Functional characterization of Na+/H+ exchangers of intracellular compartments using proton-killing selection to express them at the plasma membrane.

Endosomal acidification is critical for a wide range of processes, such as protein recycling and degradation, receptor desensitization, and neurotransmitter loading in synaptic vesicles. This acidification is described to be mediated by proton ATPases, coupled to ClC chloride transporters. Highly-conserved electroneutral protons transporters, the Na+/H+ exchangers (NHE) 6, 7 and 9 are also expressed in these compartments.

The intracellular Na(+)/H(+) exchanger NHE7 effects a Na(+)-coupled, but not K(+)-coupled proton-loading mechanism in endocytosis.

Vesicular H(+)-ATPases and ClC-chloride transporters are described to acidify intracellular compartments, which also express the highly conserved Na(+)/H(+) exchangers NHE6, NHE7, and NHE9. Mutations of these exchangers cause autism-spectrum disorders and neurodegeneration. NHE6, NHE7, and NHE9 are hypothesized to exchange cytosolic K(+) for H(+) and alkalinize vesicles, but this notion has remained untested in K(+) because their intracellular localization prevents functional measurements.

Molecular and electrophysiological changes in the prefrontal cortex-amygdala-dorsal periaqueductal grey pathway during persistent pain state and fear-conditioned analgesia.

Fear-conditioned analgesia (FCA) is the reduction in pain responding which is expressed upon re-exposure to a context previously paired with an aversive stimulus. Projections along the prefrontal cortex (PFC)-amygdala-dorsal periaqueductal grey (dPAG) pathway may mediate FCA. However, there is a paucity of studies measuring both molecular and electrophysiological changes in this pathway in rats expressing persistent pain-related behaviour or FCA.

Mechanisms underlying a life-threatening skeletal muscle Na+ channel disorder.

Myotonia is an intrinsic muscular disorder caused by muscle fibre hyperexcitability, which produces a prolonged time for relaxation after voluntary muscle contraction or internal mechanical stimulation. Missense mutations in skeletal muscle genes encoding Cl− or Na+ channels cause non-dystrophic myotonias.Mutations of the SCN4A gene that encodes the skeletal voltage-gated Na+ channel Nav1.

Alterations in prefrontal glutamatergic and noradrenergic systems following MK-801 administration in rats prenatally exposed to methylazoxymethanol at gestational day 17.

Rationale: Prenatal methylazoxymethanol (MAM) administration at gestational day 17 has been shown to induce in adult rats schizophrenia-like behaviours as well as morphological and/or functional abnormalities in structures such as the hippocampus, medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), consistent with human data.

Objectives: The aim of the present study was to further characterize the neurochemical alterations associated with this neurodevelopmental animal model of schizophrenia.

Materials And Methods: We performed simultaneous measurements of locomotor activity and extracellular concentrations of glutamate, dopamine and noradrenaline in the mPFC and the NAcc of adult rats prenatally exposed to MAM or saline after acute systemic injection of a noncompetitive NMDA antagonist, MK-801 (0.

Prefrontal infusion of PD098059 immediately after fear extinction training blocks extinction-associated prefrontal synaptic plasticity and decreases prefrontal ERK2 phosphorylation.

A previous study has demonstrated that disruption of fear extinction-induced long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) is associated with the return of fear responding. Given that immediate posttraining infusion of PD098059, an inhibitor of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascade, into the mPFC also promotes recovery of fear, we investigated whether impairment of mPFC ERK/MAPK cascade also interferes with development of extinction-related LTP in the mPFC in rats. In Experiment 1, extinction training consisting of repetitive presentations of a tone previously associated with eyelid-shock application induced LTP-like changes at hippocampal inputs to the mPFC that were evident for approximately 2 h following fear extinction.

Ketamine, at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens.

Noncompetitive N-methyl-D-aspartate (NMDA) antagonists such as ketamine represent useful pharmacological tools to model, in both healthy humans and rodents, behavioral and cerebral abnormalities of schizophrenia. These compounds are thought to exert some of their disruptive effects by impairing glutamatergic transmission in corticolimbic circuits including the nucleus accumbens (NAc). In this study, we investigated in freely moving rats behavioral changes as well as electrophysiological and neurochemical alterations in the NAc following acute systemic injection of a subanesthetic dose (25 mg/kg) of ketamine.

Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia.

Opioid and tachykinin systems are involved in modulation of pain transmission in the spinal cord. Regulation of surface opioid receptors on nociceptive afferents is critical for opioid analgesia. Plasma-membrane insertion of delta-opioid receptors (DORs) is induced by stimulus-triggered exocytosis of DOR-containing large dense-core vesicles (LDCVs), but how DORs become sorted into the regulated secretory pathway is unknown.

Quantitative autoradiography of dopamine receptors in the brains of micro-opioid receptor knockout mice.

Given the existence of functional interactions between opioidergic and dopaminergic systems, we have analyzed by quantitative autoradiography the possible long-term adaptive changes in the expression of D(1)- and D(2)-like dopamine receptors in the brains of mice lacking the micro-opioid receptor gene. An overall significant increase in D(1) and D(2) receptors (7.4 and 12.

The entorhinal cortex-nucleus accumbens pathway and latent inhibition: a behavioral and neurochemical study in rats.

Latent inhibition (LI) refers to the decrease in conditioned response produced by the repeated nonrein-forced preexposure to the to-be-conditioned stimulus. Experiment I investigated the effects of electrolytic lesions of the entorhinal cortex on LI in a conditioned emotional response procedure. Entorhinal cortex lesions attenuated LI.