Abstract
Stressful life events induce abnormalities in emotional and cognitive behaviour. The endogenous opioid system plays an essential role in stress adaptation and coping strategies. In particular, the µ-opioid receptor (μR), one of the major opioid receptors, strongly influences memory processing in that alterations in μR signalling are associated with various neuropsychiatric disorders. However, it remains unclear whether μR signalling contributes to memory impairments induced by acute stress. Here, we utilized pharmacological methods and cell-type-selective/non-cell-type-selective μR depletion approaches combined with behavioural tests, biochemical analyses, and in vitro electrophysiological recordings to investigate the role of hippocampal μR signalling in memory-retrieval impairment induced by acute elevated platform (EP) stress in mice. Biochemical and molecular analyses revealed that hippocampal μRs were significantly activated during acute stress. Blockage of hippocampal μRs, non-selective deletion of μRs or selective deletion of μRs on GABAergic neurons (μRGABA) reversed EP-stress-induced impairment of memory retrieval, with no effect on the elevation of serum corticosterone after stress. Electrophysiological results demonstrated that stress depressed hippocampal GABAergic synaptic transmission to CA1 pyramidal neurons, thereby leading to excitation/inhibition (E/I) imbalance in a μRGABA-dependent manner. Pharmaceutically enhancing hippocampal GABAA receptor-mediated inhibitory currents in stressed mice restored their memory retrieval, whereas inhibiting those currents in the unstressed mice mimicked the stress-induced impairment of memory retrieval. Our findings reveal a novel pathway in which endogenous opioids recruited by acute stress predominantly activate μRGABA to depress GABAergic inhibitory effects on CA1 pyramidal neurons, which subsequently alters the E/I balance in the hippocampus and results in impairment of memory retrieval.
Highlights
These authors contributed : Mei-Mei Shi, Ka-Min Fan, YanNing Qiao
No difference in motor capacity, shown as average swimming speed, was observed between the two groups (Supplementary Figure 1b), the unstressed mice performed well and spent significantly longer in the target quadrant than in the opposite quadrant (23.33 ± 1.58 s vs. 7.01 ± 0.78 s), whereas the stressed mice spent similar amounts of time in each of those two quadrants, spending significantly less time in the target quadrant than the unstressed mice (Supplementary Figure 1c). These results demonstrate that acute elevated platform (EP) stress before the probe test significantly impairs the retrieval of spatial reference memory
F3,26 = 4.73, p = 0.009; one-way analysis of variance (ANOVA). *, vs. unstressed μ-opioid receptors (μRs) on GABAergic neurons (μRGABA)+/+ or stressed μRGABA−/−. d Deletion of μRGABA prevents the decrease in miniature inhibitory postsynaptic currents (mIPSCs) frequency induced by EP stress or DAMGO perfusion. p < 0.05 for cumulative probability of inter-event intervals (IEIs) and p > 0.05 for cumulative probability of amplitude, K-S test. mIPSC frequency F7,64 = 4.37, p = 0.000; mIPSC amplitude F7,64 = 0.85, p = 0.554; one-way ANOVA
Summary
Extensive studies have demonstrated that elevated glucocorticoid hormones during stress impair memory retrieval by modulating glutamatergic synaptic plasticity at the Schaffer collateral/commissural-CA1 synapses in the hippocampus, likely through inhibiting LTP induction or facilitating LTD [4,5,6,7,8]. In addition to the direct effects of glucocorticoids on hippocampal glutamatergic synaptic plasticity, increased EOPs may regulate stress-induced impairment of memory retrieval by inhibiting GABAergic interneurons in CA1. Such a regulatory mechanism of EOPs in local inhibitory circuitry in the hippocampus would be a novel pathway underpinning stress-induced memory impairments
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