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KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition.

ABSTRACT: Although cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of perisomatic-targeting parvalbumin-positive (PV+) interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches from an anti-ictal to a pro-ictal effect within a few seconds of seizure initiation. The pro-ictal effect of delayed photostimulation of PV+ interneurons was not shared with dendrite-targeting somatostatin-positive (SOM+) interneurons. We also show that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons. These results suggest that strategies aimed at improving the ability of principal neurons to maintain a trans-membrane chloride gradient in the face of excessive network activity can prevent interneurons from contributing to seizure perpetuation.

SUBMITTER: Magloire V

PROVIDER: S-EPMC6420604 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition.

Magloire Vincent V Cornford Jonathan J Lieb Andreas A Kullmann Dimitri M DM Pavlov Ivan I

Nature communications 20190315 1

Although cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of perisomatic-targeting parvalbumin-positive (PV+) interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches fro ...[more]

PMID: 30874549

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Project description:Background Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is characterized by a pathological cascade of excitotoxicity that leads to neuroinflammation, progressive neuronal loss, and subsequent cognitive decline. Despite its prevalence, effective disease-modifying therapies remain lacking. Previous studies have demonstrated that the endocannabinoid system contributes to epileptic activity. In particular, inactivation of monoacylglycerol lipase (MAGL), the key rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG), an endogenous lipid mediator with anti-inflammatory and neuroprotective properties, suppresses seizures and reduces neuroinflammation. However, the cellular and molecular mechanisms underlying these protective effects remain unclear. Methods To dissect the cellular mechanisms underlying MAGL-mediated neuroprotection, we employed a kainic acid (KA)-induced status epilepticus model in mice with global, astrocyte-specific (aKO), and neuron-specific (nKO) deletion of mgll. We combined single-nucleus RNA sequencing (snRNA-seq) to map the transcriptomic landscape of glial responses with pharmacological interventions to validate key signaling pathways, as well as behavioral assays to assess functional recovery. Results We demonstrated that astrocyte-specific, but not neuron-specific, mgll deletion was sufficient to attenuate seizure susceptibility and hippocampal neurodegeneration, thereby recapitulating the protective phenotype observed in global knockouts. Transcriptomic profiling revealed that astrocytic MAGL deficiency fundamentally reshaped the glial response to injury by preventing the transition to pro-inflammatory reactive astrocyte states and suppressing the activation of disease-associated microglia (DAM). Mechanistically, we identified a signaling pathway in which the neuroprotective effects of MAGL inhibition depend on cannabinoid receptor 1 (CB1) activation and are mediated by downstream peroxisome proliferator-activated receptor γ (PPAR-γ) signaling. Either genetic deletion of CB1 or pharmacological blockade of PPAR-γ abolished the protective effects. Furthermore, aKO mice exhibited reduced neuronal loss, preserved synaptic structural integrity and protection against post-seizure cognitive deficits. Conclusion These findings reveal astrocytic MAGL as a crucial regulatory node in the epileptic brain and demonstrated that enhancing 2-AG signaling in astrocytes orchestrates neuroprotection via CB1-PPAR-γ signaling pathways, thereby reducing neuroinflammation, preserving synaptic function, and preventing the cognitive comorbidities associated with epilepsy.

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KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition.

Publications

KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition.

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