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

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.

New Insights Into the Role of Aberrant Hippocampal Neurogenesis in Epilepsy

“…With the extensive research and understanding of stem cells, hyperactivation of NSCs has been studied in detail in recent years. Upon stimulation with inflammation and stress from convulsive seizures, quiescent NSCs (qNSCs, a type of slowly dividing cells) in the subgranular zone (SGZ) enter the cell cycle and become proliferative NSCs ( 27 ). Once activated after epilepsy, the activated NSCs (aNSCs) have the potential to principally divide asymmetrically to generate another NSC and amplify neural progenitors, which are representative of a pluripotent and highly proliferative state to maintain the NSC pool while expanding the progenitor pool ( 28 ).…”

The role of adult hippocampal neurogenesis in epilepsy and comorbidities

“…成体新生神经元除了在数量上的改变以外，其在形态、位置以及电生理等特性上也发生了 改变 [52][53][54][55][56] 。生理状态下的新生神经元通常仅有一个从胞体顶部产生的树突，树突产生的分支向 着 DG 的颗粒细胞层外侧或者分子层的内侧伸展，而癫痫发作后产生的部分新生神经元则可能 会额外产生门区基底树突，并 伸向 DG 的门区内部 [52,57]…”

What do Newborn Granule Cells Do, and When Do They Do It?

“… 3 Utilizing newly available DREADD technology (Designer Receptors Exclusively Activated by Designer Drugs), Lybrand and colleagues further investigated this critical period of cell morphogenesis and migration by selectively activating or silencing immature granule cells at specific developmental ages. 4 Daily activation of newborn granule cells during their first or second week of development was sufficient to promote abnormal hilar migration. Furthermore, this early neuronal activation was associated with spontaneous seizures in the mice when cells were 8 weeks old.…”