Glutamate and γ-aminobutyric acid mediate a heterosynaptic depression at mossy fiber synapses in the hippocampus

Mossy fiber synapses form the major excitatory input into the autoassociative network of pyramidal cells in the CA3 area of the hippocampus. Here we demonstrate that at the mossy fiber synapses, glutamate and gamma-aminobutyric acid (GABA) act as autaptic and heterosynaptic presynaptic inhibitory transmitters through metabotropic glutamate receptors (mGluRs) and GABA(B) receptors, respectively. Both GABA(B) receptors and mGluRs are activated through spillover from adjacent synapses. We demonstrate that glutamate spillover caused by brief tetanic activation of mossy fiber terminals remains intact at physiological temperatures. The activation of GABA(B) receptors increased the threshold for mossy fiber long-term potentiation (LTP), whereas activation of mGluRs did not have such an effect. We speculate that this heterosynaptic depression provides the mossy fiber synapses with a mechanism to efficiently shape input patterns into CA3, increasing the sparseness of the mossy fiber signal and enhancing the capacity and performance of the CA3 associative network. The increase in LTP threshold through activation of presynaptic inhibitory receptors imparts a piesynoptic associative nature to mossy fiber LTP.