Abstract
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.
Highlights
Fast synaptic inhibition in the brain is primarily mediated by GABAA receptors (GABAAR), which are ligand-gated receptors associated with an anion-permeable conductance
We investigated the impact of a chronic KCC2 suppression in the dentate gyrus using in vivo RNAi
KCC2 knockdown in transduced neurons was first confirmed by immunofluorescence imaging 2 weeks after in vivo infection (Figures 1A and 1B) and quantified by western blot analysis of primary hippocampal neurons 10 days after in vitro infection (Figure 1C)
Summary
Fast synaptic inhibition in the brain is primarily mediated by GABAA receptors (GABAAR), which are ligand-gated receptors associated with an anion-permeable conductance. The net ion flux through GABAAR channels relies on both the transmembrane gradients of these ions and the neuronal resting membrane potential, which determine the driving force of GABAAR currents. Postnatal upregulation of KCC2 expression is associated with a progressive hyperpolarizing shift in the reversal potential of GABAAR-mediated currents (EGABA) (Rivera et al, 1999). Ca2+ influx through postsynaptic NMDA receptors or during prolonged postsynaptic firing (Fiumelli et al, 2005) rapidly reduces KCC2 membrane expression and function through proteinphosphatase-1-dependent dephosphorylation of its Ser940 residue and protein cleavage by the calcium-activated protease calpain (Chamma et al, 2013; Lee et al, 2011; Puskarjov et al, 2012). KCC2 expression is regulated by several neuromodulators acting on G-protein-coupled receptors (Mahadevan and Woodin, 2016) as well as neurotrophins, such as brain-derived neurotrophic factor (BDNF), acting via TrkB signaling (Rivera et al, 2002)
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