KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels

Abstract

Graphical AbstractHighlights d KCC2 interacts with Task-3 potassium channels and regulates their membrane traffic d KCC2 knockdown depolarizes rat hippocampal neurons and increases their excitability d Chronic KCC2 knockdown in rat dentate gyrus is not sufficient to induce seizures d Network activity is altered by KCC2 knockdown, mostly independent of GABA signaling SUMMARY KCC2 regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in numerous neurological and psychiatric disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents is depolarized in KCC2 knockdown neurons, this shift is compensated by depolarization of the resting membrane potential. This reflects downregulation of leak potassium currents. We show KCC2 interacts with Task-3 (KCNK9) channels and is required for their membrane expression. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis, which could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that perturb network activity thus offering additional targets for therapeutic intervention.

Multimodal determinants of phase-locked dynamics across deep-superficial hippocampal sublayers during theta oscillations

“…In turns, these intrinsically generated resonant behavior can interact with rhythmic glutamatergic inputs to produce transient interference patterns giving rise to different phase precession dynamics 25,60 . We also found other critical factors such as the potassium leakage current, which can be transcriptionally regulated to adjust the resting membrane potential 61,62 . Interestingly, depolarization of silent CA1 pyramidal cells by artificial manipulations or sustained dendritic plateau are known factor that modulate the oscillatory dynamics of CA1 place cells 36,63,64 .…”

Cation–chloride cotransporters and the polarity of GABA signalling in mouse hippocampal parvalbumin interneurons

“…2014), ion channels (Goutierre et al . 2019) and cytoskeleton‐related proteins (Li et al . 2007; Gauvain et al .…”

Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons

“…In addition, since KCC2 is involved in a variety of molecular interactions with synaptic proteins (Ivakine et al , 2013; Mahadevan et al , 2014), ion channels (Goutierre et al , 2019) and cytoskeleton-related proteins (Li et al , 2007; Gauvain et al , 2011; Chevy et al , 2015; Llano et al , 2015), the loss of its expression also affects several physiological properties beyond the mere control of chloride transport and GABA signaling (Chamma et al , 2012). Thus, KCC2 knockdown in cortical PCs was shown to also profoundly perturb neuronal excitability as well as network activity (Kelley et al , 2018; Goutierre et al , 2019). Since PV INs exert a critical control over the activity of cortical PCs (Pouille & Scanziani, 2001) and shape their rhythmic activities (Klausberger & Somogyi, 2008; Amilhon et al , 2015; Gan et al , 2017), altered CCC expression in these cells would be expected to profoundly perturb cortical rhythmogenesis.…”