Abstract
We used virus-mediated anterograde and retrograde tracing, optogenetic modulation, immuno-staining, 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 VTA and supramammillary nucleus to the granule cells of 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 strongly inhibits the glutamate and GABA release, mostly through inhibition of presynaptic N-type channels. However, the modulation by μ-opioid receptors of these dual synapses is complex, as it likely includes also a disinhibition due to down-modulation 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.
Significance Statement Corelease of an excitatory (glutamate) and an inhibitory (GABA) neurotransmitter from the same synapse is a rare finding in the nervous system and the detailed mechanisms of this transmission are still incompletely described. Here we show that in dual glutamatergic/GABAergic synapses from the midbrain to the dentate gyrus of the dorsal hippocampus similar calcium microdomains control the release of both transmitters. Additionally, we show that activation of μ-opioid receptors limits release by strong inhibition of presynaptic N-type calcium channels in the mixed glutamatergic/GABAergic terminals, while likely potentiating release by inhibition of axo-axonic synapses from local inhibitory interneurons. Modulation of these synapses by μ-opioid receptors might help reinforce memories of drug-associated contexts.
Footnotes
This work was supported by NIH grants DA044121 and NS112292.
The authors thank Dr. Yen-Hsin Cheng for outstanding management of mouse colonies and Dr. Anis Contractor for critical reading of the manuscript.
Part of the imaging work was performed using instrumentation at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center
The authors declare they have no conflicts of interest to disclose.
↵*These authors share equal contributions
