Article | Published:

Protein kinase C acts as a molecular detector of firing patterns to mediate sensory gating in Aplysia

Nature Neuroscience volume 15, pages 11441152 (2012) | Download Citation

Abstract

Habituation of a behavioral response to a repetitive stimulus enables animals to ignore irrelevant stimuli and focus on behaviorally important events. In Aplysia, habituation is mediated by rapid depression of sensory synapses, which could leave an animal unresponsive to important repetitive stimuli, making it vulnerable to injury. We identified a form of plasticity that prevents synaptic depression depending on the precise stimulus strength. Burst-dependent protection from depression is initiated by trains of 2–4 action potentials and is distinct from previously described forms of synaptic enhancement. The blockade of depression is mediated by presynaptic Ca2+ influx and protein kinase C (PKC) and requires localization of PKC via a PDZ domain interaction with Aplysia PICK1. During protection from depression, PKC acts as a highly sensitive detector of the precise pattern of sensory neuron firing. Behaviorally, burst-dependent protection reduces habituation, enabling animals to maintain responsiveness to stimuli that are functionally important.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Analysis of synaptic depression contributing to habituation of gill-withdrawal reflex in Aplysia californica. J. Neurophysiol. 48, 431–438 (1982).

  2. 2.

    , & Modulation of spontaneous transmitter release during depression and posttetanic potentiation of Aplysia sensory-motor neuron synapses isolated in culture. J. Neurosci. 14, 3280–3292 (1994).

  3. 3.

    & A quantal analysis of the synaptic depression underlying habituation of the gill-withdrawal reflex in Aplysia. Proc. Natl. Acad. Sci. USA 71, 5004–5008 (1974).

  4. 4.

    , , & A simplified preparation for relating cellular events to behavior: mechanisms contributing to habituation, dishabituation and sensitization of the Aplysia gill-withdrawal reflex. J. Neurosci. 17, 2886–2899 (1997).

  5. 5.

    et al. A simplified preparation for relating cellular events to behavior: contribution of LE and unidentified siphon sensory neurons to mediation and habituation of the Aplysia gill- and siphon-withdrawal reflex. J. Neurosci. 17, 2900–2913 (1997).

  6. 6.

    , & The contribution of facilitation of monosynaptic PSPs to dishabituation and sensitization of the Aplysia siphon withdrawal reflex. J. Neurosci. 19, 10438–10450 (1999).

  7. 7.

    , & Persistent, exocytosis-independent silencing of release sites underlies homosynaptic depression at sensory synapses in Aplysia. J. Neurosci. 22, 1942–1955 (2002).

  8. 8.

    & Mechanosensory neurons innervating Aplysia siphon encode noxious stimuli and display nociceptive sensitization. J. Neurosci. 17, 459–469 (1997).

  9. 9.

    & Presynaptic facilitation revisited: state and time dependence. J. Neurosci. 16, 425–435 (1996).

  10. 10.

    & Post-tetanic potentiation in Aplysia sensory neurons. Brain Res. 293, 377–380 (1984).

  11. 11.

    & Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002).

  12. 12.

    , , & A cellular mechanism of classical conditioning in Aplysia: activity-dependent amplification of presynaptic facilitation. Science 219, 400–405 (1983).

  13. 13.

    & Associative conditioning of single sensory neurons suggests a cellular mechanism for learning. Science 219, 405–408 (1983).

  14. 14.

    & Use-dependent decline of paired-pulse facilitation at Aplysia sensory neuron synapses suggests a distinct vesicle pool or release mechanism. J. Neurosci. 18, 10310–10319 (1998).

  15. 15.

    & Serotonin release evoked by tail nerve stimulation in the CNS of Aplysia: characterization and relationship to heterosynaptic plasticity. J. Neurosci. 22, 2299–2312 (2002).

  16. 16.

    , , & Pharmacological and kinetic characterization of two functional classes of serotonergic modulation in Aplysia sensory neurons. J. Neurophysiol. 75, 855–866 (1996).

  17. 17.

    , & In Aplysia sensory neurons, the neuropeptide SCPB and serotonin differ in efficacy both in modulating cellular properties and in activating adenylyl cyclase: implications for mechanisms underlying presynaptic facilitation. Brain Res. 616, 188–199 (1993).

  18. 18.

    , & Serotonin and cyclic AMP close single K+ channels in Aplysia sensory neurones. Nature 299, 413–417 (1982).

  19. 19.

    , & Switching off and on of synaptic sites at Aplysia sensorimotor synapses. J. Neurosci. 20, 626–638 (2000).

  20. 20.

    , , & Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse. J. Neurosci. 11, 1496–1507 (1991).

  21. 21.

    , & Involvement of pre- and postsynaptic mechanisms in posttetanic potentiation at Aplysia synapses. Science 275, 969–973 (1997).

  22. 22.

    , , & Activity-dependent presynaptic facilitation and Hebbian LTP are both required and interact during classical conditioning in Aplysia. Neuron 37, 135–147 (2003).

  23. 23.

    & Enhancement of sensorimotor connections by conditioning-related stimulation in Aplysia depends upon postsynaptic Ca2+. Proc. Natl. Acad. Sci. USA 93, 9931–9936 (1996).

  24. 24.

    et al. The atypical protein kinase C in Aplysia can form a protein kinase M by cleavage. J. Neurochem. 109, 1129–1143 (2009).

  25. 25.

    Isoform specificity of protein kinase Cs in synaptic plasticity. Learn. Mem. 14, 236–246 (2007).

  26. 26.

    et al. Inhibition of protein kinase C zeta subspecies blocks the activation of an NF-κB–like activity in Xenopus laevis oocytes. Mol. Cell. Biol. 13, 1290–1295 (1993).

  27. 27.

    & Possible role of protein kinase C zeta in muscarinic receptor–induced proliferation of astrocytoma cells. Biochem. Pharmacol. 60, 1457–1466 (2000).

  28. 28.

    , , & Imaging terminals of Aplysia sensory neurons demonstrates role of enhanced Ca2+ influx in presynaptic facilitation. Nature 361, 634–637 (1993).

  29. 29.

    , , , & C2 domains of protein kinase C isoforms alpha, beta, and gamma: activation parameters and calcium stoichiometries of the membrane-bound state. Biochemistry 41, 11411–11424 (2002).

  30. 30.

    , & Specific interaction of the PDZ domain protein PICK1 with the COOH terminus of protein kinase C-alpha. J. Biol. Chem. 272, 32019–32024 (1997).

  31. 31.

    et al. Cloning and characterization of Ca2+-dependent and Ca2+-independent PKCs expressed in Aplysia sensory cells. J. Neurosci. 11, 2303–2313 (1991).

  32. 32.

    , & Characterization of two isoforms of protein kinase C in the nervous system of Aplysia californica. J. Biol. Chem. 268, 5763–5768 (1993).

  33. 33.

    , , , & Serotonin receptor antagonists discriminate between PKA- and PKC-mediated plasticity in Aplysia sensory neurons. J. Neurophysiol. 95, 2713–2720 (2006).

  34. 34.

    , , , & Role of nitric oxide in classical conditioning of siphon withdrawal in Aplysia. J. Neurosci. 27, 10993–11002 (2007).

  35. 35.

    , & Parallel processing of short-term memory for sensitization in Aplysia. J. Neurobiol. 19, 297–334 (1988).

  36. 36.

    & Simulation of synaptic depression, posttetanic potentiation, and presynaptic facilitation of synaptic potentials from sensory neurons mediating gill-withdrawal reflex in Aplysia. J. Neurophysiol. 53, 652–669 (1985).

  37. 37.

    & Modulation of the readily releasable pool of transmitter and of excitation-secretion coupling by activity and by serotonin at Aplysia sensorimotor synapses in culture. J. Neurosci. 22, 10671–10679 (2002).

  38. 38.

    & Morphological basis of short-term habituation in Aplysia. J. Neurosci. 8, 2452–2459 (1988).

  39. 39.

    , , , & Effects of mobile buffers on facilitation: experimental and computational studies. Biophys. J. 78, 2735–2751 (2000).

  40. 40.

    , & A quantitative analysis of presynaptic calcium dynamics that contribute to short-term enhancement. J. Neurosci. 15, 7940–7952 (1995).

  41. 41.

    & Protein kinase C as a molecular machine for decoding calcium and diacylglycerol signals. Cell 95, 307–318 (1998).

  42. 42.

    et al. Isoform specificity of PKC translocation in living Aplysia sensory neurons and a role for Ca2+-dependent PKC APL I in the induction of intermediate-term facilitation. J. Neurosci. 26, 8847–8856 (2006).

  43. 43.

    , & Synaptic plasticity and the modulation of the Ca2+ current. J. Exp. Biol. 89, 117–157 (1980).

  44. 44.

    , , , & Ca2+-independent protein kinase C Apl II mediates the serotonin-induced facilitation at depressed Aplysia sensorimotor synapses. J. Neurosci. 21, 1247–1256 (2001).

  45. 45.

    , , & Habituation and dishabituation of the gill-withdrawal reflex in Aplysia. Science 167, 1740–1742 (1970).

  46. 46.

    & Selective gating of visual signals by microstimulation of frontal cortex. Nature 421, 370–373 (2003).

  47. 47.

    & Top-down control of multimodal sensitivity in the barn owl optic tectum. J. Neurosci. 27, 13279–13291 (2007).

  48. 48.

    , & Attention and performance. Annu. Rev. Psychol. 52, 629–651 (2001).

  49. 49.

    Control from below: the role of a midbrain network in spatial attention. Eur. J. Neurosci. 33, 1961–1972 (2011).

  50. 50.

    & Mediation of classical conditioning in Aplysia californica by long-term potentiation of sensorimotor synapses. Science 278, 467–471 (1997).

  51. 51.

    et al. Serotonin stimulation of cAMP-dependent plasticity in Aplysia sensory neurons is mediated by calmodulin-sensitive adenylyl cyclase. Proc. Natl. Acad. Sci. USA 107, 15607–15612 (2010).

Download references

Acknowledgements

We thank W. Sossin, S. Thompson and E. Walters for commenting on an earlier version of this manuscript. We thank P. Shrestha for performing the co-immunoprecipitation and immunoblot experiments. We thank I. Antonov and R. Hawkins for introducing us to their behavioral preparation. This work was supported by US National Institutes of Health grant R01 MH-55880 to T.W.A.

Author information

Author notes

    • Qin Wan
    •  & Xue-Ying Jiang

    These authors contributed equally to this work.

Affiliations

  1. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Qin Wan
    • , Xue-Ying Jiang
    • , Andreea M Negroiu
    • , Shao-Gang Lu
    •  & Thomas W Abrams
  2. Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Kimberly S McKay
    •  & Thomas W Abrams

Authors

  1. Search for Qin Wan in:

  2. Search for Xue-Ying Jiang in:

  3. Search for Andreea M Negroiu in:

  4. Search for Shao-Gang Lu in:

  5. Search for Kimberly S McKay in:

  6. Search for Thomas W Abrams in:

Contributions

X.-Y.J. and T.W.A. discovered the BDP phenomenon. Q.W., K.S.M. and T.W.A. designed the experiments. Q.W., X.-Y.J., A.M.N. and S.-G.L. carried out the experiments analyzing the mechanism of BDP. K.S.M. performed the behavioral experiments. T.W.A., K.S.M. and Q.W. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thomas W Abrams.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11 and Supplementary Table 1

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn.3158

Further reading