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    ABSTRACT: Experiences with a high degree of emotional salience are better remembered than events that have little emotional context and the amygdala is thought to play an important role in this enhancement of memory. Visual recognition memory relies on synaptic plasticity in the perirhinal cortex but little is known about the mechanisms that may underlie emotional enhancement of this form of memory. There is good evidence that noradrenaline acting via β-adrenoceptors can enhance memory consolidation. In the present study we examine the role of β-adrenoceptors in synaptic plasticity at the amygdala-perirhinal pathway (LA-PRh) and compare this to mechanisms of intra-perirhinal (PRh-PRh) synaptic plasticity. We demonstrate that activity-dependent PRh-PRh LTP does not rely on β1- or β2-adrenoceptors and that LA-PRh LTP relies on β1-adrenoceptors but not β2-adrenoceptors. We further demonstrate that application of the β-adrenoceptor agonist isoprenaline produces lasting PRh-PRh potentiation but only transient potentiation at the LA-PRh input. However, at the LA-PRh input, combining stimulation that is subthreshold for LTP induction with isoprenaline results in long-lasting potentiation. Isoprenaline-induced and isoprenaline plus subthreshold stimulation-induced potentiation in the PRh-PRh and LA-PRh inputs, respectively were both dependent on activation of NMDARs, voltage gated calcium channels and PKA. Understanding the mechanisms of amygdala-perirhinal cortex plasticity will allow a greater understanding of how emotionally-charged events are remembered.
    Neuroscience 05/2014;
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    ABSTRACT: Defective epithelial ion transport is the hallmark of the life-limiting genetic disease cystic fibrosis (CF). This abnormality is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), the ATP-binding cassette transporter that functions as a ligand-gated anion channel. Since the identification of the CFTR gene, almost 2,000 disease-causing mutations associated with a spectrum of clinical phenotypes have been reported, but the majority remain poorly characterised.Studiesof a small number of mutations including the most common, F508del-CFTR, have identified six general mechanisms of CFTR dysfunction. Here, we review selectively progress to understand how CF mutations disrupt CFTR processing, stability and function. We explore CFTR structure and function to explain the molecular mechanisms of CFTR dysfunction and highlight new knowledge of disease pathophysiology emerging from large animal models of CF. Understanding CFTR dysfunction is crucial to the development of transformational therapies for CF patients.
    The international journal of biochemistry & cell biology 04/2014;
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    ABSTRACT: L-type Ca channels (LTCC), which play a key role in cardiac excitation-contraction coupling, are located predominantly at the transverse (t-) tubules in ventricular myocytes. Caveolae and the protein caveolin-3 (Cav-3) are also present at the t-tubules and have been implicated in localizing a number of signaling molecules, including protein kinase A (PKA) and β2-adrenoreceptors. The present study investigated whether disruption of Cav-3 binding to its endogenous binding partners influenced LTCC activity. Ventricular myocytes were isolated from male Wistar rats and LTCC current (ICa) recorded using the whole-cell patch-clamp technique. Incubation of myocytes with a membrane-permeable peptide representing the scaffolding domain of Cav-3 (C3SD) reduced basal ICa amplitude in intact, but not detubulated, myocytes, and attenuated the stimulatory effects of the β2-adrenergic agonist zinterol on ICa. The PKA inhibitor H-89 also reduced basal ICa; however, the inhibitory effects of C3SD and H-89 on basal ICa amplitude were not summative. Under control conditions, myocytes stained with antibody against phosphorylated LTCC (pLTCC) displayed a striated pattern, presumably reflecting localization at the t-tubules. Both C3SD and H-89 reduced pLTCC staining at the z-lines but did not affect staining of total LTCC or Cav-3. These data are consistent with the idea that the effects of C3SD and H-89 share a common pathway, which involves PKA and is maximally inhibited by H-89, and suggest that Cav-3 plays an important role in mediating stimulation of ICa via PKA-induced phosphorylation under basal conditions, and in response to β2-adrenoceptor stimulation.
    Journal of Molecular and Cellular Cardiology 01/2014;
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    ABSTRACT: Somatostatin (SRIF), by acting mainly through sst2 and sst5 receptors, is a potent inhibitor of hormonal secretion by human anterior pituitary. However the pattern of protein expression of these SRIF receptors remains unknown during pituitary development. To get further insights into the physiological role of SRIF receptor in human development and pituitary function, the present study examined the developmental expression of the sst2 and sst5 receptors in the individual cell types of the anterior human pituitary. Thirteen fetal human pituitaries between 13 to 38 weeks of gestation (WG) were investigated by double-labeling immunofluorescence with antibodies raised against sst2 or sst5 receptors and GH, LH, FSH, TSH or Pro-opiomelanocortin (POMC) proteins. SRIF immunoreactivity in hypothalamus and median eminence was investigated at the same developmental ages. Immunoreactivity for the sst2 receptor was evident as early as 13-15 WG and onward mainly in TSH, LH and FSH expressing cells, whereas sst5 immunoreactivity was apparent at the late development stages (35-38 WG). GH expressing cells mainly expressed sst5 immunoreactivity. SRIF positive fibers and cells were detected as soon as 13-16 GW in the hypothalamus and median eminence and their densities increased with gestational age. Early appearance of hypothalamic SRIF cells and fibers suggests a physiological link between SRIF and its receptors during pituitary development. While sst2 receptors might play a primary role on the differentiation and regulation of TSH, LH and FSH cells, sst5 receptors appear to be mainly involved in GH regulation from birth onward.
    Endocrinology 11/2013;
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    ABSTRACT: The topography of the cerebellar cortex is described by at least three different maps, with the basic units of each map termed "microzones," "patches," and "bands." These are defined, respectively, by different patterns of climbing fiber input, mossy fiber input, and Purkinje cell (PC) phenotype. Based on embryological development, the "one-map" hypothesis proposes that the basic units of each map align in the adult animal and the aim of the present study was to test this possibility. In barbiturate anesthetized adult rats, nanoinjections of bidirectional tracer (Retrobeads and biotinylated dextran amine) were made into somatotopically identified regions within the hindlimb C1 zone in copula pyramidis. Injection sites were mapped relative to PC bands defined by the molecular marker zebrin II and were correlated with the pattern of retrograde cell labeling within the inferior olive and in the basilar pontine nuclei to determine connectivity of microzones and patches, respectively, and also with the distributions of biotinylated dextran amine-labeled PC terminals in the cerebellar nuclei. Zebrin bands were found to be related to both climbing fiber and mossy fiber inputs and also to cortical representation of different parts of the ipsilateral hindpaw, indicating a precise spatial organization within cerebellar microcircuitry. This precise connectivity extends to PC terminal fields in the cerebellar nuclei and olivonuclear projections. These findings strongly support the one-map hypothesis and suggest that, at the microcircuit level of resolution, the cerebellar cortex has a common plan of spatial organization for major inputs, outputs, and PC phenotype.
    Journal of Neuroscience 10/2013; 33(42):16427-42.
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    ABSTRACT: Loop diuretics are widely used to inhibit the Na(+) , K(+) , 2Cl(-) cotransporter. However, these agents also inhibit the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. Here, we investigate the mechanism of CFTR inhibition by loop diuretics and explore the impact of chemical structure on channel blockade. We tested the effects of bumetanide, furosemide, piretanide and xipamide on recombinant wild-type human CFTR using the patch-clamp technique. When added to the intracellular solution, loop diuretics inhibited CFTR Cl(-) currents with potency approaching that of glibenclamide, a widely used CFTR blocker with some structural similarity to loop diuretics. To begin to study the kinetics of channel blockade, we examined the time-dependence of macroscopic current inhibition following a hyperpolarizing voltage step. Like glibenclamide, piretanide blockade of CFTR was time- and voltage-dependent. By contrast, furosemide blockade was voltage-dependent, but time-independent. Consistent with these data, furosemide blocked individual CFTR Cl(-) channels with 'very fast' speed and drug-induced blocking events overlapped brief channel closures, whereas piretanide inhibited individual channels with 'intermediate' speed and drug-induced blocking events were distinct from channel closures. Analysis of the chemical structures of loop diuretics suggests that the phenoxy group present in bumetanide and piretanide, but absent in furosemide and xipamide might account for the different kinetics of channel block by locking loop diuretics within the intracellular vestibule of the CFTR pore. We conclude that loop-diuretics are open-channel blockers of CFTR with distinct kinetics, influenced by molecular dimensions and lipophilicity.
    British Journal of Pharmacology 10/2013;
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    ABSTRACT: Rho GTPases such as Rac, RhoA and Cdc42 are vital for normal platelet function, but the role of RhoG in platelets has not been studied. In other cells RhoG orchestrates processes integral to platelet function including actin cytoskeletal rearrangement and membrane trafficking. We therefore hypothesized that RhoG would play a critical role in platelets. Here we show that RhoG is expressed in human and in mouse platelets, and is activated by both collagen-related peptide (CRP) and thrombin stimulation. We used RhoG-/- mice to study the function of RhoG in platelets. Integrin activation and aggregation are reduced in RhoG-/- platelets stimulated by CRP, but responses to thrombin are normal. The central defect in RhoG-/- platelets is reduced secretion from alpha- and dense-granules and lysosomes following CRP stimulation. The integrin activation and aggregation defects can be rescued by ADP co-stimulation, indicating they are a consequence of diminished dense granule secretion. Defective dense granule secretion in RhoG-/- platelets limits recruitment of additional platelets to growing thrombi in flowing blood in vitro and translates into reduced thrombus formation in vivo. Interestingly, tail bleeding times are normal in RhoG-/- mice, suggesting that the functions of RhoG in platelets are particularly relevant to thrombotic disorders.
    Journal of Biological Chemistry 10/2013;
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    ABSTRACT: Deep brain stimulation (DBS) in humans has come of age as a tool to treat a panoply of disease states including Parkinson's disease tremor and dystonia and a panoply of other disease states including headache, epilepsy, obesity, eating disorders, depression, obsessive compulsive disorder, Tourette's syndrome, addiction and chronic pain. Increasingly, practitioners of DBS are reporting autonomic side effects, which intriguingly, sometimes result in improved autonomic function. Focussing on the effects of stimulation at periaqueductal and periventricular sites on cardiovascular function and control of micturition, this review shows that data obtained from studies in both animals is now being confirmed in humans. Lowering of blood pressure, improved baroreflex function can be evoked by midbrain DBS in animals and humans. Increased bladder capacity has also been shown in rats and humans following midbrain DBS. The findings highlight the tantalizing possibility that DBS could be developed for treatment of dysfunctional autonomic states in humans.
    Experimental physiology 09/2013;
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    ABSTRACT: Transgenic mice that accumulate Aβ peptides in the CNS are commonly used to interrogate functional consequences of Alzheimer's disease-associated amyloidopathy. In addition to changes to synaptic function, there is also growing evidence that changes to intrinsic excitability of neurones can arise in these models of amyloidopathy. Furthermore, some of these alterations to intrinsic properties may occur relatively early within the age-related progression of experimental amyloidopathy. Here we report a detailed comparison between the intrinsic excitability properties of hippocampal CA1 pyramidal neurones in wild-type (WT) and PDAPP mice. The latter are a well-established model of Aβ accumulation which expresses human APP harbouring the Indiana (V717F) mutation. At the age employed in this study (9-10 months) CNS Abeta was elevated in PDAPP mice but significant plaque pathology was absent. PDAPP mice exhibited no differences in subthreshold intrinsic properties including resting potential, input resistance, membrane time constant and sag. When CA1 cells of PDAPP mice were given depolarizing stimuli of various amplitudes they initially fired at a higher frequency than WT cells. Commensurate with this, PDAPP cells exhibited a larger fast afterdepolarizing potential. PDAPP mice had narrower spikes but action potential threshold, rate of rise and peak were not different. Thus not all changes seen in our previous studies of amyloidopathy models were present in PDAPP mice; however, narrower spikes, larger ADPs and the propensity to fire at higher frequencies were consistent with our prior work and thus may represent robust, cross-model, indices of amyloidopathy.
    Neuropharmacology 09/2013;
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    ABSTRACT: Object-in-place associative recognition memory depends on an interaction between the hippocampus (HPC), perirhinal (PRH), and medial prefrontal (mPFC) cortices, yet the contribution of glutamate receptor neurotransmission to these interactions is unknown. NMDA receptors (NMDAR) in the HPC were critical for encoding of object-in-place memory but not for single-item object recognition. Next, a disconnection procedure was used to examine the importance of "concurrent" glutamate neurotransmission in the HPC-mPFC and HPC-PRH. Contralateral unilateral infusions of NBQX (AMPAR antagonist), into the HPC-mPFC, or HPC-PRH, either before acquisition or test, impaired object-in-place performance. Thus, both circuits are necessary for encoding and retrieval. Crossed unilateral AP5 (NMDAR antagonist) infusions into the HPC-mPFC or HPC-PRH impaired encoding, but not retrieval. Specifically crossed HPC-mPFC infusions impaired both short-term (5 min) and longer term (1 h) memory while HPC-PRH infusions impaired longer term memory only. This delay-dependent effect of AP5 in the HPC-PRH on object-in-place memory, accords with its effects in the PRH, on single item object recognition memory, thereby suggesting that a single PRH synaptic plasticity mechanism underpins different recognition memory processes. Further, blocking excitatory neurotransmission in any pair of structures within the networks impaired "both" encoding and retrieval, thus object-in-place memory clearly requires network interdependency across multiple structures.
    Cerebral Cortex 09/2013;
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