# Accumulation of GSK‐3β in Interneurons Impairs Adult Hippocampal Neurogenesis by Inhibiting GABAergic Transmission

## TL;DR

This study shows that increased GSK-3β in brain interneurons disrupts new neuron formation in Alzheimer's disease, and this can be reversed by boosting GABA signaling.

## Contribution

The study reveals a novel mechanism linking GSK-3β overexpression in interneurons to impaired neurogenesis via disrupted GABAergic transmission in Alzheimer's disease.

## Key findings

- Overexpression of GSK-3β in DG inhibitory interneurons causes reduced GABA release and impaired adult hippocampal neurogenesis.
- Pharmacological enhancement of GABAergic transmission rescues neurogenesis deficits and spatial memory impairments in AD models.

## Abstract

The activation of glycogen synthase kinase 3β (GSK‐3β) and the deterioration of spatial memory represent prominent pathological and clinical manifestations of Alzheimer's disease (AD). Nevertheless, the precise intrinsic mechanisms linking these pathological features remain poorly elucidated. In this study, we identified significant upregulation of GSK‐3β activity in inhibitory interneurons within the hippocampal dentate gyrus (DG) of 3×Tg‐AD mice. Subsequent investigations demonstrated that targeted overexpression of GSK‐3β in these interneurons triggered aberrant activation of neural stem cells (NSCs), culminating in apoptotic cell death and consequent deficits in adult hippocampal neurogenesis (AHN). Utilizing in vivo fiber‐optic recording techniques, we further established that GSK‐3β overexpression in DG inhibitory interneurons elicited hyperactivation of excitatory neurons, thereby disrupting the excitation–inhibition (E/I) balance within the DG circuitry. Notably, these pathological alterations were ameliorated through chemogenetic suppression of excitatory neuronal activity. Mechanistically, we determined that impaired GABAergic transmission, characterized by reduced GABA release in the DG region, underlies these observed effects. Pharmacological intervention with GABA receptor agonists effectively rescued AHN impairment and attenuated spatial cognitive deficits. Collectively, these findings demonstrate that GSK‐3β overexpression in GABAergic interneurons compromises AHN and promotes NSC apoptosis via disruption of GABAergic signaling, while pharmacological potentiation of GABAergic transmission exerts neuroprotective effects. This study elucidates a previously unrecognized mechanism contributing to AHN impairment in AD and identifies a promising therapeutic target for pro‐neurogenic strategies.

Overexpression of GSK‐3β in DG GABAergic neurons impairs neurogenesis by reducing GABA release, which can be reversed by enhancing GABAergic transmission.