Endogenous Activation of Kainate Receptors Regulates Glutamate Release and Network Activity in the Developing Hippocampus

Abstract

Kainate receptors (KARs) are highly expressed throughout the neonatal brain, but their function during development is unclear. Here, we show that the maturation of the hippocampus is associated with a switch in the functional role of presynaptic KARs. In a developmental period restricted to the first postnatal week, endogenous L-glutamate tonically activates KARs at CA3 glutamatergic synapses to regulate release in an action potential-independent manner. At synapses onto pyramidal cells, KARs inhibit glutamate release via a G-protein and PKC-dependent mechanism. In contrast, at glutamatergic terminals onto CA3 interneurons, presynaptic KARs can facilitate release in a G-protein-independent mechanism. In both cell types, however, KAR activation strongly upregulates inhibitory transmission. We show that, through the interplay of these novel diverse mechanisms, KARs strongly regulate the characteristic synchronous network activity observed in the neonatal hippocampus. By virtue of this, KARs are likely to play a central role in the development of hippocampal synaptic circuits.

Glia-Dependent Switch of Kainate Receptor Presynaptic Action

“…An indirect action involving thirdparty signaling molecules, like endocannabinoids, dopamine, adenosine (Chergui et al, 2000), or glutamate, is unlikely in view of the results obtained with the mixture of antagonists for various receptors including GABA-B, CB 1 , A 1 , D 4 , mGluRs, NMDA, nicotinic and ␣-2 adrenergic receptors. A direct action of KARs on transmitter release involving a G-protein-coupled signaling pathway has already been reported in other structures (Rodríguez-Moreno and Lerma, 1998;Cunha et al, 2000;Frerking et al, 2001;Lauri et al, 2005Lauri et al, , 2006Negrete-Diaz et al, 2006;Jin and Smith, 2007). This seems to be also the case in our recordings as indicated by the abolition of the KAR-mediated inhibitory effect in the presence of the PLC inhibitor, U73122.…”

“…We first investigated indirect effects, including the activation of GABA-B autoreceptors (Kerchner et al, 2001) and other types of presynaptic receptors whose stimulation may take place in a retrograde (Chergui et al, 2000) This result argues against an indirect mechanism mediating the inhibitory effect of GluK1 activation on GABA release. We then investigated the possibility that the inhibitory action of GluK1 activation on GABA release depends on a direct coupling between KARs and transmitter release through a metabotropic G-protein pathway, a mechanism already described (Rodríguez-Moreno and Lerma, 1998;Cunha et al, 2000;Frerking et al, 2001;Lauri et al, 2005Lauri et al, , 2006Negrete-Diaz et al, 2006;Jin and Smith, 2007). To test for a similar mechanism in our recordings, we first tried to incubate hypothalamic slices for at least 5 h in the presence of pertussis toxin to block G-proteins.…”

“…However, this procedure consistently caused a deterioration of the slices, making stable and prolonged recordings impossible. Because most reported KAR-mediated metabotropic effects are associated with the activation of the phospholipase C (PLC) pathway downstream of G-protein stimulation (Rodríguez-Moreno and Lerma, 1998;Lauri et al, 2005;Jin and Smith, 2007), we tried to disrupt this intracellular cascade using the PLC inhibitor U73122 (10 M). In its presence, the facilitation induced by blocking the tonic activation of KARs with UBP302 was no longer observed.…”

In the Developing Rat Hippocampus, Endogenous Activation of Presynaptic Kainate Receptors Reduces GABA Release from Mossy Fiber Terminals

“…In particular, the depression of transmitter release seems to occur via G-protein-coupled KARs (Rodríguez-Moreno and Lerma, 1998;Cunha et al, 2000;Frerking et al, 2001;Lauri et al, 2005Lauri et al, , 2006. Also in our case, the depressant effect of kainate on GABA release was likely dependent on a metabotropic type of mechanism since the potentiating effects of both UBP 302 and the glutamate scavenger on GPSCs were prevented by PTx.…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…Activation of kainate receptors in have been shown to regulate glutamate release (Jane et al, 2009) and to both depress and factilitate transmission in different synapses. Presynaptic kainate receptors in the hippocampus facilitate AMPA and NMDA receptor-mediated transmission at mossy fibre-CA3 synapses (Lauri et al, 2005). Activation of post-synaptic KARs facilitates activation of NMDARs as it has been described in the context of DomA exposure.…”