| Abstract No.: | A-B1036 |
| Country: | Canada |
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| Title: | ANESTHETIC-INDUCED IMPAIRMENT OF MEMORY AND LTP IS RESCUED BY BLOCKADE OF α5GABA(A) RECEPTORS |
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| Authors/Affiliations: | 1 Loren Martin*; 1 Gabriel Oh; 1 John Macdonald; 1 Beverley Orser;
1 University of Toronto, ON, Canada
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| Content: | GABA(A) receptors that contain the α5 subunit (α5GABA(A)Rs) are expressed predominantly in extrasynaptic regions of hippocampal neurons (Brain Res. 1999:822(1-2):265-70). The α5GABA(A)R has been strongly implicated in learning and memory processes. Genetic or pharmacological interventions that reduce α5GABA(A)R function improve performance for hippocampus-dependent learning tasks (J Neurosci. 2002:22(13):5572-80; J Pharmacol Exp Ther. 2006:316(3):1335-45). Conversely, we showed that the prototypic general anesthetic etomidate increases α5GABA(A)R function in vitro and thereby impairs learning and memory in vivo (J Neurosci. 2006:26(14):3713-20).
OBJECTIVE: The purpose of this study was to determine whether L-655,708, an inverse agonist selective for α5GABA(A)Rs, rescues hippocampus dependent memories and long-term potentiation (LTP) which are impaired following etomidate treatment.
MATERIALS AND METHODS: In order to asses hippocampal performance in vivo, we used a classical fear conditioning paradigm, which consisted of a baseline period followed by 3 unsignaled foot shocks separated by 60 s (0.7 mA, 2 s). As an indication of memory, freezing behaviour was assessed every 8 s for 8 min, 24 hr following the conditioning protocol. Additionally, we assessed the spatial performance of the mice during the probe trial of the Morris water maze. LTP was induced at CA1 Schaffer collateral synapses with a theta-burst protocol (4 pulses @ 100 Hz presented 10 times separated by 200 ms).
RESULTS: Etomidate (4 mg/kg) impaired the performance of WT littermates in contextual fear conditioning and the probe trial of the water maze, as previously reported (J Neurosci. 2006:26(14):3713-20). While, mice treated with both L-655,708 (0.7 mg/kg) and etomidate did not show impaired performance during either task. Etomidate (1 μM) abolished LTP induced by theta-burst stimulation (TBS) in WT but not α5-/- slices. Co-application of L-655,708 (10 μM) and etomidate reversed the inhibition of LTP in WT slices. Interestingly, the application of L-655,708 alone did not enhance LTP. PPF is a form of short-term plasticity, which is thought to be a consequence of presynaptic factors. No difference in PPF was detected in slices from α5-/- and WT mice. Etomidate did not influence PPF when administered alone. In addition, etomidate did not change the input/output relationship when slices were stimulated at various intensities as determined by a plot of the presynaptic fiber volley versus the slope of the fEPSPs.
CONCLUSION: These results suggest that etomidate impairs hippocampus-dependent memory and LTP but not short-term plasticity via a α5GABAAR-dependent mechanism. An inverse agonist selective for α5GABA(A)Rs reverses etomidate-impairment of memory and synaptic plasticity.
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