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Published on: June 20, 2018
Layer selective presynaptic modulation of excitatory inputs to hippocampal cornu Ammon 1 by mu-opioid receptor
1Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA. amcquiston@vcu.edu
Abstract:
Chronic and acute activation of mu-opioid receptors (MOR) in hippocampal cornu Ammon 1 (CA1) disrupts rhythmic activity, alters activity-dependent synaptic plasticity and impairs spatial memory formation. In CA1, MORs act by hyperpolarizing inhibitory interneurons and suppressing inhibitory synaptic transmission. MOR modulation of inhibitory synaptic function translates into an increase in excitatory activity in all layers of CA1. However, the exact anatomical sites for MOR actions are not completely known. Therefore, we used voltage-sensitive dye imaging, whole cell patch clamping, photolysis of alpha-carboxy-2-nitrobenzyl ester, trifluoroacetic acid salt (CNB) -caged GABA, and micro-sectioned slices of rat hippocampus to investigate the effect of MOR activation in CA1. First, we investigated the effect of MOR activation using a MOR agonist [d-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO) on the direct activation of GABA receptors by photolysis of CNB-caged GABA in all layers of CA1. MOR activation did not affect hyperpolarizations due to direct GABA receptor activation in any layer of CA1, but MOR activation did suppress GABAergic inhibitory postsynaptic potentials suggesting that MOR activation acts by presynaptically inhibiting interneuron function. We next examined whether MOR activation was equivalently effective in all anatomical layers of CA1. To do this, cuts were made between anatomical layers of CA1 and isolated layers were stimulated electrically (five pulses at 20 Hz) to produce excitatory postsynaptic potentials (EPSPs). Under these conditions, MOR activation significantly increased EPSP areas in stratum radiatum (SR), stratum pyramidale (SP) and stratum oriens (SO) relative to stratum lacunosum-moleculare (SLM). When compared with the effect of GABA(A) and GABA(B) receptor antagonists on EPSP areas, the effect of DAMGO was proportionately larger in SR, SP and SO than in SLM. We conclude that MOR activation is more effective at directly modulating activity in SR, SP and SO, and the smaller effect in SLM is likely due to a smaller MOR inhibition of GABA release in SLM.
Insights
Activation of mu-opioid receptors (MOR) in the hippocampus affects inhibitory interneurons. MOR activation is more potent in specific CA1 layers, impacting synaptic plasticity and spatial memory.
Area of Science:
- Neuroscience
- Neuropharmacology
- Synaptic Plasticity
Background:
- Mu-opioid receptors (MOR) in hippocampal CA1 disrupt neural rhythms, synaptic plasticity, and spatial memory.
- MORs hyperpolarize inhibitory interneurons, suppress synaptic transmission, and increase CA1 excitatory activity.
- The precise anatomical locations of MOR actions within CA1 remain unclear.
Purpose of the Study:
- To investigate the anatomical sites of mu-opioid receptor (MOR) activation within the hippocampal CA1 region.
- To determine how MOR activation affects GABA receptor function and inhibitory synaptic transmission in different CA1 layers.
- To elucidate the impact of MOR activation on excitatory postsynaptic potentials (EPSPs) across CA1 layers.
Main Methods:
- Utilized voltage-sensitive dye imaging and whole-cell patch clamping in rat hippocampus slices.
- Employed photolysis of caged GABA to assess direct GABA receptor activation.
- Applied electrical stimulation to isolated CA1 layers to evoke EPSPs and tested the effects of MOR agonist DAMGO.
Main Results:
- MOR activation did not alter direct GABA receptor activation but suppressed GABAergic inhibitory postsynaptic potentials, indicating presynaptic action.
- MOR activation significantly increased EPSP areas in stratum radiatum (SR), stratum pyramidale (SP), and stratum oriens (SO) compared to stratum lacunosum-moleculare (SLM).
- The effect of MOR activation was proportionally larger in SR, SP, and SO than in SLM, suggesting layer-specific modulation.
Conclusions:
- MOR activation primarily acts presynaptically to inhibit interneuron function in hippocampal CA1.
- MOR-mediated inhibition of GABA release is less effective in the stratum lacunosum-moleculare (SLM) compared to other CA1 layers.
- These findings clarify the anatomical specificity of MOR actions in CA1, contributing to understanding their role in synaptic plasticity and memory.
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