Kainate Receptors Depress Excitatory Synaptic Transmission at CA3→CA1 Synapses in the Hippocampus via a Direct Presynaptic Action

Abstract

Kainate receptor activation depresses synaptic release of neurotransmitter at a number of synapses in the CNS. The mechanism underlying this depression is controversial, and both ionotropic and metabotropic mechanisms have been suggested. We report here that the AMPA/kainate receptor agonists domoate (DA) and kainate (KA) cause a presynaptic depression of glutamatergic transmission at CA33CA1 synapses in the hippocampus, which is not blocked by the AMPA receptor antagonist GYKI 53655 but is blocked by the AMPA/KA receptor antagonist CNQX. Neither a blockade of interneuronal discharge nor antagonists of several neuromodulators affect the depression, suggesting that it is not the result of indirect excitation and subsequent release of a neuromodulator. Presynaptic depolarization, achieved via increasing extracellular K ϩ , caused a depression of the presynaptic fiber volley and an increase in the frequency of miniature EPSCs. Neither effect was observed with DA, suggesting that DA does not depress transmission via a presynaptic depolarization. However, the effects of DA were abolished by the G-protein inhibitors N-ethylmaleimide and pertussis toxin. These results suggest that KA receptor activation depresses synaptic transmission at this synapse via a direct, presynaptic, metabotropic action. Key words: domoate; kainate; metabotropic; presynaptic; hippocampus; CA1Neurotransmitter receptors in the CNS can be separated into two broad classes: ionotropic receptors, which are coupled to ligandgated conductances, and metabotropic receptors, which couple to GTP-binding proteins. Kainate receptors (KARs) are ionotropic glutamate receptors that, in addition to having conventional postsynaptic actions, are thought to act as presynaptic inhibitors of transmitter release at a number of synapses in the CNS (for review, see Frerking and Nicoll, 2000). The mechanisms underlying this depression are controversial. Both direct actions of presynaptic KARs (Chittajallu et al., 1996;Rodríguez-Moreno et al., 1997;Schmitz et al., 2000) and indirect actions of somatodendritic KARs (Frerking et al., 1999;Chergui et al., 2000;Schmitz et al., 2000) have been proposed to account for this presynaptic effect. The depression has also been suggested to be the downstream result of presynaptic depolarization via the conventional ionotropic actions of KARs (Chittajallu et al., 1996;Kamiya and Ozawa, 1998;Schmitz et al., 2000) or alternatively via a novel KAR-coupled metabotropic cascade (Rodríguez-Moreno and Lerma, 1998;Rodríguez-Moreno et al., 2000).One difficulty in interpreting the effects of KAR activation is the frequent presence of somatodendritic KARs on the presynaptic neurons, which can lead to a number of different types of use-dependent depression. Glutamatergic CA33 CA1 synapses in the hippocampus provide a good system in which to study the KAR-induced depression, because the somatodendritic region of the presynaptic CA3 cells can be removed by microdissection. At these synapses, the KAR agonists kainate (KA) and domoate (DA) both indu...

Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus

“…In these experiments, CA3 region was surgically removed to eliminate any potential effects of reelin on CA3 somatodendritic regions. According to binomial models of synaptic transmission, 1/CV 2 is determined only by properties of presynaptic release and provides an empirical tool for comparing locus of synaptic action (Bolshakov and Siegelbaum, 1994;Frerking et al, 2001). When 1/CV 2 ratios were plotted versus mean EPSC NMDA ratios before and after a 30 min reelin application in nine experiments, no correlation was established (Fig.…”

AMPA Receptors and Kainate Receptors Encode Different Features of Afferent Activity

“…However, we note that this does not exclude the possibility that KARs have additional functions that are not strictly dependent on the depolarization induced by the KARmediated EPSP. Because recent reports suggest that KARs can engage metabotropic signaling cascades (Rodriguez-Moreno and Lerma, 1998;Frerking et al, 2001), one possibility is that postsynaptic KARs can affect biochemical pathways in the cell in addition to their direct effects on membrane potential. Postsynaptic KARs also may allow calcium entry, because some KARs are calcium-permeable (for review, see Lerma et al, 2001) and the calcium permeability of interneuronal KARs has not been determined.…”

“…Indeed, the KAR-mediated EPSC is so small relative to the AMPAR-mediated EPSC that it seems possible that the ionotropic activity of KARs has no significant role at all. This possibility is reinforced by studies suggesting that KARs may act, at least in part, via metabotropic actions that are independent of depolarization (Rodriguez-Moreno and Lerma, 1998;Frerking et al, 2001).…”

Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics

“…9 While located both pre-and postsynapticlly, KA receptors play significant roles in the regulation of hippocampal excitability. They inhibit glutamate release presynaptially [10][11][12] and also regulate action potential-dependent GABA release from interneurons. KA receptor mediated increase of interneuronal GABA release may function as an important homeostatic mechanism that prevents overexcitation of hippocampal CA1 pyramidal neurons.…”