GABAB 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 a crucial role in information transferring between the forebrain and the midbrain, and 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_B receptors. 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_B 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. Activation of GABA_B receptors produces a robust potentiation of ventral MHb-mediated glutamatergic transmission in PV neurons, while a modest effect was observed in IPN SST neurons. In addition, activation of GABA_B receptors causes transient conversion of non-responding ventral MHb synapses into active synapses in some IPN VGLUT3 neurons. Thus, our results demonstrate that GABA_B receptor activation produces a differential effect on ventral MHb-mediated glutamatergic transmission onto PV, SST, and VGLUT3 neurons in the IPN.