Kainate Receptors and Synaptic Plasticity

Long Term Potentiation at the Mossy Fibre-CA3 synapse

LTP at the MF-CA3 synapse is independent of NMDA receptors

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Pre-synaptic kainate receptors play a very significant role in this form of long-term potentiation. The mossy fibres (MF) are axons of granule cells in the dendate gyrus of the hippocampal formation that project to the CA3 region of the hippocampus. The MF-CA3 synapse is unusual in that it contains multiple sites for the release of glutamate, each of which has a corresponding post-synaptic density (see animation). During basal transmission, there is a low probability that any one of these sites will release neurotransmitter. In addition, unlike synapses in the CA1 region, there are few NMDA receptors located within the PSD. LTP in this synapse is NMDA receptor-independent and must follow a different mechanism to those found in other hippocampal synapses (eg. CA3-CA1 synapses).

LY382884, an antagonist that is selective for GluK1 containing receptors, was shown to block the induction of NMDA receptor-independent LTP in CA3 hippocampal neurons (Mossy Fibre LTP or MF-LTP; Bortolotto et al, 1999), indicating the involvement of GluK1-containing receptors. This has been confirmed by the use of the more recently developed GluK1 selective antagonist, UBP296 (More et al, 2004,). We have also demonstrated that this effect on MF-LTP is due to a selective inhibition of pre-synaptic kainate receptors located in the CA3 region if the hippocampus (Lauri et al, 2001a,). A train of high frequency stimulation results in a modification of the pre-synaptic bouton that increases the probablilty of glutamate release from any given site.

Mechanism of LTP induction

The mechanism of induction of MF-LTP has been under intense investigation. It is interesting that induction of MF-LTP also results in the complete inhibition of kainate receptor-mediatedfacilitation of synaptic transmission. Such facilitation is the result of a positive feedback loop in which the synaptic activation of pre-synaptic kainate receptors leads to the increased release of glutamate leading to increased synaptic transmission and increased activation of pre-synaptic kainate receptors...and so on (Lauri et al, 2001b). The occlusion of this frequency facilitation by the induction of MF-LTP suggests that these two processes are linked and it may well be that frequency facilitation is the trigger for the induction of MF-LTP.

Further evidence linking these two forms of plasticity comes from the demonstration that the concentration of Ca2+ions is critical in enabling LY382884 to block both procesess. In a low Ca2+ concentration (2 mM), MF-LTP induction and the facilitation of synaptic transmission is susceptible to blockade by GluK1 antagonists, but in higher Ca2+ concentrations (4 mM), they are not (Lauri et al, 2003). Furthermore, both processes are blocked by ryanodine (an inhibitor of Ca2+ induced Ca2+ release from intracellular stores) but only in low Ca2+; similarly both processes are blocked by philanthotoxin (an inhibitor of unedited Ca2+ permeable glutamate receptors), but again only in low Ca2+.

mechanism of mossy fibre LTPCa 2+ dependence of Mossy Fibre LTP induction. Based on results from Lauri et al (2003) Neuron 39, 327-341

The evidence summarised here shows that in low Ca2+ conditions, MF-LTP and the facilitation of MF synaptic transmission is dependent on Ca2+ permeable, GluK1 containing kainate receptors and Ca2+ release from intracellular stores. However, in conditions of high Ca2+ concentrations, the block of these processes can be overcome, indicating the presence of an alternative route for Ca2+ entry into the pre-synaptic bouton. This has been shown to be via L-type Ca2+ channels - both MF-LTP and facilitation of MF synaptic transmission are blocked by co-application of LY382884 and nifedipine, an inhibitor of L-type Ca2+ channels, even at high Ca2+ concentrations (Lauri et al, 2003). Thus a mechanism for the induction of MF-LTP can be proposed that involves the influx of Ca2+ ions through GluK1 containing kainate receptors that induces a release of Ca2+ from intracellular stores that in turn results in an increase in glutamate release from the pre-synaptic terminal in response to baseline stimulation. The mechanism by which the long-term increase in glutamate release is generated is still under investigation.

MF-LTP also involved mGlu Receptors

In addition to the direct role of kainate receptors in MF-LTP, it has been known for many years that metabotropic glutamate receptors also play a part. It was shown that MF-LTP can be blocked by (S)-MCPG, an antagonist of Group I/II mGlu receptors (Bashir et al, 1993,). However, it has been subsequently shown that LY341495, a broad spectrum mGlu receptor antagonist, failed to block MF-LTP (Fitzjohn et al, 1998), suggesting the existence of a novel mGlu receptor subtype.

Different kainate receptor subunits in MF-LTP

There has been considerable discussion over the role different kainate receptor subunits play in MF-LTP. Work with transgenic mice appeared to show that loss of the GluK1 subunit had no effect on this form of synaptic plasticity whereas loss of the GluK2 subunit substantially reduced MF-LTP. This is in direct contrast to the pharmacological evidence that shows that the pre-synaptic GluK1 subunit is crucial in the induction of MF-LTP. It appears that compensatory mechanisms in the GluK1 knockout mice could account for this discrepancy, as they show a normal level of kainate receptor-mediated facilitaion of synaptic transmission, albeit insensitive to inhibition by LY382884. The role played by GluK2 subunits remains to be fully explored once selective GluK2 antagonists are developed.