The Multifaceted Roles of KCC2 in Cortical Development

Trends in Neurosciences, Journal Year: 2021, Volume and Issue: 44(5), P. 378 - 392

Published: Feb. 24, 2021

KCC2, best known as the neuron-specific chloride-extruder that sets strength and polarity of GABAergic currents during neuronal maturation, is a multifunctional molecule can regulate cytoskeletal dynamics via its C-terminal domain (CTD). We describe molecular cellular mechanisms involved in multiple functions KCC2 splice variants, ranging from developmental apoptosis control early network events to formation plasticity cortical dendritic spines. The versatility actions at subcellular levels also evident mature neurons plasticity, disease, aging. Thus, has emerged one most important molecules shape overall phenotype.

Language: Английский

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CNS pharmacology of NKCC1 inhibitors

Neuropharmacology, Journal Year: 2021, Volume and Issue: 205, P. 108910 - 108910

Published: Dec. 6, 2021

The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation consequent effects on GABAergic signaling have been implicated in numerous disorders. While modulators not yet clinically available, loop diuretic bumetanide has used clinical studies to treat brain disorders as a tool for inhibition preclinical models. Bumetanide is known anticonvulsant neuroprotective under some pathophysiological conditions. However, shown several species from neonates adults (mice, rats, dogs, by extrapolation humans), at low doses of approved diuresis, this negligible access into CNS, reaching levels that much lower than what needed inhibit cells within parenchyma. Several discovery strategies over last ∼15 years develop brain-permeant compounds that, ideally, should be selective eliminate diuresis mediated renal NKCC2. employed improve pharmacokinetic pharmacodynamic properties blockers include evaluation other diuretics; development lipophilic prodrugs bumetanide; side-chain derivatives unbiased high-throughput screening approaches based large chemical compound libraries. main outcomes (1), non-acidic diuretics such azosemide torasemide may advantages inhibitors vs. (2), achieve significantly higher parent activity; (3), novel do exhibit any functionally relevant improvement accessibility or selectivity (4) discovered resolve inherent problems bumetanide, but achieved. Thus, further research optimize design inhibitors. Another major challenge identify mechanisms whereby various NKCC1-expressing cellular these (e.g., neurons, oligodendrocytes astrocytes) outside parenchyma blood-brain barrier, choroid plexus, endocrine immune system), well molecular off-target effects, might contribute their reported therapeutic adverse effects.

Language: Английский

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Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Jan. 5, 2022

The construction of the brain relies on a series well-defined genetically and experience- or activity -dependent mechanisms which allow to adapt external environment. Disruption these processes leads neurological psychiatric disorders, in many cases are manifest already early postnatal life. GABA, main inhibitory neurotransmitter adult is one major players assembly formation neuronal circuits. In prenatal immediate period acting GABA A receptors, depolarizes excites targeted cells via an outwardly directed flux chloride. this way it activates NMDA receptors voltage-dependent calcium channels contributing, through intracellular rise, shape establish, new synapses elimination others, direction -mediated neurotransmission (depolarizing hyperpolarizing) depends levels chloride [Cl − ] i , turn maintained by cation-chloride importer exporter KCC2 NKCC1, respectively. Thus, premature hyperpolarizing action its persistent depolarizing effect beyond period, behavioral deficits associated with morphological alterations excitatory (E)/inhibitory (I) imbalance selective areas. aim review summarize recent data concerning functional role GABAergic transmission building up refining circuits development dysfunction neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), schizophrenia epilepsy. particular, we focus novel information co-transporters (CCC) generate cognitive impairment diseases. We discuss also possibility re-establish proper balance within areas CCC.

Language: Английский

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Chloride transporters controlling neuronal excitability

Physiological Reviews, Journal Year: 2022, Volume and Issue: 103(2), P. 1095 - 1135

Published: Oct. 27, 2022

Synaptic inhibition plays a crucial role in regulating neuronal excitability, which is the foundation of nervous system function. This largely mediated by neurotransmitters GABA and glycine that activate Cl − -permeable ion channels, means strength depends on gradient across membrane. In neurons, primarily two secondarily active cation-chloride cotransporters (CCCs), NKCC1 KCC2. CCC-mediated regulation critical for healthy brain function, as dysregulation CCCs has emerged key mechanism underlying neurological disorders including epilepsy, neuropathic pain, autism spectrum disorder. review begins with an overview chloride transporters before explaining dependent relationship between these CCCs, regulation, inhibitory synaptic transmission. We then discuss evidence how can be regulated, activity their protein interactions, underlie plasticity. For readers who may interested conducting experiments we have included section techniques estimating recording intracellular , advantages limitations. Although focus this also examine regulated glial cells, turn regulate excitability through tight nonneuronal cell type synapses. Finally, relatively extensive growing literature contributes to disorders.

Language: Английский

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Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Oct. 15, 2021

Between 6-20% of the cellular proteome is under circadian control and tunes mammalian cell function with daily environmental cycles. For viability, to maintain volume within narrow limits, variation in osmotic potential exerted by changes soluble must be counterbalanced. The mechanisms consequences this compensation have not been investigated before. In cultured cells tissue we find that involves electroneutral active transport Na+, K+, Cl- through differential activity SLC12A family cotransporters. cardiomyocytes ex vivo vivo, compensatory ion fluxes confer electrical activity. Perturbation protein abundance has commensurate effects on composition across cycle. Thus, regulation impacts homeostasis substantial for physiology electrically such as cardiomyocytes.

Language: Английский

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Gabaergic Interneurons in Early Brain Development: Conducting and Orchestrated by Cortical Network Activity

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: Jan. 3, 2022

Throughout early phases of brain development, the two main neural signaling mechanisms-excitation and inhibition-are dynamically sculpted in neocortex to establish primary functions. Despite its relatively late formation persistent developmental changes, GABAergic system promotes ordered shaping neuronal circuits at structural functional levels. Within this frame, interneurons participate first spontaneous later sensory-evoked activity patterns that precede cortical functions mature brain. Upon their subcortical generation, embryonic must orderly migrate settle respective target layers before they can actively engage network activity. During process, changes molecular synaptic level allow not only coordinated but also pruning connections as well excitatory inhibitory synapses. At postsynaptic site, shift from an towards response is required enable synchronization within networks. Concomitantly, progressive specification different interneuron subtypes endows with distinct local region-specific modulation firing. Finally, apoptotic process further refines populations by constantly maintaining a controlled ratio neurons. Interestingly, many these fundamental complex processes are influenced-if directly controlled-by electrical Interneurons on subcellular, cellular, affected high frequency patterns, such spindle burst gamma oscillations rodents delta brushes humans. Conversely, maturation structure function each scales feeds back contributes generation essential for proper peri- postnatal development. Overall, more precise description conducting role terms how contribute specific patterns-as impinge orchestra members-will lead better understanding physiological pathophysiological development nervous system.

Language: Английский

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Expression patterns of NKCC1 in neurons and non-neuronal cells during cortico-hippocampal development

Cerebral Cortex, Journal Year: 2022, Volume and Issue: 33(10), P. 5906 - 5923

Published: Dec. 27, 2022

Abstract The Na-K-2Cl cotransporter NKCC1 is widely expressed in cells within and outside the brain. However, our understanding of its roles brain functions throughout development, as well neuropsychiatric neurological disorders, has been severely hindered by lack reliable data on developmental (sub)cellular expression patterns. We provide here first properly controlled analysis protein various cell types mouse using custom-made antibodies an knock-out validated immunohistochemical procedure, with parallel based advanced mRNA approaches. are at remarkably high levels oligodendrocytes. In immature neurons, was located somata, whereas adult only could be clearly detected. immunoreactivity also seen microglia, astrocytes, developing pericytes, progenitor dentate gyrus. Finally, a differential splice variants observed, NKCC1a predominating non-neuronal NKCC1b neurons. Taken together, cellular basis for enable identification major limitations promises development neuron-targeting NKCC1-blockers.

Language: Английский

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Nicotinic acetylcholine receptors and epilepsy

Pharmacological Research, Journal Year: 2023, Volume and Issue: 189, P. 106698 - 106698

Published: Feb. 14, 2023

Despite recent advances in understanding the causes of epilepsy, especially genetic, comprehending biological mechanisms that lead to epileptic phenotype remains difficult. A paradigmatic case is constituted by epilepsies caused altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions mature as well developing brain. The ascending cholinergic projections potent control forebrain excitability, and wide evidence implicates nAChR dysregulation both cause effect epileptiform activity. First, tonic-clonic seizures are triggered administration high doses agonists, whereas non-convulsive have kindling effects. Second, sleep-related epilepsy can be mutations on genes encoding subunits widely expressed (CHRNA4, CHRNB2, CHRNA2). Third, animal models acquired time-dependent alterations innervation observed following repeated seizures. Heteromeric nAChRs central players epileptogenesis. Evidence for autosomal dominant hypermotor (ADSHE). Studies ADSHE-linked expression systems suggest epileptogenic process promoted overactive receptors. Investigation ADSHE indicates mutant lifelong hyperexcitability altering i) function GABAergic populations neocortex thalamus, ii) synaptic architecture during synaptogenesis. Understanding balance effects adult networks essential plan rational therapy at different ages. Combining this knowledge with a deeper functional pharmacological properties individual will advance precision personalized medicine nAChR-dependent epilepsy.

Language: Английский

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When Are Depolarizing GABAergic Responses Excitatory?

Frontiers in Molecular Neuroscience, Journal Year: 2021, Volume and Issue: 14

Published: Nov. 24, 2021

The membrane responses upon activation of GABA(A) receptors critically depend on the intracellular Cl − concentration ([Cl ] i ), which is maintained by a set transmembrane transporters for . During neuronal development, but also under several pathophysiological conditions, prevailing expression loader NKCC1 and low extruder KCC2 causes elevated [Cl , result in depolarizing GABAergic responses. However, are not necessarily excitatory, as reduces input resistance neurons thereby shunt excitatory inputs. To summarize our knowledge effect GABA excitability, this review discusses theoretical considerations experimental studies illustrating relation between conductances, reversal potential excitability. In addition, evidences complex spatiotemporal interaction glutamatergic inputs described. Moreover, mechanisms that influence beyond presented. And finally, vitro vivo directly investigated whether mediates excitation or inhibition during early developmental stages summarized. summary, these suggest can act inhibitory neurotransmitter even conditions maintain substantial

Language: Английский

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The NKCC1 ion transporter modulates microglial phenotype and inflammatory response to brain injury in a cell-autonomous manner

PLoS Biology, Journal Year: 2022, Volume and Issue: 20(1), P. e3001526 - e3001526

Published: Jan. 27, 2022

The NKCC1 ion transporter contributes to the pathophysiology of common neurological disorders, but its function in microglia, main inflammatory cells brain, has remained unclear date. Therefore, we generated a novel transgenic mouse line which microglial was deleted. We show that shapes both baseline and reactive microglia morphology, process recruitment site injury, adaptation changes cellular volume cell-autonomous manner via regulating membrane conductance. In addition, deficiency results NLRP3 inflammasome priming increased production interleukin-1β (IL-1β), rendering prone exaggerated responses. with this, central (intracortical) administration blocker, bumetanide, potentiated intracortical lipopolysaccharide (LPS)-induced cytokine levels. contrast, systemic bumetanide application decreased inflammation brain. Microglial KO animals exposed experimental stroke showed significantly brain inflammation, cerebral edema worse outcome. Thus, emerges as an important player controlling homeostasis responses through modulate injury. contribution actions is likely be relevant for disorders.

Language: Английский

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