Disruption of KCC2 in Parvalbumin-Positive Interneurons Is Associated With a Decreased Seizure Threshold and a Progressive Loss of Parvalbumin-Positive Interneurons

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.

Unilateral optogenetic kindling of hippocampus leads to more severe impairments of the inhibitory signaling in the contralateral hippocampus

“…A hypothesis to explain this result is that these animals may have developed reactive astrogliosis ( Khurgel et al, 1995 ; Cole-Edwards et al, 2006 ). This hypothesis is based on the premise that, unlike KCC2, which is expressed exclusively in neurons ( Papp et al, 2008 ; Moore et al, 2017 ; Herrmann et al, 2021 ), NKCC1 is also largely present in astrocytes ( Khirug et al, 2008 ; Löscher et al, 2013 ; Virtanen et al, 2020 ). Extensive data has shown that the animal models of epilepsy mentioned earlier rapidly develops reactive astrogliosis in the brain, either directly, as in the KA-SE model ( Vargas et al, 2013 ), or indirectly, as the pilocarpine-induced SE ( Shapiro et al, 2008 ), and in EK ( Khurgel et al, 1995 ).…”

“…Our results indicate that the OpK model induces some level of epileptogenesis, and the loss of PV-INs from OpK can be more severe and extensive compared to previous reports which found only mild PV-INs loss ipsilaterally ( Ryu et al, 2021 ). The chronic loss of PV-INs may also be associated with the chronic disruption of KCC2, via mitogen-activated protein kinase- (MAPK) dependent apoptosis ( Herrmann et al, 2021 ).…”

“…Increased [Cl − ]i and [K + ]o results in the shift of the GABA A R-mediated postsynaptic potentials (EGABA) by the generation of an inwardly-directed electrical depolarizing GABAergic effect ( Pathak et al, 2007 ; Viitanen et al, 2010 ; Doyon et al, 2015 ; Liu et al, 2019 ). This shift may turn the normal GABAergic feedback inhibition into a positive ictogenic feedback loop ( Kahle et al, 2016 ), and result in network overexcitation, increasing neuronal susceptibility to abrupt transitions from interictal to ictal states ( Pathak et al, 2007 ; Sen et al, 2007 ; Kahle et al, 2016 ; Liu et al, 2019 ; Herrmann et al, 2021 ). This mechanism is also described to be the biochemical basis of a disinhibitory GABA-mediated neurotransmission that contributes to the increased seizure susceptibility observed in patients with epilepsy ( Kamphuis et al, 1991 ; Cobb et al, 1995 ; Nusser et al, 1998 ; Dzhala et al, 2005 ; Kahle et al, 2016 ).…”

Synaptic Proteomes of Cortical Interneuron Classes Revealed by Antibody Directed Proximity Labeling

“…Moreover, disruptions in GABAergic interneurons in cortex have been implicated in several neurological conditions including Alzheimer's Disease [10][11][12] , schizophrenia 13,14 , autism spectrum disorder 15,16 , and epilepsy [17][18][19] .…”

“…GABAergic interneurons provide a break on excitation, control timing and synchrony within neural circuits 4–7 , and can be modulated differentially according to cell class 8,9 . Moreover, disruptions in GABAergic interneurons in cortex have been implicated in several neurological conditions including Alzheimer’s Disease 10–12 , schizophrenia 13,14 , autism spectrum disorder 15,16 , and epilepsy 17–19 .…”