Acute neuroinflammation leads to disruption of neuronal chloride regulation and consequent hyperexcitability in the dentate gyrus

Cell Reports, Год журнала: 2023, Номер 42(11), С. 113379 - 113379

Опубликована: Ноя. 1, 2023

Neuroinflammation is a salient part of diverse neurological and psychiatric pathologies that associate with neuronal hyperexcitability, but the underlying molecular cellular mechanisms remain to be identified. Here, we show peripheral injection lipopolysaccharide (LPS) renders dentate gyrus (DG) hyperexcitable perforant pathway stimulation in vivo increases internal spiking propensity granule cells (DGCs) vitro 24 h post-injection (hpi). In parallel, LPS leads prominent downregulation chloride extrusion via KCC2 emergence NKCC1-mediated uptake DGCs under experimental conditions optimized detect specific changes transporter efficacy. These data acute neuroinflammation disruption regulation, which unequivocally results loss GABAergic inhibition DGCs, collapsing gating function DG. The present work provides mechanistic explanation for neuroinflammation-driven hyperexcitability consequent cognitive disturbance.

Язык: Английский

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The expression system influences stability, maturation efficiency, and oligomeric properties of the potassium-chloride co-transporter KCC2

Neurochemistry International, Год журнала: 2024, Номер 174, С. 105695 - 105695

Опубликована: Фев. 17, 2024

Язык: Английский

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IL-1β, the first piece to the puzzle of sepsis-related cognitive impairment?

Frontiers in Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Апрель 11, 2024

Sepsis is a leading cause of death resulting from an uncontrolled inflammatory response to infectious agent. Multiple organ injuries, including brain are common in sepsis. The underlying mechanism sepsis-associated encephalopathy (SAE), which associated with neuroinflammation, not yet fully understood. Recent studies suggest that the release interleukin-1β (IL-1β) following activation microglial cells plays crucial role development long-lasting neuroinflammation after initial sepsis episode. This review provides comprehensive analysis recent literature on molecular signaling pathways involved cell and release. It also explores physiological pathophysiological IL-1β cognitive function, particular focus its contribution findings this may assist healthcare providers developing novel interventions against SAE.

Язык: Английский

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A combination of phenobarbital and the bumetanide derivative bumepamine prevents neonatal seizures and subsequent hippocampal neurodegeneration in a rat model of birth asphyxia

Epilepsia, Год журнала: 2021, Номер 62(6), С. 1460 - 1471

Опубликована: Май 6, 2021

Abstract Objectives Bumetanide was suggested as an adjunct to phenobarbital for suppression of neonatal seizures. This suggestion based on the idea that bumetanide, by reducing intraneuronal chloride accumulation through inhibition Na‐K‐2Cl cotransporter NKCC1, may attenuate or abolish depolarizing γ‐aminobutyric acid (GABA) responses caused birth asphyxia. However, a first proof‐of‐concept clinical trial failed. could have had several reasons, including bumetanide's poor brain penetration, wide cellular NKCC1 expression pattern in brain, and problems with general concept NKCC1’s role We recently replicated failure bumetanide potentiate phenobarbital's effect novel rat model In this study, clinically relevant dose (0.3 mg/kg) used does not lead NKCC1‐inhibitory levels. The aim present experiments examine whether much higher (10 is capable potentiating model. Furthermore, effects two lipophilic derivatives, ester prodrug N,N ‐dimethylaminoethylester (DIMAEB) benzylamine derivative bumepamine, were examined at equimolar doses. Methods Intermittent asphyxia induced 30 min exposing male female P11 pups three 7 + 3 cycles 9% 5% O 2 constant 20% CO . All control exhibited seizures after Results Even 10 mg/kg, did submaximal (15 seizure incidence, whereas significant determined combinations DIMAEB or, more effectively, which, however, inhibit NKCC1. Of interest, bumepamine/phenobarbital combination prevented neurodegenerative consequences hippocampus. Significance Both bumepamine are promising tools help develop effective compounds trials.

Язык: Английский

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Gephyrin Interacts with the K-Cl Cotransporter KCC2 to Regulate Its Surface Expression and Function in Cortical Neurons

Journal of Neuroscience, Год журнала: 2021, Номер 42(2), С. 166 - 182

Опубликована: Ноя. 22, 2021

The K+-Cl- cotransporter KCC2, encoded by the Slc12a5 gene, is a neuron-specific chloride extruder that tunes strength and polarity of GABAA receptor-mediated transmission. In addition to its canonical ion transport function, KCC2 also regulates spinogenesis excitatory synaptic function through interaction with variety molecular partners. enriched in vicinity both glutamatergic GABAergic synapses, activity which turn membrane stability function. submembrane actin cytoskeleton via 4.1N known control anchoring near synapses on dendritic spines. However, determinants clustering remain unknown. Here, we used proteomics identify novel interacting proteins adult rat neocortex. We identified candidate partners, including some involved neuronal development These include gephyrin, main scaffolding molecule at synapses. Gephyrin endogenous was confirmed immunoprecipitation from neocortical extracts. showed gephyrin stabilizes plasmalemmal promotes hippocampal neurons, mostly but not exclusively thereby controlling KCC2-mediated extrusion. This study identifies as expression cortical neurons.SIGNIFICANCE STATEMENT Fast inhibition brain mediated chloride-permeable receptors (GABAARs) therefore relies transmembrane gradients. these gradients are primarily maintained K/Cl KCC2. Therefore, understanding mechanisms crucial understand physiological regulation rescue pathology. depends clustering, underlying describe between protein inhibitory show controls loss compromises Our data suggest functional units comprising GABAARs, act regulate GABA signaling.

Язык: Английский

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