Acute Stress Regulates Synaptic Transmission And Plasticity In The CA1 Region Via The μ Receptor On Hippocampal GABAergic Neurons

Stress influences the cognitive function profoundly via multiple and complicate ways.The hippocampus,one of the most important brain areas for memory formation,is particularly vulnerable to stress.It is widely accepted that the elevated corticosteroid hormones together with their receptors in hippocampus alter glutamatergic synaptic plasticity,thus affecting learning and memory.On the contrary,it remains unknown if stress also regulates hippocampal inhibitory circuits.In addition,multiple of the neurotransmitter and/or neuromodulator system(aminoacidergic,monoaminergic,peptidergic...)is responsible for stress response and stress-related memory alteration.Among these modulators,the endogenous opioid system(EOS)is one of the most important candidates,which has been shown to involve in the stress-related behaviors and physiological responses.However,it is still unknown if EOS is involved in alteration of hippocampus-dependent memory induced by stress.Our previous study indicated that 50-min acute stress of elevated platform(EP)impaired hippocampus-dependent spatial reference memory and μ receptors(μRs)played an important role on it.Here,we investigated the effects of acute EP-stress on synaptic transmission in hippocampal CA3-CA1 and the role of μRs by in vivo electrophysiological recording of field excitatory postsynaptic potentials(fEPSPs)and population spikes(PSs)on anesthetized C57BL/6 mice following a series of pharmacological intervention.The main results were as follows:(1)Acute EP-stress inhibits LTP but facilitates LTD on hippocampal CA1 glutamatergic synapses in mice;In control mice,high-frequency stimulation(HFS)evoked a robust LTP of fEPSPs,whereas low-frequency stimulation(LFS)failed to evoke LTD of fEPSPs.EP stress abolished LTP induction but facilitated LTD induction.(2)LTD induction by LFS on hippocampal CA1 depends on μ receptor on GABAergic neurons(μRGABA);In the μ receptor deletion on GABAergic neurons(μRGABA-/-)mice,LTD induction by LFS was failed either in non-stressed group or in stressed group.(3)Acute EP-stress has no significant influence on basal synaptic transmission in hippocampal CA3-CA1;Input/Output(I/O)intensity of fEPSPs had no significant change after the acute EP-stress;The paired-pulse ratio(PPR)with interval of 25 ms,50 ms,100 ms and 200 ms also had no significant change after the acute EP-stress;The treatment of morphine(Mor,15 mg/Kg i.p.)had no significant influence on basal synaptic transmission of CA3-CA1;The treatment of Mor(15 mg/Kg,i.p.)also had no significant influence on fEPSP PPR with interval of 25 ms,50 ms,100 ms and 200 ms.(4)Acute EP-stress weakens the effect of GABAergic feedforward inhibition on CA1 pyramidal neurons;In control mice,the treatment of Mor(15 mg/Kg,i.p.)increased the amplitude of PSs significantly;Blocking of GABAA receptor could weaken the enhancement of PS amplitude induced by Mor;μ receptors deletion on GABAergic neurons(μRGABA-/-)antagonized the enhancement of PS amplitude by Mor;All these results indicate that activation of μRs weakens GABAergic feedforward on CA1 pyramidal neurons.Notably particularly,acute EP-stress inhibited the enhancement of PS amplitude by Mor,suggesting that stress endogenously activates hippocampal μRs which occupies the effects of exogenous agonist(such as Mor).(5)Acute EP-stress weakens the effect of GABAergic feedback inhibition on CA1 pyramidal neurons;In wild type(WT)mice,paired-pulse stimulation(interpulse interval of 25 ms)induced a depression of PS amplitude which reflects GABAergic feedback inhibition on pyramidal neurons.This paired-pulse depression(PPD)increased significantly after the treatment of Mor(15 mg/Kg,i.p.).The enhanced PPD induced by Mor treatment was abolished in μRGABA-/-mice,indicating μRs activation weakens GABAergic feedback inhibition.Acute EP-stress significantly decreased PS PPD,and this stress-induced PPD inhibition was prevented either by naloxone pre-treatment(3 mg/Kg,i.p.)or by μreceptors deletion on GABAergic neurons.These results indicate that stress suppresses GABAergic feedback inhibition via activating μRs.In summary,acute EP-stress inhibits LTP but facilitates LTD on hippocampal CA1 glutamatergic synapses in mice;LTD induction by LFS on hippocampal CA1 depends on μRGABA;Acute EP-stress has no significant influence on synaptic transmission in hippocampal CA3-CA1,but it weakens the effect of GABAergic feedforward and feedback inhibition on CA1 pyramidal neurons.These results indicate that paralleling with corticosterone and their receptors mediated pathway,acute stress selectively actives μ receptors on GABAergic neurons thereby attenuating inhibitory activity and inhibitory synaptic transmission,which in turn impairs learning and memory.