Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear

Institute of Biomedicine, University of Helsinki, Helsinki, Uusimaa, Finland
Molecular Pharmacology (Impact Factor: 4.13). 08/2005; 68(1):61-8. DOI: 10.1124/mol.104.009936
Source: PubMed


Inhaled anesthetics are believed to produce anesthesia by their actions on ion channels. Because inhaled anesthetics robustly enhance GABA A receptor (GABA(A)-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABA(A)-Rs and individual GABA(A)-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that inhaled anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABA(A)-Rs that harbor the alpha1 subunit. To test this, we used global knockout mice that completely lack the alpha1 subunit and forebrain-specific, conditional knockout mice that lack the alpha1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145% less sensitive to the amnestic effects of the inhaled anesthetic isoflurane. These results indicate that alpha1-containing GABA(A)-Rs in the hippocampus, amygdala, and/or cortex influence the amnestic effects of inhaled anesthetics and may be an important molecular target of the drug isoflurane.

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    • "To delete N-cadherin from excitatory neurons of the hippocampus , we crossed a mouse line expressing floxed N-cadherin with another line expressing Cre recombinase driven by the aCaMKII promoter as we reported previously (Bozdagi et al., 2010). As expected from the onset of expression of Cre recombinase (Tsien et al., 1996; Fukaya et al., 2003; Sonner et al., 2005; Gould et al., 2008), N-cadherin levels in hippocampal lysates taken from conditional knockout (cKO) mice (Ncad flox/flox ; Cre 2/1 ) were comparable to floxed control mice (Ncad flox/flox ; Cre 2/2 ) at 2 postnatal weeks, but then declined significantly thereafter (Fig. 2A, P < 0.01). In sections from hippocampus, Ncadherin immunofluorescence, which is typically punctate reflecting localization at synapses, was also largely eliminated throughout hippocampus in dentate gyrus (DG) and CA3 as well as in CA1 in the cKO mice (Figs. "
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    ABSTRACT: N-cadherin and β-catenin form a transsynaptic adhesion complex required for spine and synapse development. In adulthood, N-cadherin mediates persistent synaptic plasticity, but whether the role of N-cadherin at mature synapses is similar to that at developing synapses is unclear. To address this, we conditionally ablated N-cadherin from excitatory forebrain synapses in mice starting in late postnatal life and examined hippocampal structure and function in adulthood. In the absence of N-cadherin, β-catenin levels were reduced, but numbers of excitatory synapses were unchanged, and there was no impact on number or shape of dendrites or spines. However, the composition of synaptic molecules was altered. Levels of GluA1 and its scaffolding protein PSD95 were diminished and the density of immunolabeled puncta was decreased, without effects on other glutamate receptors and their scaffolding proteins. Additionally, loss of N-cadherin at excitatory synapses triggered increases in the density of markers for inhibitory synapses and decreased severity of hippocampal seizures. Finally, adult mutant mice were profoundly impaired in hippocampal-dependent memory for spatial episodes. These results demonstrate a novel function for the N-cadherin/β-catenin complex in regulating ionotropic receptor composition of excitatory synapses, an appropriate balance of excitatory and inhibitory synaptic proteins and the maintenance of neural circuitry necessary to generate flexible yet persistent cognitive and synaptic function. © 2014 Wiley Periodicals, Inc.
    Hippocampus 08/2014; 24(8). DOI:10.1002/hipo.22282 · 4.16 Impact Factor
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    • "In general, class A γ-aminobutyric acid (GABA A ) receptors are positively modulated by conventional inhaled anesthetics whereas N-methyl- D-aspartate (NMDA) receptors are negatively modulated by these same agents. Increasing inhibitory GABA A chloride currents and decreasing excitatory NMDA cation currents both cause neuronal hyperpolarization that reduces cell excitability and likely contributes to the immobilizing (Stabernack et al. 2003) and amnestic (Sonner et al. 2005) effects of anesthetics. "
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    ABSTRACT: At the minimum alveolar concentration (MAC), isoflurane potentiates GABA(A) receptor currents and inhibits NMDA receptor currents, and these actions may be important for producing anesthesia. However, isoflurane modulates GABA(A) receptors more potently than NMDA receptors. The objective of this study was to test whether isoflurane would function as a more potent NMDA receptor antagonist if its efficacy at GABA(A) receptors was decreased. Prospective experimental study. Fourteen 10-week-old male Sprague-Dawley rats weighing 269 ± 12 g. Indwelling lumbar subarachnoid catheters were surgically placed in isoflurane-anesthetized rats. Two days later, the rats were anesthetized with isoflurane, and artificial CSF containing either 0 or 1 mg kg(-1) picrotoxin, a GABA(A) receptor antagonist, was infused intrathecally at 1 μL minute(-1). The baseline isoflurane MAC was then determined using a standard tail clamp technique. MK801 (dizocilpine), an NMDA receptor antagonist, was then administered intravenously at 0.5 mg kg(-1). Isoflurane MAC was re-measured. Picrotoxin increased isoflurane MAC by 16% compared to controls. MK801 significantly decreased isoflurane MAC by 0.72% of an atmosphere in controls versus 0.47% of an atmosphere in rats receiving intrathecal picrotoxin. A smaller MK801 MAC-sparing effect in the picrotoxin group is consistent with greater NMDA antagonism by isoflurane in these animals, since it suggests that fewer NMDA receptors are available upon which MK801 could act to decrease isoflurane MAC. Decreasing isoflurane GABA(A) potentiation increases isoflurane NMDA antagonism at MAC. Hence, the magnitude of an anesthetic effect on a given channel or receptor at MAC may depend upon effects at other receptors.
    Veterinary Anaesthesia and Analgesia 05/2011; 38(3):231-9. DOI:10.1111/j.1467-2995.2011.00605.x · 1.72 Impact Factor
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    • "Floxed N-cadherin mice were characterized previously (Kostetskii et al., 2005), backcrossed to a C57Bl6 background (MaxBax, Charles River), then mated to a C57Bl6 αCaMKII-Cre driver line (Camk2a-Cre; T29-1 line; Jackson Labs (Tsien et al., 1996)). In hippocampus, Cre expression commences by the end of the third postnatal week and includes all excitatory neurons in CA1 by 8 weeks (Tsien et al., 1996; Fukaya et al., 2003; Sonner et al., 2005; Gould et al., 2008). Mice were genotyped by PCR. "
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    ABSTRACT: Persistent changes in spine shape are coupled to long-lasting synaptic plasticity in hippocampus. The molecules that coordinate such persistent structural and functional plasticity are unknown. Here, we generated mice in which the cell adhesion molecule N-cadherin was conditionally ablated from postnatal, excitatory synapses in hippocampus. We applied to adult mice of either sex a combination of whole-cell recording, two-photon microscopy, and spine morphometric analysis to show that postnatal ablation of N-cadherin has profound effects on the stability of coordinated spine enlargement and long-term potentiation (LTP) at mature CA1 synapses, with no effects on baseline spine density or morphology, baseline properties of synaptic neurotransmission, or long-term depression. Thus, N-cadherin couples persistent spine structural modifications with long-lasting synaptic functional modifications associated selectively with LTP, revealing unexpectedly distinct roles at mature synapses in comparison with earlier, broader functions in synapse and spine development.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2010; 30(30):9984-9. DOI:10.1523/JNEUROSCI.1223-10.2010 · 6.34 Impact Factor
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