VTA projection neurons releasing GABA and glutamate in the dentate gyrus

Abstract

Both dopamine and non-dopamine neurons from the VTA project to a variety of brain regions. Here we examine non-dopaminergic neurons in the mouse VTA that send long-range projections to the hippocampus. Using a combination of retrograde tracers, optogenetic tools, and electrophysiological recordings, we show that VTA GABAergic axons make synaptic contacts in the granule cell layer of the dentate gyrus, where we can elicit small postsynaptic currents (PSCs). Surprisingly, the currents displayed a partial sensitivity to both bicuculline and NBQX, suggesting that these meso-hippocampal neurons co-release both GABA and glutamate. Finally, we show that this projection is functional in vivo and its stimulation reduces granule cell-firing rates under anesthesia. Altogether, the present results describe a novel connection between GABA and glutamate co-releasing cells of the VTA and the dentate gyrus. This connection could be relevant for a variety of functions, including reward-related memory and neurogenesis.

Significance Statement: The present studies uncover a projection from VTA neurons that release both GABA and glutamate to the granule cells of the dentate gyrus. The VTA is important for reward-related behaviors, while the DG has been implicated in discriminative memory functions. Revealing the identity of the connection of the VTA to the DG thus opens avenues of investigation into how reward-related circuits might modulate memory-related circuits.