kCC2

Serotonergic neurons in the dorsal raphe nucleus (DRN) act as wake-inducing neurons in the sleep-wake cycle and are controlled by gamma-aminobutyric acid (GABA) synaptic inputs. We investigated daily changes in GABAergic inhibition of the rat DRN neurons and the role of nitric oxide (NO) and cation-chloride co-transporters in the GABAergic action. Neuronal NO synthase (nNOS) was co-expressed in 74% of serotonergic DRN neurons and nNOS expression was higher during daytime (the sleep cycle) than that during nighttime (the wake cycle)...

Potassium-chloride cotransporter 2 (KCC2) has been indicated to serve a crucial role during chronic neuropathic pain (NP). Following the emergence of NP, γ‑aminobutyric acid (GABA) A receptor‑mediated signaling may be further impaired by the changes of KCC2 chloride anion gradient. In the present study, the authors investigate the effect of electro-acupuncture (EA) on the behavior and the expression of KCC2 and GABAA receptor γ2 subunit in the spinal cord of chronic constriction injury (CCI) model rats...

Epigenetic modulation participates in the mechanism of multiple types of pathological pain, so targeting the involved regulators may be a promising strategy for pain treatment. Our previous research identified the analgesic effect of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on mechanical hyperalgesia in a rat model of bone cancer pain (BCP) via restoration of μ-opioid receptor (MOR) expression. However, the specific types of HDACs contributing to BCP have not been explored. The present study investigated the expression pattern of some common HDACs and found that HDAC2 was up-regulated in a time-dependent manner in the lumbar spinal cord of BCP rats...

Quantitative phase imaging (QPI) has recently emerged as a powerful new quantitative microscopy technique suitable for the noninvasive exploration of the structure and dynamics of transparent specimens, including living cells in culture. Indeed, the quantitative phase signal (QPS), induced by transparent living cells, can be detected with a nanometric axial sensitivity, and contains a wealth of information about both cell morphology and content. However, QPS is also sensitive to various sources of experimental noise...

Neuronal intracellular Cl- concentration ([Cl-]i) influences a wide range of processes such as neuronal inhibition, membrane potential dynamics, intracellular pH (pHi) or cell volume. Up to date, neuronal [Cl-]i has predominantly been studied in model systems of reduced complexity. Here, we implemented the genetically encoded ratiometric Cl- indicator Superclomeleon (SCLM) to estimate the steady-state [Cl-]i in cortical neurons from anesthetized and awake mice using 2-photon microscopy. Additionally, we implemented superecliptic pHluorin (SE-pHluorin) as a ratiometric sensor to estimate the intracellular steady-state pH (pHi) of mouse cortical neurons in vivo...

KCC2 (a brain-specific potassium-chloride cotransporter) affects development of the cerebral cortex, including aspects of neuronal migration and cellular maturation and differentiation. KCC2 also modulates chloride homeostasis by influencing the switch of GABA from depolarizing in young neurons to hyperpolarizing in mature neurons. We describe the expression pattern, regional distribution, and cellular colocalization of KCC2 in the ferret cortex in normal kits and those treated with methylazoxymethanol acetate (MAM)...

Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice...

Chronic inflammatory and neuropathic pains are major public health concerns. Potential therapeutic targets include the ATP-gated purinergic receptors (P2RX) that contribute to these pathological types of pain in several different cell types. The purinergic receptors P2RX2 and P2RX3 are expressed by a specific subset of dorsal root ganglion neurons and directly shape pain processing by primary afferents. In contrast the P2RX4 and P2RX7 are mostly expressed in myeloid cells, where activation of these receptors triggers the release of various pro-inflammatory molecules...

Autism spectrum disorder (ASD) and temporal lobe epilepsy exhibit remarkable comorbidity, but for reasons not clearly understood. To reveal a common pathophysiological mechanism, we here describe and characterize an in vitro epileptiform activity in the rat hippocampus that exhibits common features with in vivo activity in rodent ASD models. We discovered the development of this activity in the CA1 region of horizontal slices after prolonged interictal-like epileptiform activity in the CA3 region that was provoked by incubation in high potassium artificial cerebrospinal fluid...

Reduced top-down control by cortical areas is assumed to underlie pathological forms of aggression. While the precise underlying molecular mechanisms are still elusive, it seems that balancing the excitatory and inhibitory tones of cortical brain areas has a role in aggression control. The molecular mechanisms underpinning aggression control were examined in the BALB/cJ mouse model. First, these mice were extensively phenotyped for aggression and anxiety in comparison to BALB/cByJ controls. Microarray data was then used to construct a molecular landscape, based on the mRNAs that were differentially expressed in the brains of BALB/cJ mice...

The stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is normally suppressed during pregnancy. Dysregulation of the HPA axis has been proposed to play a role in postpartum depression. However, direct investigation into the relationship between the HPA axis and postpartum depression has been hindered by the lack of useful animal models. Building on our discovery of a role for the K+/Cl-co-transporter, KCC2, in the GABAergic regulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN), critical for mounting the body's physiological response to stress, we assessed the role of KCC2 in the regulation of the HPA axis during pregnancy and the postpartum period...

Maintenance of a low intracellular Cl- concentration ([Cl- ]i ) is critical for enabling inhibitory neuronal responses to GABAA receptor-mediated signaling. Cl- transporters, including KCC2, and extracellular impermeant anions ([A]o ) of the extracellular matrix are both proposed to be important regulators of [Cl- ]i Neurons of the reticular thalamic (RT) nucleus express reduced levels of KCC2, indicating that GABAergic signaling may produce excitation in RT neurons. However, by performing perforated patch recordings and calcium imaging experiments in rats (male and female), we find that [Cl- ]i remains relatively low in RT neurons...

Songbirds learn to produce vocalizations early in life by listening to, then copying the songs of conspecific males. The anterior forebrain pathway, homologous to a basal ganglia-forebrain circuit, is essential for song learning. The projection between the striato-pallidal structure, Area X, and the medial portion of the dorsolateral thalamic nucleus (DLM) is strongly hyperpolarizing in adults, due to a very negative chloride reversal potential (Person & Perkel, Neuron 46:129-140, 2005). The chloride reversal potential is determined, in part, by the expression level of a neuron-specific potassium-chloride cotransporter, KCC2, which is developmentally upregulated in mammals...

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No abstract text is available yet for this article.

Diabetes mellitus (DM) is associated with increased plasma levels of arginine-vasopressin (AVP), which may aggravate hyperglycemia and nephropathy. However, the mechanisms by which DM may cause the increased AVP levels are not known. Electrophysiological recordings in supraoptic nucleus (SON) slices from streptozotocin (STZ)-induced DM rats and vehicle-treated control rats revealed that γ-aminobutyric acid (GABA) functions generally as an excitatory neurotransmitter in the AVP neurons of STZ rats, whereas it usually evokes inhibitory responses in the cells of control animals...

The K+ -Cl- co-transporter KCC2 is a neuron-specific, Cl- extruder that uses K+ gradient for maintaining low intracellular [Cl- ]. It is indeed well established that sustaining an outwardly-directed electrochemical Cl- gradient across the neuronal membrane is fundamental for a proper function of postsynaptic GABAA receptor signaling. In particular, studies in the last two decades have shown that KCC2 activity is important to maintain a hyperpolarizing GABAergic neurotransmission. Conversely, low KCC2 activity should lead to depolarizing, and under specific conditions, excitatory GABAergic transmission...

KCC2 is a neuron specific K+ -Cl- co-transporter that controls neuronal chloride homeostasis, and is critically involved in many neurological diseases including brain trauma, epilepsies, autism and schizophrenia. Despite significant accumulating data on the biology and electrophysiological properties of KCC2, structure-function relationships remain poorly understood. Here we used calixarene detergent to solubilize and purify wild-type non-aggregated and homogenous KCC2. Specific binding of inhibitor compound VU0463271 was demonstrated using surface plasmon resonance (SPR)...

The K+ -Cl- co-transporter KCC2 (SLC12A5) tunes the efficacy of GABAA receptor-mediated transmission by regulating the intraneuronal chloride concentration [Cl- ]i . KCC2 undergoes activity-dependent regulation in both physiological and pathological conditions. The regulation of KCC2 by synaptic excitation is well documented; however, whether the transporter is regulated by synaptic inhibition is unknown. Here we report a mechanism of KCC2 regulation by GABAA receptor (GABAA R)-mediated transmission in mature hippocampal neurons...

The inhibitory neurotransmitter gamma-amino butyric acid (GABA) plays important roles in energy balance and feeding behavior in the hypothalamus. To reveal the time course of GABAergic network formation, we examined the immunohistochemical localization of glutamic acid decarboxylase (GAD), a GABAergic neuron marker, vesicular GABA transporter (VGAT), a marker of inhibitory terminals, and K+ -Cl- -cotransporter2 (KCC2), which shifts GABA action from excitation to inhibition, in the developing mouse hypothalamus...