Raphe-driven feed-forward inhibition of the hippocampus by glutamate co-transmission

Abstract

The raphe nuclei contain heterogeneous cell populations including serotonergic, dopaminergic, glutamatergic, and GABAergic neurons. While the investigations on the modulation by raphe nuclei have focused on their serotonergic slow synaptic transmission, accumulating evidence suggests an emerging role of GABA- or glutamate-mediated fast synaptic transmission by raphe neurons. Specifically, glutamate co-transmission from serotonergic neurons is observed in a variety of brain regions including the hippocampus, amygdala, and VTA. Interestingly, in the amygdala and hippocampus, raphe-driven glutamate co-transmission tends to modulate inhibitory rather than excitatory neurons, suggesting a conversion of raphe-mediated fast excitatory transmission to inhibitory tone in the target regions. In this study, we focused on the inhibitory effect of raphe-mediated fast synaptic transmission in the major targets of the raphe nuclei. Using optogenetic approaches, immunohistochemistry, and confocal imaging, we found that multiple brain regions, particularly the hippocampus, receive disynaptic inhibitory inputs from raphe neurons and this feed-forward inhibition is mediated by the glutamatergic transmission of the raphe neurons. Most notably, raphe-driven feed-forward inhibition influences synaptic transmission at Schaffer collateral-CA1 synapses in the hippocampus. Our findings demonstrate the functional significance of raphe-mediated fast synaptic transmission and provide new insights into the complex synaptic connectivity of raphe serotonergic neurons.