Median raphe glutamatergic neuron-mediated enhancement of GABAergic transmission and suppression of long-term potentiation in the hippocampus

The ascending neuromodulatory pathway from the median raphe nucleus (MRN) extends widely throughout midline/para-midline regions and robustly innervates the hippocampus. This neuromodulatory pathway is believed to be critical for regulating emotional and affective behaviors. Although the MRN primarily contains serotoninergic (5-HTergic), GABAergic, and glutamatergic neurons, glutamatergic neurons expressing vesicular glutamate transporter 3 (VGLUT3) form the primary MRN input to the hippocampus. Despite the earlier demonstration of the robust MRN VGLUT3 innervation of the hippocampus, little is known about how this MRN glutamatergic input modulates synaptic transmission and plasticity in the hippocampus. Our studies show that MRN VGLUT3 neurons activate serotonin 3a receptor (5-HT3aR)-expressing GABAergic neurons, including VGLUT3-expressing neurons, at the stratum radiatum (SR)/stratum lacunosum moleculare (SLM) border. This MRN VGLUT3 neuron-mediated glutamatergic transmission onto SR/SLM 5-HT3aR neurons is negatively regulated by 5-HT through 5-HT1B receptors. In agreement with the MRN VGLUT3 neuron-mediated activation of the 5-HT3aR GABAergic neurons, activation of MRN VGLUT3 projections induces a long-lasting increase in GABAergic transmission but not glutamatergic transmission in CA1 pyramidal neurons from male but not female mice. Consistent with the MRN VGLUT3 neuron-mediated enhancement of GABAergic transmission in male mice, activation of MRN VGLUT3 projections suppresses Schaffer collateral (SC)-CA1 long-term potentiation (LTP) in male but not female mice. Thus, our results show that MRN VGLUT3 neurons modulate the dorsal hippocampus by augmenting synaptic inhibition of CA1 pyramidal neurons and by suppressing SC-CA1 LTP in a sex-specific manner.