Identification of the kainate receptor subunits underlying modulation of excitatory synaptic transmission in the CA3 region of the hippocampus

To understand the physiological role of kainate receptors and their partici pation in seizure induction in animal models of epilepsy, it will be necess ary to develop a comprehensive description of their action in the CA3 regio n of the hippocampus. Activation of presynaptic kainate receptors depresses excitatory synaptic transmission at mossy fiber and associational-commissu ral inputs to CA3 pyramidal neurons (Vignes et al., 1998; Bortolotto et al. , 1999; Kamiya and Ozawa, 2000). In this study, we use gene-targeted mice l acking glutamate receptor 5 (GluR5) or GluR6 kainate receptor subunits to i dentify the receptor subunits that comprise the kainate receptors responsib le for presynaptic modulation of CA3 transmission. We found that bath appli cation of kainate (3 muM) profoundly reduced EPSCs at mossy fiber and colla teral synapses in neurons from wild-type and GluR5(-/-) mice but had no eff ect on EPSCs in neurons from GluR6(-/-) mice. These results therefore contr ast with previous studies that supported a role for GluR5-containing recept ors at mossy fiber and associational-commissural synapses (Vignes et al., 1 998; Bortolotto et al., 1999). Surprisingly, at perforant path synapses kai nate receptor activation enhanced transmission; this potentiation was aboli shed in both GluR5 and GluR6 knockout mice. Kainate receptors thus play mul tiple and complex roles to modulate excitatory synaptic transmission in the CA3 region of the hippocampus.