µ-Opioid Receptor Control of Glutamate/GABA Coreleasing SUM and VTA Projections to the Dentate Gyrus

The dentate gyrus (DG) is a hippocampal structure responsible for filtering cortical input and conveying it to CA3, where it forms associative memories. Granule cells, the principal excitatory neurons of the DG, have extensive dendritic arbors that occupy the molecular layer of the DG. The excitability of these neurons is tightly controlled by GABAergic basket cells, which synapse onto the proximal dendrites and soma of granule cells (Amaral et al., 2007). While granule cells receive the majority of their inputs from the entorhinal cortex, other cortical and subcortical structures provide input that modulates granule cell activity. For example, DG receives input from the ventral tegmental area (VTA) and the supramammillary nucleus (SUM), midbrain structures involved in control of motivation and learning (Ntamati and Lüscher, 2016; Hashimotodani et al., 2018). The VTA is best known for regulating reward and aversion behaviors through dopamine release, but its dopaminergic projections to the hippocampus are quite sparse (Han et al., 2020). Instead, most VTA–DG projections corelease glutamate and GABA. Activation of these projections reduces granule cell firing in anesthetized animals (Ntamati and Lüscher, 2016). Chemogenetic inactivation of these projections impairs acquisition and reinstatement of fear conditioning in mice, suggesting they aid the formation and retrieval of emotionally valent memories (Han et al., 2020). SUM–hippocampus projections also corelease glutamate and GABA, and they synapse onto both granule cells and surrounding interneurons. Recent studies show that stimulation of SUM fibers causes an overall increase in granule cell activity (Hashimotodani et al., 2018) and inactivation of these projections in vivo impairs retrieval of spatial memories (Li et al., 2020). They have also been linked to emotional memory processing. Granule cell activity is also regulated by activation of µ-opioid receptors (MOR), which are abundantly expressed in the DG, rendering it susceptible to the effects of MOR … Correspondence should be addressed to Daria Oleinichenko at daria.oleinichenko{at}ubc.ca.

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