Cell Reports (Nov 2023)

Acute neuroinflammation leads to disruption of neuronal chloride regulation and consequent hyperexcitability in the dentate gyrus

  • Samu N. Kurki,
  • Rakenduvadhana Srinivasan,
  • Jens Laine,
  • Mari A. Virtanen,
  • Tommi Ala-Kurikka,
  • Juha Voipio,
  • Kai Kaila

Journal volume & issue
Vol. 42, no. 11
p. 113379

Abstract

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Summary: Neuroinflammation is a salient part of diverse neurological and psychiatric pathologies that associate with neuronal hyperexcitability, but the underlying molecular and cellular mechanisms remain to be identified. Here, we show that peripheral injection of lipopolysaccharide (LPS) renders the dentate gyrus (DG) hyperexcitable to perforant pathway stimulation in vivo and increases the internal spiking propensity of dentate granule cells (DGCs) in vitro 24 h post-injection (hpi). In parallel, LPS leads to a prominent downregulation of chloride extrusion via KCC2 and to the emergence of NKCC1-mediated chloride uptake in DGCs under experimental conditions optimized to detect specific changes in transporter efficacy. These data show that acute neuroinflammation leads to disruption of neuronal chloride regulation, which unequivocally results in a loss of GABAergic inhibition in the DGCs, collapsing the gating function of the DG. The present work provides a mechanistic explanation for neuroinflammation-driven hyperexcitability and consequent cognitive disturbance.

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