Abstract
Cortical map formation requires the accurate targeting, synaptogenesis, elaboration and refinement of thalamocortical afferents. Here we demonstrate the role of Ca2+/calmodulin–activated type-I adenylyl cyclase (AC1) in regulating the strength of thalamocortical synapses through modulation of AMPA receptor (AMPAR) trafficking using barrelless mice, a mutant without AC1 activity or cortical 'barrel' maps. Barrelless synapses are stuck in an immature state that contains few functional AMPARs that are rarely silent (NMDAR-only). Long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical synapses require postsynaptic protein kinase A (PKA) activity and are difficult to induce in barrelless mice, probably due to an inability to properly regulate synaptic AMPAR trafficking. Consistent with this, both the extent of PKA phosphorylation on AMPAR subunit GluR1 and the expression of surface GluR1 are reduced in barrelless neurons. These results suggest that activity-dependent mechanisms operate through an AC1/PKA signaling pathway to target some synapses for consolidation and others for elimination during barrel map formation.
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References
O'Leary, D.D. & Nakagawa, Y. Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr. Opin. Neurobiol. 12, 14–25 (2002).
Katz, L.C. & Shatz, C.J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).
Crair, M.C. Neuronal activity during development: permissive or instructive? Curr. Opin. Neurobiol. 9, 88–93 (1999).
Woolsey, T.A. & Van der Loos, H. The structural organization of layer IV in the somatosensory region (SI) of the mouse cerebral cortex. Brain Res. 17, 205–242 (1970).
Van der Loos, H., Welker, E., Dorfl, J. & Rumo, G. Selective breeding for variations in patterns of mystacial vibrissae of mice. Bilaterally symmetrical strains derived from ICR stock. J. Hered. 77, 66–82 (1986).
Welker, E. et al. Altered sensory processing in the somatosensory cortex of the mouse mutant barrelless. Science 271, 1864–1867 (1996).
Abdel-Majid, R.M. et al. Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nat. Genet. 19, 289–291 (1998).
Poser, S. & Storm, D.R. Role of Ca2+-stimulated adenylyl cyclases in LTP and memory formation. Int. J. Dev. Neurosci. 19, 387–394 (2001).
Malenka, R.C. & Nicoll, R.A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999).
Gutlerner, J.L., Penick, E.C., Snyder, E.M. & Kauer, J.A. Novel protein kinase A-dependent long-term depression of excitatory synapses. Neuron 36, 921–931 (2002).
Tzounopoulos, T., Janz, R., Sudhof, T.C., Nicoll, R.A. & Malenka, R.C. A role for cAMP in long-term depression at hippocampal mossy fiber synapses. Neuron 21, 837–845 (1998).
Brandon, E.P., Idzerda, R.L. & McKnight, G.S. PKA isoforms, neural pathways, and behaviour: making the connection. Curr. Opin. Neurobiol. 7, 397–403 (1997).
Kind, P.C. & Neumann, P.E. Plasticity: downstream of glutamate. Trends Neurosci. 24, 553–555 (2001).
Ehlers, M.D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).
Esteban, J.A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat. Neurosci. 6, 136–143 (2003).
Lee, H.K. et al. Phosphorylation of the AMPA Receptor GluR1 Subunit Is Required for Synaptic Plasticity and Retention of Spatial Memory. Cell 112, 631–643 (2003).
Malinow, R. & Malenka, R.C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).
Song, I. & Huganir, R.L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 25, 578–588 (2002).
Liao, D., Hessler, N.A. & Malinow, R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 (1995).
Isaac, J.T., Nicoll, R.A. & Malenka, R.C. Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427–434 (1995).
Montgomery, J.M. & Madison, D.V. State-dependent heterogeneity in synaptic depression between pyramidal cell pairs. Neuron 33, 765–777 (2002).
Crair, M.C. & Malenka, R.C. A critical period for long-term potentiation at thalamocortical synapses. Nature 375, 325–328 (1995).
Isaac, J.T., Crair, M.C., Nicoll, R.A. & Malenka, R.C. Silent synapses during development of thalamocortical inputs. Neuron 18, 269–280 (1997).
Lu, H.C., Gonzalez, E. & Crair, M.C. Barrel cortex critical period plasticity is independent of changes in NMDA receptor subunit composition. Neuron 32, 619–634 (2001).
Feldman, D.E., Nicoll, R.A., Malenka, R.C. & Isaac, J.T. Long-term depression at thalamocortical synapses in developing rat somatosensory cortex. Neuron 21, 347–357 (1998).
Erzurumlu, R.S. & Kind, P.C. Neural activity: sculptor of 'barrels' in the neocortex. Trends Neurosci. 24, 589–595 (2001).
Kidd, F.L. & Isaac, J.T. Developmental and activity-dependent regulation of kainate receptors at thalamocortical synapses. Nature 400, 569–573 (1999).
Barth, A.L. & Malenka, R.C. NMDAR EPSC kinetics do not regulate the critical period for LTP at thalamocortical synapses. Nat. Neurosci. 4, 235–236 (2001).
Goda, Y. & Stevens, C.F. Two components of transmitter release at a central synapse. Proc. Natl. Acad. Sci. USA 91, 12942–12946 (1994).
Xu-Friedman, M.A. & Regehr, W.G. Probing fundamental aspects of synaptic transmission with strontium. J. Neurosci. 20, 4414–4422 (2000).
Yeckel, M.F., Kapur, A. & Johnston, D. Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism. Nat. Neurosci. 2, 625–633 (1999).
Otmakhova, N.A., Otmakhov, N., Mortenson, L.H. & Lisman, J.E. Inhibition of the cAMP pathway decreases early long-term potentiation at CA1 hippocampal synapses. J. Neurosci. 20, 4446–4451 (2000).
Mammen, A.L., Kameyama, K., Roche, K.W. & Huganir, R.L. Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. J. Biol. Chem. 272, 32528–32533 (1997).
Buckley, K. & Kelly, R.B. Identification of a transmembrane glycoprotein specific for secretory vesicles of neural and endocrine cells. J. Cell Biol. 100, 1284–1294 (1985).
Svoboda, K., Helmchen, F., Denk, W. & Tank, D.W. Spread of dendritic excitation in layer 2/3 pyramidal neurons in rat barrel cortex in vivo. Nat. Neurosci. 2, 65–73 (1999).
Yasuda, H., Barth, A.L., Stellwagen, D. & Malenka, R.C. A developmental switch in the signaling cascades for LTP induction. Nat. Neurosci. 6, 15–16 (2003).
Greengard, P., Jen, J., Nairn, A.C. & Stevens, C.F. Enhancement of the glutamate response by cAMP-dependent protein kinase in hippocampal neurons. Science 253, 1135–1138 (1991).
Banke, T.G. et al. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J. Neurosci. 20, 89–102 (2000).
Lee, H.K., Barbarosie, M., Kameyama, K., Bear, M.F. & Huganir, R.L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).
Durand, G.M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996).
Zhu, J.J. & Malinow, R. Acute versus chronic NMDA receptor blockade and synaptic AMPA receptor delivery. Nat. Neurosci. 5, 513–514 (2002).
Huh, G.S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000).
Allen, C.B., Celikel, T. & Feldman, D.E. Long-term depression induced by sensory deprivation during cortical map plasticity in vivo. Nat. Neurosci. 6, 291–299 (2003).
Buonomano, D.V. & Merzenich, M.M. Cortical plasticity: from synapses to maps. Annu. Rev. Neurosci. 21, 149–186 (1998).
Brandon, E.P. et al. Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase. Proc. Natl. Acad. Sci. USA 92, 8851–8855 (1995).
Hansen, T.O., Rehfeld, J.F. & Nielsen, F.C. Cyclic AMP-induced neuronal differentiation via activation of p38 mitogen-activated protein kinase. J. Neurochem. 75, 1870–1877 (2000).
Bolshakov, V.Y., Carboni, L., Cobb, M.H., Siegelbaum, S.A. & Belardetti, F. Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3–CA1 synapses. Nat. Neurosci. 3, 1107–1112 (2000).
Glazewski, S. et al. Impaired experience-dependent plasticity in barrel cortex of mice lacking the alpha and delta isoforms of CREB. Cereb. Cortex 9, 249–256 (1999).
Beaver, C.J., Ji, Q., Fischer, Q.S. & Daw, N.W. Cyclic AMP-dependent protein kinase mediates ocular dominance shifts in cat visual cortex. Nat. Neurosci. 4, 159–163 (2001).
Goslin, K., Asmussen, H. & Banker, G. Rat hippocampal neurons in low-density culture. in Culturing Nerve Cells Vol. 2 (eds. Banker, G. & Goslin, K.) 339–370 (MIT press, Boston, 1998).
Acknowledgements
We thank M. Ehlers, R.W. Gereau IV and members of the Crair lab for comments and discussion on the manuscript, E. Gonzalez for technical assistance, and M. Ehlers and R. Huganir for the antibody against surface GluR1. The Hybridoma Bank provided the anti-SV2 antibody. H.L. is supported by a National Research Service Award (NRSA) fellowship (NS11034) and M.C.C. is supported by a grant (MH62639) from the National Institute of Mental Health (NIMH), the American Heart Association (9960158Y), the Merck and Klingenstein Foundations and the Mental Retardation Research Center at Baylor College of Medicine (HD24064).
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Supplementary Fig. 1.
The kinetics of evoked miniature-EPSCs and the decay kinetics of NMDAR mediated evoked EPSCs for control and barrelless neurons. (a) Summary data of the rise time from barrelless and control neurons (wt neurons, 0.757 ± 0.131 msec, n=7; barrelless neurons, 0.686 ± 0.077 msec, n= 7). Data taken from same neurons as reported in figure 2. Examples of the raw data traces are presented in figure 2. Rise time measurements show no difference between genotypes (P=0.61 for the comparison). (b) Summary data of fall time from n=7 barrelless and control neurons. The falling phase of the average evoked mEPSCs was fit with a double exponential. The fall times on average were longer in the control animals (4.957 ± 0.131 msec, n=7) than in barrelless neurons (3.0714 ± 0.337 msec, n=7; P < 0.05 for the difference). (c) Example average evoked mEPSCs from barrelless and control neurons. (d) Normalized average evoked mEPSCs from barrelless and control neurons show that the rise times are similar, but the fall times are somewhat longer in control animals. This is consistent with the direct effect of PKA phosphorylation on AMPA receptor open time in the control animals. (e) Summary measurements of the decay kinetics for NMDAR mediated evoked EPSCs at thalamocortical synapses. The developmental decrease in NMDAR decay time constant occurred in both control and barrelless thalamocortical synapses, consistent with a shift from NR2B to NR2A mediated currents as reported in Fig. 1C. There is no difference in the NMDAR kinetics between control and barrelless neurons for both age groups (For P3-5: the mean weighted time constant, 274 ± 32.6 msec, n=8 for wild type neurons; 233 ± 15.0 msec, n=6 for barrelless neurons; P=0.67 for the comparison; for P9-11: the mean weighted time constant, 160 ± 15.4 msec, n=7 for wild type neurons; 171 ± 28.2 msec, n=7 for barrelless neurons; P=0.99 for the comparison). (GIF 20 kb)
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Lu, HC., She, WC., Plas, D. et al. Adenylyl cyclase I regulates AMPA receptor trafficking during mouse cortical 'barrel' map development. Nat Neurosci 6, 939–947 (2003). https://doi.org/10.1038/nn1106
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DOI: https://doi.org/10.1038/nn1106
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