Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release

Abstract

The hippocampal CA3 subregion of the rat is characteristically enriched in kainate receptors. At the synaptic level, the subcellular localization of these receptors is still a matter of debate. The CA3 pyramidal cells are particularly sensitive to excitotoxicity induced by kainate, which is in agreement with the high levels of kainate receptors in the stratum lucidum of the hippocampal CA3 subregion. Immunocytochemical studies, using antibodies against kainate receptor subunits, clearly demonstrated the presence of postsynaptic kainate receptors. However, it was not possible at the time to identify the activity of postsynaptic kainate receptors as mediators of the synaptic transmission. There are also reports showing the labeling of unmyelinated axons and nerve terminals with antibodies against kainate receptor subunits. The evidence for the presence of presynaptic kainate receptors in the hippocampus is further substantiated by the demonstration that stimulation of kainate receptors in synaptosomes isolated from the rat hippocampal CA3 subregion increases the intracellular free Ca 2÷ concentration ([Ca2+]~) coupled to the release of glutamate. These results support the model proposed by Coyle (1983), in which the excitotoxicity induced by kainate involves the activation of presynaptic kainate receptors, causing the release of glutamate. According to this model, the neurotoxic effect of kainate in the rat hippocampal CA3 subregion involves a direct effect on presynaptic kainate receptors and an indirect effect on postsynaptic glutamate receptors due to the enhanced release of glutamate.

Presynaptic kainate receptors modulating glutamatergic transmission in the rat hippocampus are inhibited by arachidonic acid

“…As illustrated in Fig. 4A, domoate (3 M) enhanced by 14 ± 4% (n = 4) the basal outflow of tritium, in accordance with the ability of kainate receptors to trigger calcium influx and the spontaneous release of glutamate from hippocampal nerve terminals (reviewed in Malva et al, 1998). Consistent with its effect on glutamatergic transmission, application of 3 M domoate 2 min before the second stimulation period (S 2 ) caused a decreased K + -evoked release of tritium (Fig.…”

ATP as a presynaptic modulator

“…In these two systems, like for the ATP/P2 receptor, there is a clear paradox between the abundant expression of receptor subunit mRNA and robust binding by selective ligands in the CNS and the inability to clearly identify transmission mediated by these receptors [97,98]. This lead to the proposal that, instead of being involved in fast neurotransmission, kainate and nicotinic receptors would mainly behave as neuromodulatory systems [97,99]. Thus, a presynaptic locus of action of kainate and nicotinic receptors as modulators of neurotransmitter release [99,100] would reconcile a heavy expression and receptor density with their scarce involvement in fast transmission.…”

“…This lead to the proposal that, instead of being involved in fast neurotransmission, kainate and nicotinic receptors would mainly behave as neuromodulatory systems [97,99]. Thus, a presynaptic locus of action of kainate and nicotinic receptors as modulators of neurotransmitter release [99,100] would reconcile a heavy expression and receptor density with their scarce involvement in fast transmission. We will now review the evidences supporting a role for P2 receptors in the modulation of neurotransmitter release, a role which would contribute to explain the contradiction between the great expression and P2 receptor density and the difficulty of ascribing a clear role for ATP as a fast transmitter in the CNS [15].…”

Decreased kainate receptors in the hippocampus of apolipoprotein D knockout mice

“…Whilst our initial hypothesis that the absence of ApoD would affect the expression of neurotransmitter receptors that are changed by the pathophysiology of schizophrenia was not proven; our study has shown a 20% decrease in KAR in the CA 2-3 of ApoD -/-mice. KAR in the hippocampal formation have been shown to have roles in regulating glutamate (Malva et al, 1998) and GABA (Rodriguez-Moreno and Lerma, 1998) release, mediating slow postsynaptic currents (Castillo et al, 1997) and LTP (Lauri et al, 2001), regulating nitric oxide (Radenovic and Selakovic, 2005) and superoxide (Radenovic et al, 2004) production as well as modulating excitatory neurotransmission (Contractor et al, 2000) and neurogenesis (Bernabeu and Sharp, 2000). Significantly, hippocampal KAR are predominately heteromeric receptors and made up of GluR5 and Glur6 sub-units; however, pre-synaptic KAR seem to predominantly contain GluR6 sub-units (Mulle et al, 2000).…”