Paul A. Davies

Publications (28) View all

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  Available from: Paul A. Davies

  Article: Disrupted Cl(-) homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states.

  Tarek Z Deeb, Yasuko Nakamura, Greg D Frost, Paul A Davies, Stephen J Moss
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  ABSTRACT: The K(+) -Cl(-) cotransporter type 2 is the major Cl(-) extrusion mechanism in most adult neurons. This process in turn leads to Cl(-) influx upon activation of γ-aminobutyric acid type A (GABAA ) receptors and the canonical hyperpolarising inhibitory postsynaptic potential. Several neurological disorders are treated with drugs that target and enhance GABAA receptor signaling, including the commonly used benzodiazepine diazepam and the anesthetic propofol. Some of these disorders are also associated with deficits in GABAA signaling and become less sensitive to therapeutic drugs that target GABAA receptors. To date, it is unknown if alterations in the neuronal Cl(-) gradient affect the efficacies of diazepam and propofol. We therefore used the in vitro model of glutamate-induced hyperexcitability to test if alterations in the Cl(-) gradient affect the efficacy of GABAA modulators. We exclusively utilised the gramicidin perforated-patch-clamp configuration to preserve the endogenous Cl(-) gradient in rat neurons. Brief exposure to glutamate reduced the inhibitory efficacy of diazepam within 5 min, which was caused by the collapse of the Cl(-) gradient, and not due to reductions in GABAA receptor number. Unlike diazepam, propofol retained its efficacy by shunting the membrane conductance despite the glutamate-induced appearance of depolarising GABAA -mediated currents. Similarly, pharmacological inhibition of K(+) -Cl(-) cotransporter type 2 by furosemide disrupted Cl(-) homeostasis and reduced the efficacy of diazepam but not propofol. Collectively our results suggest that pathological hyperexcitable conditions could cause the rapid accumulation of intracellular Cl(-) and the appearance of depolarising GABAA -mediated currents that would decrease the efficacy of diazepam.
  European Journal of Neuroscience 04/2013; · 3.63 Impact Factor
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  Article: Enhanced tonic inhibition influences the hypnotic and amnestic actions of the intravenous anesthetics etomidate and propofol.

  Karla Kretschmannova, Rochelle M Hines, Raquel Revilla-Sanchez, Miho Terunuma, Verena Tretter, Rachel Jurd, Max B Kelz, Stephen J Moss, Paul A Davies
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  ABSTRACT: Intravenous anesthetics exert a component of their actions via potentiating inhibitory neurotransmission mediated by γ-aminobutyric type-A receptors (GABAARs). Phasic and tonic inhibition is mediated by distinct populations of GABAARs, with the majority of phasic inhibition by subtypes composed of α1-3βγ2 subunits, whereas tonic inhibition is dependent on subtypes assembled from α4-6βδ subunits. To explore the contribution that these distinct forms of inhibition play in mediating intravenous anesthesia, we have used mice in which tyrosine residues 365/7 within the γ2 subunit are mutated to phenyalanines (Y365/7F). Here we demonstrate that this mutation leads to increased accumulation of the α4 subunit containing GABAARs in the thalamus and dentate gyrus of female Y365/7F but not male Y365/7F mice. Y365/7F mice exhibited a gender-specific enhancement of tonic inhibition in the dentate gyrus that was more sensitive to modulation by the anesthetic etomidate, together with a deficit in long-term potentiation. Consistent with this, female Y365/7F, but not male Y365/7F, mice exhibited a dramatic increase in the duration of etomidate- and propofol-mediated hypnosis. Moreover, the amnestic actions of etomidate were selectively potentiated in female Y365/7F mice. Collectively, these observations suggest that potentiation of tonic inhibition mediated by α4 subunit containing GABAARs contributes to the hypnotic and amnestic actions of the intravenous anesthetics, etomidate and propofol.
  Journal of Neuroscience 04/2013; 33(17):7264-73. · 7.11 Impact Factor
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  Article: Memory Deficits Induced by Inflammation Are Regulated by alpha5-Subunit-Containing GABA(A) Receptors

  D. S. Wang, A. A. Zurek, I. Lecker, J. Yu, A. M. Abramian, S. Avramescu, P. A. Davies, S. J. Moss, W. Y. Lu, B. A. Orser
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  ABSTRACT: Systemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting alpha5-subunit-containing gamma-aminobutyric acid type A (alpha5GABA(A)) receptors and deleting the gene associated with the alpha5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of alpha5GABA(A) receptor function. A tonic inhibitory current generated by alpha5GABA(A) receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1beta through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1beta also increased the surface expression of alpha5GABA(A) receptors in the hippocampus. Collectively, these results show that alpha5GABA(A) receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.
  Cell Rep. 01/2012; 2(3):488-96.
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  Article: Hyperpolarizing GABAergic transmission depends on KCC2 function and membrane potential.

  Tarek Z Deeb, Henry H C Lee, Joshua A Walker, Paul A Davies, Stephen J Moss
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  ABSTRACT: KCC2 comprises the major Cl(-) extruding mechanism in most adult neurons. Hyperpolarizing GABAergic transmission depends on KCC2 function. We recently demonstrated that glutamate reduces KCC2 function by a phosphorylation-dependent mechanism that leads to excitatory GABA responses. Here we investigated the methods by which to estimate changes in E(GABA), as well as the processes that lead to depolarizing GABA responses and their effects on neuronal excitability. We demonstrated that current-clamp recordings of membrane potential responses to GABA can determine upper and lower limits of E(GABA). We also further characterized depolarizing GABA responses, which both excited and inhibited neurons. Our analyses revealed that persistently active GABA(A) receptors contributed to loading Cl(-) during the glutamate exposure, indicating that tonic inhibition can facilitate the development of depolarizing GABA responses and increase excitability after pathophysiological insults. Finally, we demonstrated that hyperpolarizing GABA responses could temporarily switch to depolarizing responses when they coincided with an afterhyperpolarization.
  Channels (Austin, Tex.) 11/2011; 5(6):475-81. · 1.91 Impact Factor
• Article: Functional regulation of GABAA receptors in nervous system pathologies.

  Rochelle M Hines, Paul A Davies, Stephen J Moss, Jamie Maguire
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  ABSTRACT: Inhibitory neurotransmission is primarily governed by γ-aminobutyric acid (GABA) type A receptors (GABAARs). GABAARs are heteropentameric ligand-gated channels formed by the combination of 19 possible subunits. GABAAR subunits are subject to multiple types of regulation, impacting the localization, properties, and function of assembled receptors. GABAARs mediate both phasic (synaptic) and tonic (extrasynaptic) inhibition. While the regulatory mechanisms governing synaptic receptors have begun to be defined, little is known about the regulation of extrasynaptic receptors. We examine the contributions of GABAARs to the pathogenesis of neurodevelopmental disorders, schizophrenia, depression, epilepsy, and stroke, with particular focus on extrasynaptic GABAARs. We suggest that extrasynaptic GABAARs are attractive targets for the treatment of these disorders, and that research should be focused on delineating the mechanisms that regulate extrasynaptic GABAARs, promoting new therapeutic approaches.
  Current opinion in neurobiology 10/2011; 22(3):552-8. · 7.21 Impact Factor