Abstract
GABAA receptors are ligand-gated ion channels, which are predominantly permeable for chloride. The neuronal K-Cl cotransporter KCC2 lowers the intraneuronal chloride concentration and thus plays an important role for GABA signaling. KCC2 loss-of-function is associated with seizures and epilepsy. Here, we show that KCC2 is expressed in the majority of parvalbumin-positive interneurons (PV-INs) of the mouse brain. PV-INs receive excitatory input from principle cells and in turn control principle cell activity by perisomatic inhibition and inhibitory input from other interneurons. Upon Cre-mediated disruption of KCC2 in mice, the polarity of the GABA response of PV-INs changed from hyperpolarization to depolarization for the majority of PV-INs. Reduced excitatory postsynaptic potential-spike (E-S) coupling and increased spontaneous inhibitory postsynaptic current (sIPSC) frequencies further suggest that PV-INs are disinhibited upon disruption of KCC2. In vivo, PV-IN-specific KCC2 knockout mice display a reduced seizure threshold and develop spontaneous sometimes fatal seizures. We further found a time dependent loss of PV-INs, which was preceded by an up-regulation of pro-apoptotic genes upon disruption of KCC2.
Highlights
Brain function depends on highly interconnected networks of excitatory pyramidal neurons and inhibitory interneurons
positive interneurons (PV-INs) play a major role to control the timing of pyramidal cell activity (Pouille and Scanziani, 2001), for the generation of rhythmic activities as well as the coupling of principal cells into functional assemblies (Klausberger and Somogyi, 2008; Agetsuma et al, 2018)
Our immunolabeling of brain sections dissected from 8-week-old WTPV mice shows that the majority of PV-INs in the hippocampus express KCC2
Summary
Brain function depends on highly interconnected networks of excitatory pyramidal neurons and inhibitory interneurons. The latter are predominantly locally projecting neurons, which release GABA to refine and shape circuit output by modulating the gain, timing, tuning, bursting properties of pyramidal cell firing, and selective filtering of synaptic excitation (Roux and Buzsaki, 2015). GABAergic interneurons account for roughly 20-30% of the overall neuronal population in the mammalian cerebral cortex (Hendry et al, 1987) and can be classified by different features. GABAergic interneuron subtypes target different domains of pyramidal cells and other interneurons (Gibson et al, 1999; Blatow et al, 2003; Hu et al, 2011; Jiang et al, 2013; Pfeffer et al, 2013). If interneuron function is impaired, this can affect higher brain functions and may result in seizures (Liu et al, 2014)
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