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Published on: February 12, 2020
μ-Opioid Receptor Modulation of the Glutamatergic/GABAergic Midbrain Inputs to the Mouse Dorsal Hippocampus
Haram R Kim1, Soumil Dey1, Gabriella Sekerkova1
1Department of Neuroscience, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611.
Abstract:
We used virus-mediated anterograde and retrograde tracing, optogenetic modulation, immunostaining, in situ hybridization, and patch-clamp recordings in acute brain slices to study the release mechanism and μ-opioid modulation of the dual glutamatergic/GABAergic inputs from the ventral tegmental area and supramammillary nucleus to the granule cells of the dorsal hippocampus of male and female mice. In keeping with previous reports showing that the two transmitters are released by separate active zones within the same terminals, we found that the short-term plasticity and pharmacological modulation of the glutamatergic and GABAergic currents are indistinguishable. We further found that glutamate and GABA release at these synapses are both virtually completely mediated by N- and P/Q-type calcium channels. We then investigated μ-opioid modulation of these synapses and found that activation of μ-opioid receptors (MORs) strongly inhibits the glutamate and GABA release, mostly through inhibition of presynaptic N-type channels. However, the modulation by MORs of these dual synapses is complex, as it likely includes also a disinhibition due to downmodulation of local GABAergic interneurons which make direct axo-axonic contacts with the dual glutamatergic/GABAergic terminals. We discuss how this opioid modulation may enhance LTP at the perforant path inputs, potentially contributing to reinforce memories of drug-associated contexts.
Insights
Opioid receptors (MORs) strongly inhibit glutamate and GABA release in the hippocampus, but also disinhibit these dual synapses through complex mechanisms, potentially reinforcing drug-associated memories.
Area of Science:
- Neuroscience
- Neuropharmacology
- Synaptic Plasticity
Background:
- The dorsal hippocampus receives dual glutamatergic and GABAergic inputs from the ventral tegmental area and supramammillary nucleus.
- Understanding the release mechanisms and modulation of these inputs is crucial for comprehending hippocampal function, particularly in memory formation and drug addiction.
Purpose of the Study:
- To investigate the release mechanisms of dual glutamatergic/GABAergic inputs to dorsal hippocampus granule cells.
- To elucidate the modulatory effects of mu-opioid receptors (MORs) on these dual synapses.
- To explore the potential role of this opioid modulation in reinforcing drug-associated memories.
Main Methods:
- Utilized virus-mediated tracing, optogenetics, immunostaining, in situ hybridization, and patch-clamp recordings in mice.
- Examined short-term plasticity and pharmacological modulation of glutamatergic and GABAergic currents.
- Investigated the role of N- and P/Q-type calcium channels in transmitter release and MOR modulation.
Main Results:
- Glutamate and GABA release are mediated by N- and P/Q-type calcium channels.
- Mu-opioid receptor (MOR) activation strongly inhibits both glutamate and GABA release, primarily via presynaptic N-type calcium channels.
- MOR modulation involves complex disinhibition through downmodulation of local GABAergic interneurons.
Conclusions:
- Opioid modulation of dual hippocampal synapses is complex, involving direct inhibition and indirect disinhibition.
- This modulation may enhance long-term potentiation (LTP) at perforant path inputs.
- Findings suggest a mechanism by which opioid modulation could reinforce memories of drug-associated contexts.
