The Effect And Mechanism Of Neurosteroid Pregnenolone Sulfate On Long-term Potentiation In Rat Medial Prefrontal Cortex

The effect and mechanism of neurosteroid pregnenolone sulfate on long-term potentiation in rat medial prefrontal cortexPregnenolone sulfate (PREGS) is one of the most abundantly producedneurosteroids in the brain. PREGS has extensive distribution in the brain and isinvolved in many processes of physiology and pathology. Accumulated evidencesshow that PREGS could regulate many pathophysiological changes concerned withcognition, but the mechanism is not clear. The medial prefrontal cortex is the mainbrain region for higher cognition function, which is involved in the processes ofhigher cognition and many psychiatric disorders. The glutamatergic synaptic plasticityin the medial prefrontal cortex is thought to be important for the establishment,consolidation and retrieval of permanent memory. Long-term potentiation (LTP) isone of the important indications of synaptic plasiticity and regarded as the cellularmechanism of the learning and memory. So, PREGS might have effect on LTP inmedial prefrontal cortex, which needs to be determined by experiment.The present paper studies the effect and its mechanism of PREGS on LTP in thepyramidal cells of the layersâ…¤-â…¥of the medial prefrontal cortex using whole-cellpatch-clamp with electrical stimulus and pharmacological methods in slices, and thenwe also analyzed its possible function consequence using animal behavior. We foundthat, in brain slices, 1μM PREGS had no consistent effect on the basal slope of singlestimulation evoked EPSCs, but can inhibit distinctly tetanus evoked LTP in medialprefrontal cortex. The effect of PREGS was significant at concentration of 0.3μMand increased with an increase in concentrations and appeared to reach a plateau after1μM. PREGS had no effect on the maintenance of LTP. The second tetanusstimulation could not reverse its inhibitory effect. On the contrary, 1μM PREGS hadno significant influence on the induction of LTP in CA1 pyramidal neurons of thehippocampus, but 0.3μM PREGS enhanced distinctly the LTP. This result wasconsistent with others report. To determine the position of its effect, we studied theeffect of PREGS on the amplitude of NMDA evoked current, the paired-pulsefacilitation (PPF) during the LTP induction. We found that PREGS had no effect onthe amplitude of NMDA currents, but significantly occluded the PPF change duringthe LTP induction. These results indicated PREGS inhibited the induction of LTP inthe medial prefrontal cortex by presynaptic but not postsynaptic function.To further elucidate the mechanism of the inhibitory effect of PREGS on the induction of LTP, we studied the effect of inhibtors and agonists on the function ofPREGS. We found that the selective G_i protein inhibitor N-ethylmaleimide (NEM)canceled the effect of PREGS on LTP, theα₂ receptor antagonist yohombine andα₂Areceptor antagonist RBL-44408 can also canceled the effect of PREGS, but the D₂receptor antagonist haloperidol did not have influence on the effect of PREGS, theselectiveα₂ receptor agonist B-HT 933 could mimick the effect of PREGS. We alsostudied the downstream pathway of this effect by perfusing with adenylate cyclase(AC) inhibitor MDL-12,330A and protein kinase A (PKA) inhibitor H89. The resultsshown that could also cancel the effect of PREGS on LTP completely. It's interestingthat when we added H89 into the pipette solution and allowed it to be diffused into thepostsynapfic cell, we did not found any influence of H89 on the effect of PREGS onthe LTP. In animal behavior, local injection of PREGS into the medial prefrontalcortex to measure the response learning involved in the medial prefrontal cortex usingMorris Water Maze, we founded that PREGS does not have the effect on theswimming speed, but could decrease the eacape latency and pathway.In summary, PREGS inhibits the induction of LTP via activation ofα₂A receptorcoupled with G_i protein by presynaptic in rat medial prefrontal cortex. This effect isinvolved in AC-PKA signal pathway, and then may benefit cognition function in vivo.