Dopamine D2 receptors in mossy cells reduce excitatory transmission and are essential for hippocampal function

Hilar mossy cells (MCs) are principal excitatory neurons of the dentate gyrus (DG) that play critical roles in hippocampal function and have been implicated in brain disorders such as anxiety and epilepsy. However, the mechanisms by which MCs contribute to DG function and disease are poorly understood. Expression from the dopamine D2 receptor (D2R) gene (Drd2) promoter is a defining feature of MCs, and previous work indicates a key role for dopaminergic signaling in the DG. Additionally, the involvement of D2R signaling in cognition and neuropsychiatric conditions is well-known. Surprisingly, though, the function of MC D2Rs remain largely unexplored. In this study, we show that selective and conditional removal of Drd2 from MCs of adult mice impaired spatial memory, promoted anxiety-like behavior and was proconvulsant. To determine the subcellular expression of D2Rs in MCs, we used a D2R knockin mouse which revealed that D2Rs are enriched in the inner molecular layer of the DG, where MCs establish synaptic contacts with granule cells. D2R activation by exogenous and endogenous dopamine reduced MC to dentate granule cells (GC) synaptic transmission, most likely by a presynaptic mechanism. In contrast, removing Drd2 from MCs had no significant impact on MC excitatory inputs and passive and active properties. Our findings support that MC D2Rs are essential for proper DG function by reducing MC excitatory drive onto GCs. Lastly, impairment of MC D2R signaling could promote anxiety and epilepsy, therefore highlighting a potential therapeutic target. SIGNIFICANCEGrowing evidence indicates that hilar mossy cells (MCs) of the dentate gyrus play critical but incompletely understood roles in memory and brain disorders, including anxiety and epilepsy. Dopamine D2 receptors (D2Rs), implicated in cognition and several psychiatric and neurological disorders, are considered to be characteristically expressed by MCs. Still, the subcellular localization and function of MC D2Rs are largely unknown. We report that removing the Drd2 gene specifically from MCs of adult mice impaired spatial memory and was anxiogenic and proconvulsant. We also found that D2Rs are enriched where MCs synaptically contact dentate granule cells (GC) and reduce MC-GC transmission. This work uncovered the functional significance of MC D2Rs, thus highlighting their therapeutic potential in D2R- and MC-associated pathologies.