integration of adult-born GCs (abGCs) from neural stem cells in the subgranular zone (SGZ) of the DG3,4. Infection, or status epilepticus (SE) causes abGCs to mature abnormally taking on aberrant morphology (e.g., ectopic migration, altered dendrites, mossy fiber sprouting, and accelerated maturation) that are thought to generate hyperexcitable cells, and a subsequent breakdown of the dentate gate allowing for unregulated activity to perpetuate recurrent seizures[10,11,12,13]. We conclude that activity early in abGC maturation generates aberrant neurons by disrupting migration These neurons rewire cortical inputs to the hippocampus circuitry that is associated with spontaneous seizures. Regulation of intrinsic calcium is necessary to prevent improper integration of neurons into extant circuitry and is imperative to understanding the pathological genesis of neurological and seizure disorders

Methods

Results

Conclusion