GABA receptor-mediated potentiation of ventral medial habenula glutamatergic transmission in GABAergic and glutamatergic interpeduncular nucleus neurons.

The medial habenula (MHb)-interpeduncular nucleus (IPN) pathway plays an important role in information transferring between the forebrain and the midbrain. The MHb-IPN pathway has been implicated in the regulation of fear behavior and nicotine addiction. The synapses between the ventral MHb and the IPN show a unique property, i.e., an enhancement of synaptic transmission upon activation of GABA receptors. This GABA receptor-mediated potentiation of ventral MHb-IPN synaptic transmission has been implicated in regulating fear memory. Although IPN is known to contain parvalbumin (PV) and somatostatin (SST) GABAergic neurons and vesicular glutamate transporter 3 (VGLUT3)-expressing neurons, it is unknown how GABA receptor activation affects ventral MHb-mediated glutamatergic transmission onto these three subtypes of IPN neurons. Our studies show robust glutamatergic connectivity from ventral MHb to PV and SST neurons in the IPN, while the ventral MHb-mediated glutamatergic transmission in IPN VGLUT3 neurons is weak. Although activation of GABA receptors produces a robust potentiation of ventral MHb-mediated glutamatergic transmission in PV neurons, we observed a modest effect in IPN SST neurons. Despite the diminished basal synaptic transmission between ventral MHb and IPN VGLUT3 neurons, activation of GABA receptors causes transient conversion of non-responding ventral MHb synapses into active synapses in some IPN VGLUT3 neurons. Thus, our results show strong ventral MHb connectivity to GABAergic IPN neurons compared to VGLUT3-expressing IPN neurons. Furthermore, GABA receptor activation produces a differential effect on ventral MHb-mediated glutamatergic transmission onto PV, SST, and VGLUT3 neurons in the IPN.