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
Affiliations
Samu N. Kurki
Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland; Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland; Corresponding author
Rakenduvadhana Srinivasan
Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland; Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland
Jens Laine
Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland; Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland
Mari A. Virtanen
Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland; Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland
Tommi Ala-Kurikka
Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland; Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland
Juha Voipio
Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland
Kai Kaila
Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland; Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland; Corresponding author
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.
