In contrast with conventional NMDA receptor–dependent synaptic plasticity, the synaptic events controlling the plasticity of GluR2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) remain unclear. At parallel fiber synapses onto cerebellar stellate cells, Ca2+ influx through AMPARs triggers a switch in AMPAR subunit composition, resulting in loss of Ca2+ permeabilty. Paradoxically, synaptically induced depolarization will suppress this Ca2+ entry by promoting polyamine block of CP-AMPARs. We therefore examined other mechanisms that may control this receptor regulation under physiological conditions. We found that activation of both mGluRs and CP-AMPARs is necessary and sufficient to drive an AMPAR subunit switch and that by enhancing mGluR activity, GABABR activation promotes this plasticity. Furthermore, we found that mGluRs and GABABRs are tonically activated, thus setting the basal tone for EPSC amplitude and rectification. Regulation by both excitatory and inhibitory inputs provides an unexpected mechanism that determines the potential of these synapses to show dynamic changes in AMPAR Ca2+ permeability.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Bredt, D.S. & Nicoll, R.A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).
Collingridge, G.L., Isaac, J.T. & Wang, Y.T. Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962 (2004).
Liu, S.Q. & Cull-Candy, S.G. Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405, 454–458 (2000).
Lei, S. & McBain, C.J. Two Loci of expression for long-term depression at hippocampal mossy fiber-interneuron synapses. J. Neurosci. 24, 2112–2121 (2004).
Gardner, S.M. et al. Calcium-permeable AMPA receptor plasticity is mediated by subunit-specific interactions with PICK1 and NSF. Neuron 45, 903–915 (2005).
Bellone, C. & Luscher, C. Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat. Neurosci. 9, 636–641 (2006).
Ge, W.P. et al. Long-term potentiation of neuron-glia synapses mediated by Ca2+-permeable AMPA receptors. Science 312, 1533–1537 (2006).
Ho, M.T. et al. Developmental expression of Ca2+-permeable AMPA receptors underlies depolarization-induced long-term depression at mossy fiber CA3 pyramid synapses. J. Neurosci. 27, 11651–11662 (2007).
Geiger, J.R. et al. Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 15, 193–204 (1995).
Swanson, G.T., Kamboj, S.K. & Cull-Candy, S.G. Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation and subunit composition. J. Neurosci. 17, 58–69 (1997).
Bowie, D., Lange, G.D. & Mayer, M.L. Activity-dependent modulation of glutamate receptors by polyamines. J. Neurosci. 18, 8175–8185 (1998).
Rozov, A. & Burnashev, N. Polyamine-dependent facilitation of postsynaptic AMPA receptors counteracts paired-pulse depression. Nature 401, 594–598 (1999).
Aizenman, C.D., Muñoz-Elías, G. & Cline, H.T. Visually driven modulation of glutamatergic synaptic transmission is mediated by the regulation of intracellular polyamines. Neuron 34, 623–634 (2002).
Soto, D., Coombs, I.D., Kelly, L., Farrant, M. & Cull-Candy, S.G. Stargazin attenuates intracellular polyamine block of calcium-permeable AMPA receptors. Nat. Neurosci. 10, 1260–1267 (2007).
Jonas, P., Bischofberger, J., Fricker, D. & Miles, R. Interneuron Diversity series: Fast in, fast out—temporal and spatial signal processing in hippocampal interneurons. Trends Neurosci. 27, 30–40 (2004).
Chávez, A.E., Singer, J.H. & Diamond, J.S. Fast neurotransmitter release triggered by Ca influx through AMPA-type glutamate receptors. Nature 443, 705–708 (2006).
Clark, B.A. & Cull-Candy, S.G. Activity-dependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse. J. Neurosci. 22, 4428–4436 (2002).
Carter, A.G. & Regehr, W.G. Prolonged synaptic currents and glutamate spillover at the parallel fiber to stellate cell synapse. J. Neurosci. 20, 4423–4434 (2000).
Mittmann, W., Koch, U. & Hausser, M. Feed-forward inhibition shapes the spike output of cerebellar Purkinje cells. J. Physiol. (Lond.) 563, 369–378 (2005).
Mann-Metzer, P. & Yarom, Y. Pre- and postsynaptic inhibition mediated by GABA(B) receptors in cerebellar inhibitory interneurons. J. Neurophysiol. 87, 183–190 (2002).
Rancillac, A. & Crepel, F. Synapses between parallel fibres and stellate cells express long-term changes in synaptic efficacy in rat cerebellum. J. Physiol. (Lond.) 554, 707–720 (2004).
Karakossian, M.H. & Otis, T.S. Excitation of cerebellar interneurons by group I metabotropic glutamate receptors. J. Neurophysiol. 92, 1558–1565 (2004).
Hirono, M., Yoshioka, T. & Konishi, S. GABA(B) receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses. Nat. Neurosci. 4, 1207–1216 (2001).
Häusser, M. & Clark, B.A. Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron 19, 665–678 (1997).
Nusser, Z., Cull-Candy, S. & Farrant, M. Differences in synaptic GABAA receptor number underlie variation in GABA mini amplitude. Neuron 19, 697–709 (1997).
Feldmeyer, D. et al. Neurological dysfunctions in mice expressing different levels of the Q/R site-unedited AMPAR subunit GluR-B. Nat. Neurosci. 2, 57–64 (1999).
Mameli, M., Balland, B., Lujan, R. & Luscher, C. Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science 317, 530–533 (2007).
Noel, J. et al. Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism. Neuron 23, 365–376 (1999).
Bähring, R. & Mayer, M.L. An analysis of philanthotoxin block for recombinant rat GluR6(Q) glutamate receptor channels. J. Physiol. (Lond.) 509, 635–650 (1998).
Chevaleyre, V., Takahashi, K.A. & Castillo, P.E. Endocannabinoid-mediated synaptic plasticity in the CNS. Annu. Rev. Neurosci. 29, 37–76 (2006).
Beierlein, M. & Regehr, W.G. Local interneurons regulate synaptic strength by retrograde release of endocannabinoids. J. Neurosci. 26, 9935–9943 (2006).
Hashimotodani, Y., Ohno-Shosaku, T., Maejima, T., Fukami, K. & Kano, M. Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release. Neuropharmacology 54, 58–67 (2008).
Soler-Llavina, G.J. & Sabatini, B.L. Synapse-specific plasticity and compartmentalized signaling in cerebellar stellate cells. Nat. Neurosci. 9, 798–806 (2006).
Liu, S.J. & Cull-Candy, S.G. Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses. Nat. Neurosci. 8, 768–775 (2005).
Ango, F. et al. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411, 962–965 (2001).
Hartmann, B. et al. The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron 44, 637–650 (2004).
Brasnjo, G. & Otis, T.S. Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression. Neuron 31, 607–616 (2001).
Baude, A. et al. The metabotropic glutamate receptor (mGluR1α) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 11, 771–787 (1993).
Chaudhry, F.A. et al. Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron 15, 711–720 (1995).
Chadderton, P., Margrie, T.W. & Hausser, M. Integration of quanta in cerebellar granule cells during sensory processing. Nature 428, 856–860 (2004).
Jörntell, H. & Ekerot, C.F. Properties of somatosensory synaptic integration in cerebellar granule cells in vivo. J. Neurosci. 26, 11786–11797 (2006).
Szapiro, G. & Barbour, B. Multiple climbing fibers signal to molecular layer interneurons exclusively via glutamate spillover. Nat. Neurosci. 10, 735–742 (2007).
Nosyreva, E.D. & Huber, K.M. Developmental switch in synaptic mechanisms of hippocampal metabotropic glutamate receptor–dependent long-term depression. J. Neurosci. 25, 2992–3001 (2005).
Zakharenko, S.S., Zablow, L. & Siegelbaum, S.A. Altered presynaptic vesicle release and cycling during mGluR-dependent LTD. Neuron 35, 1099–1110 (2002).
Xiao, M.Y., Zhou, Q. & Nicoll, R.A. Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors. Neuropharmacology 41, 664–671 (2001).
Moult, P.R. et al. Tyrosine phosphatases regulate AMPA receptor trafficking during metabotropic glutamate receptor–mediated long-term depression. J. Neurosci. 26, 2544–2554 (2006).
Linden, D.J. The expression of cerebellar LTD in culture is not associated with changes in AMPA-receptor kinetics, agonist affinity or unitary conductance. Proc. Natl. Acad. Sci. USA 98, 14066–14071 (2001).
Borgdorff, A.J. & Choquet, D. Regulation of AMPA receptor lateral movements. Nature 417, 649–653 (2002).
Kamikubo, Y. et al. Postsynaptic GABAB receptor signaling enhances LTD in mouse cerebellar Purkinje cells. J. Physiol. (Lond.) 585, 549–563 (2007).
Lawrence, J.J. & McBain, C.J. Interneuron diversity series: containing the detonation–feedforward inhibition in the CA3 hippocampus. Trends Neurosci. 26, 631–640 (2003).
We thank C. Bats, P. Chadderton, B. Clark and D. Soto for helpful discussion and comments on the manuscript. This work was supported by a Wellcome Trust Programme Grant (S.G.C.-C. and M.F.), a Wellcome Trust Studentship (L.K.) and a Royal Society-Wolfson Research Award (S.G.C.-C.).
About this article
Cite this article
Kelly, L., Farrant, M. & Cull-Candy, S. Synaptic mGluR activation drives plasticity of calcium-permeable AMPA receptors. Nat Neurosci 12, 593–601 (2009). https://doi.org/10.1038/nn.2309
This article is cited by
NMDA receptor-dependent long-term depression in the lateral habenula: implications in physiology and depression
Scientific Reports (2020)
Nature Communications (2019)
Nature Reviews Neuroscience (2016)
Molecular and anatomical evidence for the input pathway- and target cell type-dependent regulation of glutamatergic synapses
Anatomical Science International (2016)