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Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity

Nature Neuroscience volume 15, pages 250–257 (2012)Cite this article

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Abstract

Recurrent excitatory circuits face extreme challenges in balancing efficacy and stability. We recorded from CA3 pyramidal neuron pairs in rat hippocampal slice cultures to characterize synaptic and circuit-level changes in recurrent synapses resulting from long-term inactivity. Chronic tetrodotoxin treatment greatly reduced the percentage of connected CA3-CA3 neurons, but enhanced the strength of the remaining connections; presynaptic release probability sharply increased, whereas quantal size was unaltered. Connectivity was decreased in activity-deprived circuits by functional silencing of synapses, whereas three-dimensional anatomical analysis revealed no change in spine or bouton density or aggregate dendrite length. The silencing arose from enhanced Cdk5 activity and could be reverted by acute Cdk5 inhibition with roscovitine. Our results suggest that recurrent circuits adapt to chronic inactivity by reallocating presynaptic weights heterogeneously, strengthening certain connections while silencing others. This restricts synaptic output and input, preserving signaling efficacy among a subset of neuronal ensembles while protecting network stability.

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Figure 1: Adaptation of recurrent CA3 connections following chronic TTX treatment.
Figure 2: Synaptic efficacy of monosynaptically connected CA3 pyramids following chronic inactivity.
Figure 3: Chronic silencing leads to alterations in Pr between synaptically connected CA3 neurons.
Figure 4: Variance-mean analyses.
Figure 5: Morphometric change in dendrites.
Figure 6: Activation of silent synapses.

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References

  1. Silberberg, G., Grillner, S., LeBeau, F.E., Maex, R. & Markram, H. Synaptic pathways in neural microcircuits. Trends. Neurosci. 28, 541–551 (2005).

    Article  CAS  Google Scholar 

  2. Buzsaki, G. Rhythms of the Brain 464 (Oxford University Press, 2006).

  3. Wittner, L., Henze, D.A., Zaborszky, L. & Buzsaki, G. Three-dimensional reconstruction of the axon arbor of a CA3 pyramidal cell recorded and filled in vivo. Brain Struct. Funct. 212, 75–83 (2007).

    Article  Google Scholar 

  4. Guzowski, J.F., Knierim, J.J. & Moser, E.I. Ensemble dynamics of hippocampal regions CA3 and CA1. Neuron 44, 581–584 (2004).

    Article  CAS  Google Scholar 

  5. Rolls, E.T. & Kesner, R.P. A computational theory of hippocampal function, and empirical tests of the theory. Prog. Neurobiol. 79, 1–48 (2006).

    Article  CAS  Google Scholar 

  6. Song, S., Sjostrom, P.J., Reigl, M., Nelson, S. & Chklovskii, D.B. Highly nonrandom features of synaptic connectivity in local cortical circuits. PLoS Biol 3, e68 (2005).

    Article  Google Scholar 

  7. Lefort, S., Tomm, C., Floyd Sarria, J.C. & Petersen, C.C. The excitatory neuronal network of the C2 barrel column in mouse primary somatosensory cortex. Neuron 61, 301–316 (2009).

    Article  CAS  Google Scholar 

  8. Hardingham, N.R. et al. Quantal analysis reveals a functional correlation between presynaptic and postsynaptic efficacy in excitatory connections from rat neocortex. J. Neurosci. 30, 1441–1451 (2010).

    Article  CAS  Google Scholar 

  9. Bushey, D., Tononi, G. & Cirelli, C. Sleep and synaptic homeostasis: structural evidence in Drosophila. Science 332, 1576–1581 (2011).

    CAS  PubMed  Google Scholar 

  10. Butz, M., van Ooyen, A. & Worgotter, F. A model for cortical rewiring following deafferentation and focal stroke. Front. Comput. Neurosci. 3, 10 (2009).

    Article  Google Scholar 

  11. Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C. & Nelson, S.B. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892–896 (1998).

    Article  CAS  Google Scholar 

  12. O'Brien, R.J. et al. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21, 1067–1078 (1998).

    Article  CAS  Google Scholar 

  13. Aoki, C. et al. Drebrin a knockout eliminates the rapid form of homeostatic synaptic plasticity at excitatory synapses of intact adult cerebral cortex. J. Comp. Neurol. 517, 105–121 (2009).

    Article  CAS  Google Scholar 

  14. Bacci, A. et al. Chronic blockade of glutamate receptors enhances presynaptic release and downregulates the interaction between synaptophysin-synaptobrevin vesicle-associated membrane protein 2. J. Neurosci. 21, 6588–6596 (2001).

    Article  CAS  Google Scholar 

  15. Burrone, J., O'Byrne, M. & Murthy, V.N. Multiple forms of synaptic plasticity triggered by selective suppression of activity in individual neurons. Nature 420, 414–418 (2002).

    Article  CAS  Google Scholar 

  16. Thiagarajan, T.C., Lindskog, M. & Tsien, R.W. Adaptation to synaptic inactivity in hippocampal neurons. Neuron 47, 725–737 (2005).

    Article  CAS  Google Scholar 

  17. Lindskog, M. et al. Postsynaptic GluA1 enables acute retrograde enhancement of presynaptic function to coordinate adaptation to synaptic inactivity. Pro.c Natl. Acad. Sci. USA 107, 21806–21811 (2010).

    Article  CAS  Google Scholar 

  18. Jakawich, S.K. et al. Local presynaptic activity gates homeostatic changes in presynaptic function driven by dendritic BDNF synthesis. Neuron 68, 1143–1158 (2010).

    Article  CAS  Google Scholar 

  19. Beique, J.C., Na, Y., Kuhl, D., Worley, P.F. & Huganir, R.L. Arc-dependent synapse-specific homeostatic plasticity. Proc. Natl. Acad. Sci. USA 108, 816–821 (2011).

    Article  CAS  Google Scholar 

  20. Buonomano, D.V. A learning rule for the emergence of stable dynamics and timing in recurrent networks. J. Neurophysiol. 94, 2275–2283 (2005).

    Article  Google Scholar 

  21. Houweling, A.R., Bazhenov, M., Timofeev, I., Steriade, M. & Sejnowski, T.J. Homeostatic synaptic plasticity can explain post-traumatic epileptogenesis in chronically isolated neocortex. Cereb. Cortex 15, 834–845 (2005).

    Article  Google Scholar 

  22. Kim, J. & Tsien, R.W. Synapse-specific adaptations to inactivity in hippocampal circuits achieve homeostatic gain control while dampening network reverberation. Neuron 58, 925–937 (2008).

    Article  CAS  Google Scholar 

  23. Maffei, A. & Turrigiano, G.G. Multiple modes of network homeostasis in visual cortical layer 2/3. J. Neurosci. 28, 4377–4384 (2008).

    Article  CAS  Google Scholar 

  24. Desai, N.S., Rutherford, L.C. & Turrigiano, G.G. Plasticity in the intrinsic excitability of cortical pyramidal neurons. Nat. Neurosci. 2, 515–520 (1999).

    Article  CAS  Google Scholar 

  25. Trasande, C.A. & Ramirez, J.M. Activity deprivation leads to seizures in hippocampal slice cultures: is epilepsy the consequence of homeostatic plasticity? J. Clin. Neurophysiol. 24, 154–164 (2007).

    Article  Google Scholar 

  26. Maffei, A., Nataraj, K., Nelson, S.B. & Turrigiano, G.G. Potentiation of cortical inhibition by visual deprivation. Nature 443, 81–84 (2006).

    Article  CAS  Google Scholar 

  27. Muller, D., Buchs, P.A. & Stoppini, L. Time course of synaptic development in hippocampal organotypic cultures. Brain Res. Dev. Brain Res. 71, 93–100 (1993).

    Article  CAS  Google Scholar 

  28. De Simoni, A., Griesinger, C.B. & Edwards, F.A. Development of rat CA1 neurones in acute versus organotypic slices: role of experience in synaptic morphology and activity. J. Physiol. 550, 135–147 (2003).

    Article  CAS  Google Scholar 

  29. Turrigiano, G.G. & Nelson, S.B. Hebb and homeostasis in neuronal plasticity. Curr. Opin. Neurobiol. 10, 358–364 (2000).

    Article  CAS  Google Scholar 

  30. Saviane, C. & Silver, R.A. Estimation of quantal parameters with multiple-probability fluctuation analysis. Methods Mol. Biol. 403, 303–317 (2007).

    Article  CAS  Google Scholar 

  31. Graf, E.R., Daniels, R.W., Burgess, R.W., Schwarz, T.L. & DiAntonio, A. Rab3 dynamically controls protein composition at active zones. Neuron 64, 663–677 (2009).

    Article  CAS  Google Scholar 

  32. Moulder, K.L. et al. A specific role for Ca2+-dependent adenylyl cyclases in recovery from adaptive presynaptic silencing. J. Neurosci. 28, 5159–5168 (2008).

    Article  CAS  Google Scholar 

  33. Ma, L., Zablow, L., Kandel, E.R. & Siegelbaum, S.A. Cyclic AMP induces functional presynaptic boutons in hippocampal CA3–CA1 neuronal cultures. Nat. Neurosci. 2, 24–30 (1999).

    Article  CAS  Google Scholar 

  34. Su, S.C. & Tsai, L.H. Cyclin-dependent kinases in brain development and disease. Annu. Rev. Cell Dev. Biol. 27, 465–491 (2011).

    Article  CAS  Google Scholar 

  35. Lai, K.O. & Ip, N.Y. Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochim. Biophys. Acta 1792, 741–745 (2009).

    Article  CAS  Google Scholar 

  36. Kim, S.H. & Ryan, T.A. CDK5 serves as a major control point in neurotransmitter release. Neuron 67, 797–809 (2010).

    Article  CAS  Google Scholar 

  37. Tomizawa, K. et al. Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity. J. Neurosci. 22, 2590–2597 (2002).

    Article  CAS  Google Scholar 

  38. Tsai, L.H., Delalle, I., Caviness, V.S. Jr. Chae, T. & Harlow, E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419–423 (1994).

    Article  CAS  Google Scholar 

  39. Meijer, L. et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527–536 (1997).

    Article  CAS  Google Scholar 

  40. Yan, Z., Chi, P., Bibb, J.A., Ryan, T.A. & Greengard, P. Roscovitine: a novel regulator of P/Q-type calcium channels and transmitter release in central neurons. J. Physiol. 540, 761–770 (2002).

    Article  CAS  Google Scholar 

  41. Tao, L., Cai, D., McLaughlin, D.W., Shelley, M.J. & Shapley, R. Orientation selectivity in visual cortex by fluctuation-controlled criticality. Proc. Natl. Acad. Sci. USA 103, 12911–12916 (2006).

    Article  CAS  Google Scholar 

  42. Fu, W.Y. et al. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat. Neurosci. 10, 67–76 (2007).

    Article  CAS  Google Scholar 

  43. Tan, T.C. et al. Cdk5 is essential for synaptic vesicle endocytosis. Nat. Cell Biol. 5, 701–710 (2003).

    Article  CAS  Google Scholar 

  44. Park, M. et al. CYY-1/cyclin Y and CDK-5 differentially regulate synapse elimination and formation for rewiring neural circuits. Neuron 70, 742–757 (2011).

    Article  CAS  Google Scholar 

  45. Darcy, K.J., Staras, K., Collinson, L.M. & Goda, Y. Constitutive sharing of recycling synaptic vesicles between presynaptic boutons. Nat. Neurosci. 9, 315–321 (2006).

    Article  CAS  Google Scholar 

  46. Ou, C.Y. et al. Two cyclin-dependent kinase pathways are essential for polarized trafficking of presynaptic components. Cell 141, 846–858 (2010).

    Article  CAS  Google Scholar 

  47. Hanson, J.E. & Madison, D.V. Imbalanced pattern completion versus separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy. BMC Neurosci. 11, 96 (2010).

    Article  Google Scholar 

  48. Hanson, J.E., Blank, M., Valenzuela, R.A., Garner, C.C. & Madison, D.V. The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down's syndrome. J. Physiol. 579, 53–67 (2007).

    Article  CAS  Google Scholar 

  49. Costa, A.C., Stasko, M.R., Schmidt, C. & Davisson, M.T. Behavioral validation of the Ts65Dn mouse model for Down syndrome of a genetic background free of the retinal degeneration mutation Pde6b(rd1). Behav. Brain Res. 206, 52–62 (2010).

    Article  CAS  Google Scholar 

  50. Krystof, V. & Uldrijan, S. Cyclin-dependent kinase inhibitors as anticancer drugs. Curr. Drug Targets 11, 291–302 (2010).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Pathak, V. Dhani and S. Owen for comments on the manuscript, A.Y. Olson for help with spine density analysis, I. Prada for advice on immunostaining techniques, and Stanford Neuroscience Microscope Core. We also thank members of the Tsien laboratory for helpful discussions throughout the project. This work was supported by National Institute of Mental Health grant 5R37MH071739 and grants from the Mather Foundation Burnett Family Foundation to R.W.T.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA

    Ananya Mitra & Richard W Tsien

  2. Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA

    Siddhartha S Mitra

  3. New York University Institute of Neuroscience, New York University, New York, New York, USA

    Richard W Tsien

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  1. Ananya Mitra
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Contributions

A.M. and R.W.T. designed the study and wrote the manuscript. A.M. and S.S.M. conducted the experiments. A.M. analyzed the data and generated the figures.

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Correspondence to Richard W Tsien.

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Mitra, A., Mitra, S. & Tsien, R. Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity. Nat Neurosci 15, 250–257 (2012). https://doi.org/10.1038/nn.3004

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