title: Regulation of Ca²⁺/calmodulin-dependent protein kinase II signaling within hippocampal glutamatergic postsynapses during flurazepam withdrawal.
abstract: Cessation of one-week oral administration of the benzodiazepine flurazepam (FZP) to rats results in withdrawal anxiety after 1 day of withdrawal. FZP withdrawal is correlated with synaptic incorporation of homomeric GluA1-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) in the proximal stratum radiatum of CA1 neurons. After 2 days of withdrawal, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylates GluA1 subunits at Ser(831), increasing channel conductance. Secondary to AMPAR potentiation, GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), known binding partners of CaMKII, are selectively removed from the postsynaptic density (PSD). While activation of synaptic CaMKII is known to involve translocation to the PSD, CaMKII bound to NMDARs may be removed from the PSD. To distinguish these possibilities, the current studies used postembedding immunogold electron microscopy to investigate alterations in CaMKII signaling at CA1 stratum radiatum synapses after 2 days of FZP withdrawal. These studies revealed decreased total, but not autophosphorylated (Thr(286)) CaMKIIα expression in CA1 PSDs. The removal of CaMKII-GluN2B complexes from the PSD during drug withdrawal may serve as a homeostatic mechanism to limit AMPAR-mediated CA1 neuron hyperexcitability and benzodiazepine withdrawal anxiety.
authors: Department of Physiology and Pharmacology, The University of Toledo College of Medicine, Health Science Campus, 3000 Arlington Avenue, Mailstop 1008, Toledo, OH 43614, USA.
authors: Damien E
authors: DE
authors: Earl
authors: Paromita
authors: P
authors: Das
authors: William T
authors: WT
authors: Gunning
authors: Elizabeth I
authors: EI
authors: Tietz
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D049229:Dendritic Spines / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005479:Flurazepam / Q000009:adverse effects*; D005971:Glutamates / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000009:adverse effects*; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D013569:Synapses / Q000502:physiology*; D013912:Threonine / Q000378:metabolism; D016610:Tissue Embedding
chemical_list: D005971:Glutamates; D006993:Hypnotics and Sedatives; D016194:Receptors, N-Methyl-D-Aspartate; D013912:Threonine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005479:Flurazepam