Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Adenylyl cyclase I regulates AMPA receptor trafficking during mouse cortical 'barrel' map development

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: AMPAR-mediated EPSCs at barrelless thalamocortical synapses remain small after the first postnatal week.
Figure 2: Thalamocortical synapses in P4–6 barrelless mice have fewer functional AMPARs.
Figure 3: LTP deficit in barrelless thalamocortical synapses.
Figure 4: Postsynaptic PKA activity is required for thalamocortical LTP in wild-type mice.
Figure 5: Very few barrelless thalamocortical synapses are silent.
Figure 6: Thalamocortical LTD requires PKA and is impaired in barrelless mice.
Figure 7: Decreased PKA-phosphorylated GluR1 in barrelless synapses.
Figure 8: Fewer synaptic surface GluR1 clusters in barrelless neurons.

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. Katz, L.C. & Shatz, C.J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).

    CAS  PubMed  Google Scholar 

  3. Crair, M.C. Neuronal activity during development: permissive or instructive? Curr. Opin. Neurobiol. 9, 88–93 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Welker, E. et al. Altered sensory processing in the somatosensory cortex of the mouse mutant barrelless. Science 271, 1864–1867 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Abdel-Majid, R.M. et al. Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nat. Genet. 19, 289–291 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Poser, S. & Storm, D.R. Role of Ca2+-stimulated adenylyl cyclases in LTP and memory formation. Int. J. Dev. Neurosci. 19, 387–394 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Malenka, R.C. & Nicoll, R.A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. Kind, P.C. & Neumann, P.E. Plasticity: downstream of glutamate. Trends Neurosci. 24, 553–555 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Ehlers, M.D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Esteban, J.A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat. Neurosci. 6, 136–143 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. Malinow, R. & Malenka, R.C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Song, I. & Huganir, R.L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 25, 578–588 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Isaac, J.T., Nicoll, R.A. & Malenka, R.C. Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427–434 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Montgomery, J.M. & Madison, D.V. State-dependent heterogeneity in synaptic depression between pyramidal cell pairs. Neuron 33, 765–777 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Crair, M.C. & Malenka, R.C. A critical period for long-term potentiation at thalamocortical synapses. Nature 375, 325–328 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Isaac, J.T., Crair, M.C., Nicoll, R.A. & Malenka, R.C. Silent synapses during development of thalamocortical inputs. Neuron 18, 269–280 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. Erzurumlu, R.S. & Kind, P.C. Neural activity: sculptor of 'barrels' in the neocortex. Trends Neurosci. 24, 589–595 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kidd, F.L. & Isaac, J.T. Developmental and activity-dependent regulation of kainate receptors at thalamocortical synapses. Nature 400, 569–573 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. Goda, Y. & Stevens, C.F. Two components of transmitter release at a central synapse. Proc. Natl. Acad. Sci. USA 91, 12942–12946 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xu-Friedman, M.A. & Regehr, W.G. Probing fundamental aspects of synaptic transmission with strontium. J. Neurosci. 20, 4414–4422 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. 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).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Banke, T.G. et al. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J. Neurosci. 20, 89–102 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    Article  CAS  PubMed  Google Scholar 

  40. Durand, G.M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Zhu, J.J. & Malinow, R. Acute versus chronic NMDA receptor blockade and synaptic AMPA receptor delivery. Nat. Neurosci. 5, 513–514 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Huh, G.S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Buonomano, D.V. & Merzenich, M.M. Cortical plasticity: from synapses to maps. Annu. Rev. Neurosci. 21, 149–186 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

  47. 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).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Hui-Chen Lu or Michael C Crair.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1106

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing