Synaptically released glutamate reduces gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors

Exogenous application of agonists at the kainate subtype of glutamate recep tors has been shown to depress evoked monosynaptic inhibition by gamma-amin obutyric acid (GABA)ergic interneurons in the hippocampus, This observation has led to the hypothesis that synaptic release of endogenous glutamate mi ght have a disinhibitory effect on neuronal circuits, in addition to depola rizing neurons via postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoriazole propionic acid (AMPA), kainate, and N-methyl-D-aspartic acid (NMDA) recepto rs, It is not known, however, if glutamate released from excitatory neurons has the same kainate receptor-mediated effect on monosynaptic inhibitory t ransmission as exogenous agonist application. Indeed, the recent demonstrat ion that excitatory synaptic signals elicited in interneurons are partly me diated by kainate receptors suggests that these receptors may have a pro- r ather than disinhibitory role. Here, we examine the effect of synaptically released glutamate on monosynaptic inhibitory signaling, In the presence of antagonists to AMPA and NMDA receptors, brief bursts of activity in glutam atergic afferent fibers reduce GABAergic transmission. This depression of i nhibition is reversibly abolished by blocking kainate receptors, It persist s when GABA(B) receptors are blocked and is enhanced by blocking metabotrop ic glutamate receptors, possibly explained by presynaptic regulation of glu tamate release from excitatory afferents by metabotropic autoreceptors. We conclude that the net kainate receptor-mediated effect of synaptically rele ased glutamate is to reduce monosynaptic inhibition. Since this form of dis inhibition may contribute to seizure initiation, kainate receptors may cons titute an important target for anticonvulsant drug development.