kCC2

Mechanical allodynia can be evoked by punctate pressure contact with the skin (punctate mechanical allodynia) and dynamic contact stimulation induced by gentle touching of the skin (dynamic mechanical allodynia). Dynamic allodynia is insensitive to morphine treatment and is transmitted through the spinal dorsal horn by a specific neuronal pathway, which is different from that for punctate allodynia, leading to difficulties in clinical treatment. K+-Cl- cotransporter-2 (KCC2) is one of the major determinants of inhibitory efficiency, and the inhibitory system in the spinal cord is important in the regulation of neuropathic pain...

Despite considerable unmet medical needs, effective pharmacological treatments that promote functional recovery after spinal cord injury remain limited. Although multiple pathological events are implicated in spinal cord injuries, the development of a microinvasive pharmacological approach that simultaneously targets the different mechanisms involved in spinal cord injury remains a formidable challenge. Here we report the development of a microinvasive nanodrug delivery system that consists of amphiphilic copolymers responsive to reactive oxygen species and an encapsulated neurotransmitter-conjugated KCC2 agonist...

The cation-chloride cotransporters KCC2 and NKCC1 regulate the intracellular Cl- concentration and cell volume of neurons and/or glia. The Cl- extruder KCC2 is expressed at higher levels than the Cl- transporter NKCC1 in mature compared to immature neurons, accounting for the developmental shift from high to low Cl- concentration and from depolarizing to hyperpolarizing currents through GABA-A receptors. Previous studies have shown that KCC2 expression is downregulated following central nervous system injury, returning neurons to a more excitable state, which can be pathological or adaptive...

Cardiovascular diseases, the leading life-threatening conditions, involve cardiac arrhythmia, coronary artery disease, myocardial infarction, heart failure, cardiomyopathy, and heart valve disease that are associated with the altered functioning of cation-chloride cotransporters. The decreased number of cation-chloride cotransporters leads to reduced reactivity to adrenergic stimulation. The KCC family is crucial for numerous physiological processes including cell proliferation and invasion, regulation of membrane trafficking, maintaining ionic and osmotic homeostasis, erythrocyte swelling, dendritic spine formation, maturation of postsynaptic GABAergic inhibition, and inhibitory/excitatory signaling in neural tracts...

Injury to mature neurons induces downregulated KCC2 expression and activity, resulting in elevated intracellular [Cl- ] and depolarized GABAergic signaling. This phenotype mirrors immature neurons wherein GABA-evoked depolarizations facilitate neuronal circuit maturation. Thus, injury-induced KCC2 downregulation is broadly speculated to similarly facilitate neuronal circuit repair. We test this hypothesis in spinal cord motoneurons injured by sciatic nerve crush, using transgenic (CaMKII-KCC2) mice wherein conditional CaMKIIα promoter-KCC2 expression coupling selectively prevents injury-induced KCC2 downregulation...

BACKGROUND: Naloxone has been used as an opioid antagonist to prevent multiple adverse side effects of opioid-like tolerance and hyperalgesia. This study has investigated naloxone combined with morphine to limit pain hypersensitivity. In addition, the expression of brain-derived neurotrophic factor (BDNF) and K+ Cl- cotransporter2 (KCC2) were also studied. METHODS: Forty-eight adult male Wistar rats (180-220 g) were divided into eight groups, with six rats in each group...

The postsynaptic inhibition through GABAA receptors (GABAA R) relies on two mechanisms, a shunting effect due to an increase in the postsynaptic membrane conductance and, in mature neurons, a hyperpolarization effect due to an entry of chloride into postsynaptic neurons. The second effect requires the action of the K+ -Cl- cotransporter KCC2 which extrudes Cl- from the cell and maintains its cytosolic concentration very low. Neuronal chloride equilibrium seems to be dysregulated in several neurological and psychiatric conditions such as epilepsy, anxiety, schizophrenia, Down syndrome, or Alzheimer's disease...

BACKGROUND: Increased catecholamines contribute to heightened cardiovascular reactivity and behavioral deficits after traumatic brain injury (TBI); adrenergic receptor blockade has limited success in reducing adverse sequelae of TBI. Injury-induced increases in the synthesis of catecholamines could contribute to adverse outcomes in TBI. Inhibition of catecholamine synthesis with alpha-methyltyrosine (αMT) could offer a benefit after TBI. METHODS: Original research trial in mice randomized to αMT (50 mg/kg/day) or vehicle for one week after TBI induced by controlled cortical impact...

OBJECTIVE: To evaluate the therapeutic efficacy and the influence on cerebral blood supply of waggle needling Yanglingquan (GB34) on spastic paresis (SP) rats after middle cerebral artery occlusion (MCAO) induced and investigate its mechanism of relieving neurobehavior deficiency. METHODS: SP rat model was produced by permanent MCAO. Rats were divided into five groups: blank control group (Control), sham operation group (Sham), model group (Model), waggle needling group (WN) and perpendicular needling group (PN)...

The K+ /Cl- cotransporter (KCC) is the primary mechanism by which mature neurons maintain low intracellular chloride (Cl- ) concentration and has been shown to be functionally coupled to the GABA-gated chloride channels (GGCC) in Drosophila central neurons. Further, pharmacological inhibition of KCC has been shown to lead to acute toxicity of mosquitoes that highlights the toxicological relevance of insect KCC. Yet, gaps in knowledge remain regarding physiological drivers of KCC function and interactions of ion flux mechanisms upstream of GGCC in insects...

Avulsion injury results in motoneuron death due to the increased excitotoxicity developing in the affected spinal segments. This study focused on possible short and long term molecular and receptor expression alterations which are thought to be linked to the excitotoxic events in the ventral horn with or without the anti-excitotoxic riluzole treatment. In our experimental model the left lumbar 4 and 5 (L4, 5) ventral roots of the spinal cord were avulsed. Treated animals received riluzole for 2 weeks. Riluzole is a compound that acts to block voltage-activated Na+ and Ca2+ channels...

Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Treatments for the main manifestations, including cognitive dysfunction or epilepsy, are still under development. Recently, the Cl- importer Na+ -K+ -Cl- cotransporter 1 (NKCC1) and the Cl- exporter K+ -Cl- cotransporter 2 (KCC2) have garnered attention as therapeutic targets for many neurological disorders. Dysregulation of neuronal intracellular Cl- concentration ([Cl- ]i ) is generally regarded as one of the mechanisms underlying neuronal dysfunction caused by imbalanced expression of these cation-chloride cotransporters (CCCs)...

Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called "GABA-switch". Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model. In ELS mice, the GABA-switch occurred already between postnatal day (P) 6 and P9, as opposed to P15-P21 in controls...

The optimal endurance exercise parameters remain to be defined to potentiate long-term functional recovery after stroke. We aim to assess the effects of individualized high-intensity interval training (HIIT) with either long or short intervals on neurotrophic factors and their receptors, apoptosis markers and the two-main cation-chloride cotransporters in the ipsi- and contralesional cerebral cortices in rats with cerebral ischemia. Endurance performance and sensorimotor functions were also assessed METHODS: : Rats with a 2-hour transient middle cerebral artery occlusion (tMCAO) performed work-matched HIIT4 (intervals: 4min) or HIIT1 (intervals: 1min) on treadmill for 2 weeks...

OBJECTIVE: The precise intervention of K-Cl cotransporter isoform 2 (KCC2) as a promising target for drug-resistant epilepsy remains elusive. METHODS: Here, we used a CRISPRa system delivered by adeno-associated viruses to specifically upregulate KCC2 in the subiculum to confirm its therapeutic potential in various in vivo epilepsy models. Calcium fiber photometry was used to reveal the role of KCC2 in the restoration of impaired GABAergic inhibition...

The potassium chloride cotransporter 2 (KCC2) is the main Cl- extruder in neurons. Any alteration in KCC2 levels leads to changes in Cl- homeostasis and, consequently, in the polarity and amplitude of inhibitory synaptic potentials mediated by GABA or glycine. Axotomy downregulates KCC2 in many different motoneurons and it is suspected that interruption of muscle-derived factors maintaining motoneuron KCC2 expression is in part responsible. In here, we demonstrate that KCC2 is expressed in all oculomotor nuclei of cat and rat, but while trochlear and oculomotor motoneurons downregulate KCC2 after axotomy, expression is unaltered in abducens motoneurons...

BACKGROUND: Despite our poor understanding of the pathophysiology of depression, a growing body of evidence indicates the role of both glutamate and gamma-aminobutyric acid (GABA) signaling behind the effects of rapid-acting antidepressants (RAADs). GPR39 is a zinc-sensing receptor whose activation leads to a prolonged antidepressant-like response in mice. Both GPR39 and zinc can modulate glutamatergic and GABAergic neurotransmission, however, exact molecular mechanisms are still elusive...

Synaptic transmission mediated by GABA A receptors (GABA A Rs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at sub-threshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration...

The emergence of consciousness from anesthesia, once assumed to be a passive process, is now considered as an active and controllable process. In the present study, we show in mice that, when the brain is forced into a minimum responsive state by diverse anesthetics, a rapid downregulation of K+ /Cl- cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) serves as a common mechanism by which the brain regains consciousness. Ubiquitin-proteasomal degradation is responsible for KCC2 downregulation, which is driven by ubiquitin ligase Fbxl4...

We review here the neuronal mechanisms that cause seizures in focal epileptic disorders and, specifically, those involving limbic structures that are known to be implicated in human mesial temporal lobe epilepsy. In both epileptic patients and animal models, the initiation of focal seizures - which are most often characterized by a low-voltage fast onset EEG pattern - is presumably dependent on the synchronous firing of GABA-releasing interneurons that, by activating post-synaptic GABAA receptors, cause large increases in extracellular [K+ ] through the activation of the co-transporter KCC2...