kCC2

Bestrophin-1 and anoctamin-1 are members of the calcium-activated chloride channels (CaCCs) family and are involved in inflammatory and neuropathic pain. However, their role in pain hypersensitivity induced by REM sleep deprivation (REMSD) has not been studied. This study aimed to determine if anoctamin-1 and bestrophin-1 are involved in the pain hypersensitivity induced by REMSD. We used the multiple-platform method to induce REMSD. REM sleep deprivation for 48 h induced tactile allodynia and a transient increase in corticosterone concentration at the beginning of the protocol (12 h) in female and male rats...

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction...

Corticotropin-releasing hormone (CRH) neurons play an important role in the regulation of neuroendocrine responses to stress. The excitability of CRH neurons is regulated by inhibitory GABAergic inputs. However, it is unclear when GABAergic regulation of CRH neurons is established during fetal brain development. Furthermore, the exact progression of the developmental shift of GABA action from depolarization to hyperpolarization remains unelucidated. Considering the importance of CRH neuron function in subsequent hypothalamic-pituitary-adrenal (HPA) axis regulation during this critical phase of development, we investigated the ontogeny of GABAergic inputs to CRH neurons and consequent development of chloride homeostasis...

Neuroinflammation contributes to the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation of microglial brain-derived neurotrophic factor (BDNF), Na-K-Cl cotransporter-1 (NKCC1), and K-Cl cotransporter-2 (KCC2) due to activation of BDNF-tropomyosin receptor kinase B (TrkB) signaling. Allosteric modulation of α7 nAChRs has not been investigated on BDNF, KCC2, and NKCC1 during LPS-induced depressive-like behavior. Therefore, we examined the effects of PNU120596, an α7 nAChR positive allosteric modulator, on the expression of BDNF, KCC2, and NKCC1 in the hippocampus and prefrontal cortex using Western blot analysis, immunofluorescence assay, and real-time polymerase chain reaction...

Spasticity is a complex and multidimensional disorder that impacts nearly 75% of individuals with spinal cord injury (SCI) and currently lacks adequate treatment options. This sensorimotor condition is burdensome as hyperexcitability of reflex pathways result in exacerbated reflex responses, co-contractions of antagonistic muscles, and involuntary movements. Transcutaneous spinal cord stimulation (tSCS) has become a popular tool in the human SCI research field. The likeliness for this intervention to be successful as a noninvasive anti-spastic therapy after SCI is suggested by a mild and transitory improvement in spastic symptoms following a single stimulation session, but it remains to be determined if repeated tSCS over the course of weeks can produce more profound effects...

The suppression of consciousness by anesthetics and the emergence of the brain from anesthesia are complex and elusive processes. Anesthetics may exert their inhibitory effects by binding to specific protein targets or through membrane-mediated targets, disrupting neural activity and the integrity and function of neural circuits responsible for signal transmission and conscious perception/subjective experience. Emergence from anesthesia was generally thought to depend on the elimination of the anesthetic from the body...

BACKGROUND: Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Bone marrow mesenchymal stem cells (BMSCs)-derived exosomes show great therapeutic potential for SCI. Exosomes derived from miR-26a-modified MSCs promote axonal regeneration following SCI. Our study aims to uncover the mechanisms by which BMSC-derived exosomes carrying miR-26a-5p regulate SCI. METHODS: BMSCs and BMSC-derived exosomes were isolated and characterized by Oil Red O and alizarin red staining, transmission electron microscopy, flow cytometry, nanoparticle tracking analysis and Western blotting...

The neuron-specific K+ /Cl- co-transporter-2, KCC2, which is critical for brain development, regulates γ-aminobutyric acid-dependent inhibitory neurotransmission. Consistent with its function, mutations in KCC2 are linked to neurodevelopmental disorders, including epilepsy, schizophrenia, and autism. KCC2 possesses 12 transmembrane spans and forms an intertwined dimer. Based on its complex architecture and function, reduced cell surface expression and/or activity have been reported when select disease-associated mutations are present in the gene encoding the protein, SLC12A5...

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence...

Developmental neurogenesis is a tightly regulated spatiotemporal process with its dysregulation implicated in neurodevelopmental disorders. NMDA receptors are glutamate-gated ion channels that are widely expressed in the early nervous system, yet their contribution to neurogenesis is poorly understood. Notably, a variety of mutations in genes encoding NMDA receptor subunits are associated with neurodevelopmental disorders. To rigorously define the role of NMDA receptors in developmental neurogenesis, we used a mutant zebrafish line (grin1-/- ) that lacks all NMDA receptors yet survives to 10 days post-fertilization, offering the opportunity to study post-embryonic neurodevelopment in the absence of NMDA receptors...

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BACKGROUND: Retinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP...

Spasticity, impacting about 75% of patients with spinal cord injury (SCI), leads to hyperreflexia, muscle spasms and co-contractions of antagonist muscles, greatly affecting their quality of life. Spasticity primarily stems from the hyperexcitability of motoneurons below the lesion, driven by an upregulation of the persistent sodium current and a downregulation of chloride extrusion. This imbalance results from the post-SCI activation of calpain1, which cleaves Nav1.6 channels and KCC2 co-transporters. Our study was focused on mitigating spasticity by specifically targeting calpain1 in spinal motoneurons...

In physiological conditions, the intracellular chloride concentration is much lower than the extracellular. As GABAA channels are permeable to anions, the reversal potential of GABAA is very close to that of Cl- , which is the most abundant free anion in the intra- and extracellular spaces. Intracellular chloride is regulated by the activity ratio of NKCC1 and KCC2, two chloride-cation cotransporters that import and export Cl- , respectively. Due to the closeness between GABAA reversal potential and the value of the resting membrane potential in most neurons, small changes in intracellular chloride have a major functional impact, which makes GABAA a uniquely flexible signaling system...

The homozygous Bronx waltzer ( bv ) mouse, which shows hearing impairment, also exhibits anxiety accompanied by a reduction in cortical parvalbumin (PV)-positive GABAergic interneurons. Recently, a mutation in splicing factor Ser/Arg repetitive matrix 4 (Srrm4) was found in bv mice. However, the cellular consequences of the Srrm4 mutation for anxiety remain unknown. Here, we tested our hypothesis that bv mutant primarily affects interneurons through a cell-intrinsic pathology that leads to a reduction of interneurons and consequently causes anxiety...

The solute carrier family 12 ( SLC12 ) of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl- extrusion, and sodium potassium chloride cotransporters (N[K]CCs, NKCC1, NKCC2, and NCC)-mediated Cl- loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues. In recent years, there have been considerable advances in our understanding of CCCs' control mechanisms in cell volume regulations, with many techniques developed in studying the functions and activities of CCCs...

Previous studies have shown that the hyperpolarized cyclic nucleotide gated (HCN) ion channels in the spinal dorsal horn (SDH) might be involved in the development of diabetic neuropathic pain (DNP). Additionally, other studies have shown that the decreased potassium-chloride cotransporter 2 (KCC2) expression in the SDH promotes pain hypersensitivity. Both HCN channels and KCC2 were highly expressed in spinal substantia gelatinosa neurons. However, whether the K+ efflux induced by the activation of HCN channels in DNP modulate KCC2 function and subsequently affect the role of γ-aminobutyric acid (GABA)/GABA-A receptors of neurons in the SDH remains to be clarified...

K+ -Cl- cotransporter-2 (KCC2) critically controls neuronal chloride homeostasis and maintains normal synaptic inhibition by GABA and glycine. Nerve injury diminishes synaptic inhibition in the spinal cord via KCC2 impairment. However, how KCC2 regulates nociceptive input to spinal excitatory and inhibitory neurons remains elusive. Here, we show that basal GABA reversal potentials were significantly more depolarized in vesicular GABA transporter (VGAT)-expressing inhibitory neurons than in vesicular glutamate transporter-2 (VGluT2)-expressing excitatory neurons in spinal cords of male and female mice...

Kamishoyosan (KSS) and Kamikihito (KKT) have been traditionally prescribed for neuropsychiatric symptoms in Japan. However, the molecular mechanism of its effect is not elucidated enough. On the other hand, it has been reported that lipopolysaccharide derived from Porphyromonas gingivalis ( P. g LPS) is involved not only in periodontal disease but also in the systemic diseases such as psychiatric disorders via neuroinflammation. Here, we investigated the molecular mechanism of KSS and KKT treatment by LPS-induced neuropathy using PC-12 cells...

The potassium chloride cotransporter KCC2 is crucial for Cl- extrusion from mature neurons and thus key to hyperpolarizing inhibition. Auditory brainstem circuits contain well-understood inhibitory projections and provide a potent model to study the regulation of synaptic inhibition. Two peculiarities of the auditory brainstem are (i) posttranslational activation of KCC2 during development and (ii) extremely negative reversal potentials in specific circuits. To investigate the role of the potent phospho-site serine 937 therein, we generated a KCC2 Thr934Ala /Ser937Asp double mutation, in which Ser937 is replaced by aspartate mimicking the phosphorylated state, and the neighbouring Thr934 arrested in the dephosphorylated state...