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Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval.

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 (?R), one of the major opioid receptors, strongly influences memory processing in that alterations in ?R signalling are associated with various neuropsychiatric disorders. However, it remains unclear whether ?R signalling contributes to memory impairments induced by acute stress. Here, we utilized pharmacological methods and cell-type-selective/non-cell-type-selective ?R depletion approaches combined with behavioural tests, biochemical analyses, and in vitro electrophysiological recordings to investigate the role of hippocampal ?R signalling in memory-retrieval impairment induced by acute elevated platform (EP) stress in mice. Biochemical and molecular analyses revealed that hippocampal ?Rs were significantly activated during acute stress. Blockage of hippocampal ?Rs, non-selective deletion of ?Rs or selective deletion of ?Rs on GABAergic neurons (?RGABA) 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 ?RGABA-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 ?RGABA 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.

SUBMITTER: Shi MM

PROVIDER: S-EPMC7192851 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval.

Shi Mei-Mei MM Fan Ka-Min KM Qiao Yan-Ning YN Xu Jin-Hui JH Qiu Li-Juan LJ Li Xiao X Liu Ying Y Qian Zhao-Qiang ZQ Wei Chun-Ling CL Han Jing J Fan Juan J Tian Ying-Fang YF Ren Wei W Liu Zhi-Qiang ZQ

Molecular psychiatry 20190529 5

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 ...[more]

PMID: 31142818

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Project description:Background: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene. Methods: We used specific µ-, ?- and ?-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used µ- and ?-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in Nav1.7 knockouts pain free phenotype. Finally, we examined the levels of Penk mRNA in Nfat5-null mutant mice, as this transcription factor binds to consensus sequences upstream of the Penk gene. Results: The pharmacological block or deletion of both µ- and ?-opioid receptors was required to abolish Nav1.7-null opioid-related analgesia. ?-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls. Deleting Nfat5, a transcription factor with binding motifs upstream of Penk, induces the same level of enkephalin mRNA expression as found in Nav1 .7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to Scn9a gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants. Conclusions: These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development.

Dataset Information

Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval.

Publications

Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval.

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