The GABA B1a isoform mediates heterosynaptic depression at hippocampal mossy fiber synapses

GABA B receptor subtypes are based on the subunit isoforms GABA B1a and GABA B1b, which associate with GABA B2 subunits to form pharmacologically indistinguishable GABA B(1a,2) and GABA B(1b,2) receptors. Studies with mice selectively expressing GABA B1a or GABA B1b subunits revealed that GABA B(1a,2) receptors are more abundant than GABA B(1b,2) receptors at glutamatergic terminals. Accordingly, it was found that GABA B(1a,2) receptors are more efficient than GABA B(1b,2) receptors in inhibiting glutamate release when maximally activated by exogenous application of the agonist baclofen. Here, we used a combination of genetic, ultrastructural and electrophysiological approaches to analyze to what extent GABA B(1a,2) and GABA B(1b,2) receptors inhibit glutamate release in response to physiological activation. We first show that at hippocampal mossy fiber (MF)-CA3 pyramidal neuron synapses more GABA B1a than GABA B1b protein is present at presynaptic sites, consistent with the findings at other glutamatergic synapses. In the presence of baclofen at concentrations ≥1 μM, both GABA B(1a,2) and GABA B(1b,2) receptors contribute to presynaptic inhibition of glutamate release. However, at lower concentrations of baclofen, selectively GABA B(1a,2) receptors contribute to presynaptic inhibition. Remarkably, exclusively GABA B(1a,2) receptors inhibit glutamate release in response to synaptically released GABA. Specifically, we demonstrate that selectively GABA B(1a,2) receptors mediate heterosynaptic depression of MF transmission, a physiological phenomenon involving transsynaptic inhibition of glutamate release via presynaptic GABA B receptors. Our data demonstrate that the difference in GABA B1a and GABA B1b protein levels at MF terminals is sufficient to produce a strictly GABA B1a-specific effect under physiological conditions. This consolidates that the differential subcellular localization of the GABA B1a and GABA B1b proteins is of regulatory relevance.