Silent GABAASynapses during Flurazepam Withdrawal Are Region-Specific in the Hippocampal Formation

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Abstract
Whole-cell patch-clamp recordings were made from CA1 pyramidal and dentate gyrus granule cells (GCs) in hippocampal slices to assess the effects of withdrawal from chronic flurazepam (FRZ) treatment on the function of synaptic GABAA receptors. In slices from control rats, acute perfusion of FRZ (30 μm) increased the monoexponential decay time constant of miniature IPSCs (mIPSCs) in CA1 and GCs (from 3.4 ± 0.6 to 7.6 ± 2.1 msec and from 4.2 ± 0.6 to 7.1 ± 1.8 msec, respectively) but did not change their mean conductance, 10–90% rise time, or frequency of occurrence. Withdrawal (2–5 d) from chronic in vivo FRZ treatment (40–110 mg/kg per day, per os) resulted in a dramatic loss of mIPSCs in CA1 neurons. On day 5 of withdrawal, no mIPSCs could be recorded in 40% of CA1 pyramidal cells. In the remaining 60% of the neurons, mIPSCs had a reduced mean conductance (from 0.78 ± 0.12 nS in vehicle-treated controls to 0.31 ± 0.05 nS) and a diminished frequency of occurrence (from 20.7 ± 7.9 to 4.1 ± 0.6 Hz). We have estimated that >80% of GABAA synapses on CA1 pyramidal cells had become silent, whereas at still-active synapses the number of functional GABAA receptor channels decreased by 60%. This reduction rapidly reverted to control levels on day 6 of withdrawal. FRZ withdrawal did not alter mIPSC properties in GCs. Our results are consistent with the hypothesis that chronic benzodiazepine treatment leads to a reduced number of functional synaptic GABAA receptors in a region-specific manner that may stem from differences in the subunit composition of synaptic GABAA receptors.