Abstract
Benzodiazepine withdrawal anxiety is associated with potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) currents in hippocampal CA1 pyramidal neurons attributable to increased synaptic incorporation of GluA1-containing AMPARs. The contribution of calcium/calmodulin-dependent protein kinase II (CaMKII) to enhanced glutamatergic synaptic strength during withdrawal from 1-week oral flurazepam (FZP) administration was further examined in hippocampal slices. As earlier reported, AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) amplitude increased in CA1 neurons from 1- and 2-day FZP-withdrawn rats, along with increased single-channel conductance in neurons from 2-day rats, estimated by non-stationary noise analysis. Input–output curve slope was increased without a change in paired-pulse facilitation, suggesting increased AMPAR postsynaptic efficacy rather than altered glutamate release. The increased mEPSC amplitude and AMPAR conductance were related to CaMKII activity, as intracellular inclusion of CaMKIINtide or autocamtide-2-related inhibitory peptide, but not scrambled peptide, prevented both AMPAR amplitude and conductance changes. mEPSC inhibition by 1-naphthyl acetyl spermine and the negative shift in rectification index at both withdrawal time points were consistent with functional incorporation of GluA2-lacking AMPARs. GluA1 but not GluA2 or GluA3 levels were increased in immunoblots of postsynaptic density (PSD)-enriched subcellular fractions of CA1 minislices from 1-day FZP-withdrawn rats, when mEPSC amplitude, but not conductance, was increased. Both GluA1 expression levels and CaMKIIα-mediated GluA1 Ser831 phosphorylation were increased in PSD-subfractions from 2-day FZP-withdrawn rats. As phospho-Thr286CaMKIIα was unchanged, CaMKIIα may be activated through an alternative signaling pathway. Synaptic insertion and subsequent CaMKIIα-mediated Ser831 phosphorylation of GluA1 homomers contribute to benzodiazepine withdrawal-induced AMPAR potentiation and may represent an important hippocampal pathway mediating both drug-induced and activity-dependent plasticity.
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Acknowledgements
We thank Krista Pettee, Brian Behrle, Margarete Otting, and Eugene Orlowski for expert technical assistance. We also acknowledge LJ Greenfield, Jr MD PhD for critically reading the final manuscript. This work was supported by Department of Health and Human Services grant R01-DA18342 from the National Institute on Drug Abuse (NIDA) to E.I.T.; an individual predoctoral NRSA grant F30-DA06041 from NIDA to BJV; and predoctoral fellowships from the University of Toledo College of Medicine Biomedical Sciences Graduate Program (to GS and BJV). The National Institute of Drug Abuse Drug Supply Program supplied flurazepam.
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Shen, G., Van Sickle, B. & Tietz, E. Calcium/Calmodulin-Dependent Protein Kinase II Mediates Hippocampal Glutamatergic Plasticity During Benzodiazepine Withdrawal. Neuropsychopharmacol 35, 1897–1909 (2010). https://doi.org/10.1038/npp.2010.61
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DOI: https://doi.org/10.1038/npp.2010.61
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