Voltage dependent allosteric modulation of IPSCs by benzodiazepines

Abstract

GABAA receptors (GABAAR) are inhibitory ion channels ubiquitously expressed in the central nervous system and play critical roles in brain development and function. Benzodiazepines are positive allosteric modulators of GABAAR, enhancing channel opening frequency when GABA is bound to the receptor. Midazolam is a commonly used benzodiazepine. It is frequently used for premature infants, but the long-term consequences of its use in this patient population are not well established. Here, we studied the acute effects of midazolam on immature synapses. Using a rodent organotypic hippocampal slice preparation, we evaluated how midazolam affects inhibitory synaptic transmission onto CA1 pyramidal neurons. We found that 1 μM midazolam enhances evoked inhibitory post synaptic currents (eIPSCs) at a holding potential of −60 mV. Similarly, 1 μM midazolam enhances miniature IPSCs (mIPSCs) in CA1 pyramidal neurons at holding potentials of −60 mV and −30 mV. At depolarized holding potentials, however, midazolam no longer enhances mIPSCs. Depolarization of the postsynaptic cell by itself increases mIPSC decay, which occludes the allosteric effects of midazolam. These results provide insight into how a benzodiazepine and membrane voltage may modulate GABAAR function in developing circuits.