Effect And Mechanism Of Neurosteroid Pregnenolone Sulfate On Excitatory Presynaptic Transmission In Rat Medial Prefrontal Cortical Interneurons

The medial prefrontal cortex(mPFC) is a key component of the neural circuitries underlying higher cognitive processes,neuropsychiatric disorders and psychostimulant abuse.Interneurons represent fundamental modulatory elements for cortical function and are thought to be associated with physiological cortical functions underlying several cognitive tasks and some pathological phenomena.Therefore,the control or modulation of the activity of interneurons in mPFC is important in cognitive processes,neuropsychiatric disorders and psychostimulant abuse.Neurosteroids are important molecules of brain,which involve in physiological cortical functions and some pathological phenomena.Pregnenolone sulfate(PREGS) is among the most abundant and the most active members of neurosteroids.Recent evidence from our laboratory showed that PREGS could modulate presynaptic glutamatergic inputs to pyramidal cells in the medial prefrontal cortex.However, whether PREGS has actions on presynaptic glutamatergic inputs to interneurons in mPFC or not remains unknown.If this effect exists,our further interest is that is there any difference on interneurons and pyramidal cells concerning the effects PREGS on presynaptic glutamate release,and finally on action potentials.Therefore,in the present paper we studied the effect of neurosteroid PREGS on presynaptic glutamate release in intemeurons of mPFC by examining the frequency of miniature excitatory postsynaptic currents(mEPSCs) using whole-cell patch clamp method in slices and further studied its underlying mechanisms with a comparison with that in pyramidal cells of mPFC.And we also investigated whether PREGS has effects on spontaneous excitatory postsynaptic currents(sEPSCs),evoked excitatory postsynaptic current, (eEPSC) and action potential.The results showed that PREGS had an increasing effect on the frequency of mEPSCs in the interneurons of mPFC.This effect is same as that in pyramidal cells. However,the mechanism of these increasing effects is different between interneurons and pyramidal cells.For intemeurons,σ₁ receptor antagonist can block the increasing effect completely,whereasα₁ receptor antagonist has no influence on it. Andσ₁ receptor agonist can mimic the increasing effect,whereasα₁ receptor agonist cannot.Moreover,α₁ receptor agonist has no influence on that effect ofσ₁ receptor agonist.By contrast,σ₁ receptor antagonist can partly block the increasing effect of PREGS,whereasα₁ receptor antagonist can block it completely.Andα₁ receptor agonist can partly mimic the increasing effect in pyramidal cells,whereasσ₁ receptor agonist cannot.Moreover,the combination ofα₁ receptor agonist andσ₁ receptor agonist can completely mimic the increasing effect in pyramidal cells. These data suggested that the effect of PREGS in intemeurons is only throughσ₁ receptor but notα₁ receptor.We found the pathway of transduction of intracellular signals under the effect of PREGS is only through PKC but not PKA by our further study.In addition,we also investigated the other effects of PREGS in interneurons. PREGS can enhance the frequency of sEPSCs and the amplitude of eEPSC,and shorten the latency of action potential in intemeurons,whereas lengthen that in pyramidal cells.