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Subcellular interactions between parallel fibre and climbing fibre signals in purkinje cells predict sensitivity of classical conditioning to interstimulus interval

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Abstract

Classical conditioning of the nictitating membrane response requires a specific temporal interval between conditioned stimulus and unconditioned stimulus, and produces an incrase in Protein Kinase C (PKC) activation in Purkinje cells. To evaluate whether biochemical interactions within the Purkinje cell may explain the temporal sensitivity, a model of PKC activation byCa 2+, diacylglycerol (DAG), and arachidonic acid (AA) is developed.Ca 2+ elevation is due to CF stimulation and IP3 inducedCa 2+ release (IICR). DAG andIP 3 result from PF stimulation, while AA results from phospholipase A2 (PLA 2). Simulations predict increased PKC activation when PF stimulation precedes CF stimulation by 0.1 to 3 s. The sensitivity of IICR to the temporal relation between PF and CF stimulation, together with the buffering system of Purkinje cells, significantly contribute to the temporal sensitivity.

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References

  • Allbritton, N. L., Meyer, T., & Stryer, L. (1992). Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate.Science, 258, 1812–1815.

    Article  PubMed  Google Scholar 

  • Berthier, N. E. & Moore, J. W. (1986). Cerebellar purkinje cell activity related to the classically conditioned nictitating membrane response.Exp Brain Res, 63, 341–350.

    Article  PubMed  Google Scholar 

  • Bhalla, U. S. (2000). Temporal pattern decoding by synaptic signaling pathways.Soc., for Neurosci. Abstr, 26, 1903.

    Google Scholar 

  • Bhalla, U. S. & Iyengar, R. (1999). Emergent properties of networks of biological signaling pathays.Science 283, 381–387.

    Article  PubMed  Google Scholar 

  • Bramham, C. R., Alkon, D. L., & Lester, D. S. (1994). Arachidonic acid and diacylglycerol act synergistically through protein kinase C to persistently enhance synaptic transmission in the hippocampus.Neuroscience, 60, 734–743.

    Article  Google Scholar 

  • Bredt, D.S., Hwang, P. M., & Snyder, S. H. (1990). Localization of nitric oxide synthase indicating a neural role for nitric oxide.Nature, 347, 768–770.

    Article  PubMed  Google Scholar 

  • Brown, I. E. & Bower, J. M. (2001). Congruence of mossy fiber and climbing fiber tactile projections in the lateral hemispheres of the rat cerebellum.J. Comp. Neurol, 429, 59–70.

    Article  PubMed  Google Scholar 

  • Callaway, J. C., Lasser-Ross, N., & Ross, W. N. (1995). IPSPs strongly inhibit climbing fiberactivated [Ca 2+ji increases in the dendrites of cerebellar Purkinje neurons.J. Neurosci, 15, 2777–2787.

    PubMed  Google Scholar 

  • Canepari, M., Papageorgiou, G., Corrie, J. E., Watkins, C., & Ogden, D. (2001). The conductance underlying the parallel fibre slow epsp in rat cerebellar purkinje neurones studied with photolytic release of I-glutamate.J. Physiol, 533, 765–72.

    Article  PubMed  Google Scholar 

  • Chen, C. & Thompson, R. F. (1995). Temporal specificity of long-term depression in parallel fiber-purkinje synapses in rat cerebellar slice.Learning and Memory, 2 185–198.

    Article  PubMed  Google Scholar 

  • Daniel, H., Levenes, C., & Crepel, F. (1998). Cellular mechanisms of cerebellar LTD.Trends in Neurosciences, 21, 401–407.

    Article  PubMed  Google Scholar 

  • De Schutter, E. & Bower, J. M. (1994). An active membrane model of the cerebellar Purkinje cell. I. Simulation of current clamps in slice.J. Neurophysiol 71, 375–400.

    PubMed  Google Scholar 

  • Destexhe, A., Mainen, Z. F., & Sejnowski, T. J. (1994). Synthesis of models for excitable membranes, synaptic transmission and neuromodulation using a common kinetic formalism.J Comput Neurosci, 1, 195–230.

    Article  PubMed  Google Scholar 

  • Ekerot, C. F. & Kano, M. (1989). Stimulation parameters influencing climbing fibre induced long-term depression of parallel fibre synapses.Neurosci. Res, 6 264–268.

    Article  PubMed  Google Scholar 

  • Fiala, J. C., Grossberg, S., & Bullock, D. (1996). Metabotropic glutamate receptor activation in cerebellar Purkinje cells as substrate for adaptive timing of the classically conditioned eye-blink response.J. Neurosci, 16, 3760–3774.

    PubMed  Google Scholar 

  • Finch, E. A. & Augustine, G. J. (1998). Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites.Nature, 396, 753–756.

    Article  PubMed  Google Scholar 

  • Freeman jr, J. H., Schaarenberg, A. M., Olds, J. L., & Schreurs, B. G. (1998). Classical conditioning increases membrane-bound protein kinase C in rabbit cerebellum.NeuroReport, 9, 2237–2241.

    Article  PubMed  Google Scholar 

  • Freeman Jr, J. H., Shi, T., & Schreurs, B. G. (1998). Pairing-specific long-term depression prevented by blockade of PKC or intracellularCa 2+.NeuroReport, 9, 2237–2241.

    Article  PubMed  Google Scholar 

  • Gormezano, I., Kehoe, E. J., & Marshall, B. S. (1983). Twenty years of classical conditioning research with the rabbit.Prog Psychobiol and Physiol Psych, 10, 197–275.

    Google Scholar 

  • Goto, K. & Kondo, H. (1999). Diacylglycerol kinase in the central nervous system-molecular heterogeneity and gene expression.Chem Phys Lipids, 98, 109–117.

    Article  PubMed  Google Scholar 

  • Gould, T. J. & Steinmetz, J. E. (1996). Changes in rabbit cerebellar cortical and interpositus nucleus activity during acquisition, extinction, and backward classical eyelid conditioning.Neurobiology of Learning and Memory, 65, 17–34.

    Article  PubMed  Google Scholar 

  • Green, J. T. & Woodruff-Pak, D. S. (2000). Eyeblink classical conditioning: hippocampal formation is for neutral stimulus associations as cerebellum is for association-response.Psychol Bull, 126, 138–158.

    Article  PubMed  Google Scholar 

  • Gruart, A., Guillazo-Blanch, G., Fernandez-Mas, R., Jimenez-Diaz, L., & Delgado-Garcia, J. M. (2000). Cerebellar posterior interpositus nucleus as an enhancer of classically conditioned eyelid responses in alert cats.J. Neurophysiol, 84, 2680–90.

    PubMed  Google Scholar 

  • Gunduppa-Sulur, G., De Schutter, E., & Bower, J. M. (1999). Ascending granule cell axon: an important component of cerebellar cortical circuitry.J. Comp. Neur, 408, 580–596.

    Article  Google Scholar 

  • Hartell, N. A. (1996). Strong activation of parallel fibers produces localized calcium transients and a form of LTD that spreads to distant synapses.Neuron, 16, 601–610.

    Article  PubMed  Google Scholar 

  • Hemart, N., Daniel, H., Jaillard, D., & Crepel, F. (1995). Receptors and second messengers involved in longterm depression in rat cerebellar slices in vitro: a reappraisal.Eur. J. Neurosci, 7, 45–53.

    Article  PubMed  Google Scholar 

  • Hirono, M., Konishi, S., & Yoshioka, T. (1998). Phospholipase C-independent group I metabotropic glutamate receptor-mediated inward current in mouse purkinje cells.Biochem Biophys Res Commun, 251, 753–8.

    Article  PubMed  Google Scholar 

  • Hirono, M., Sugiyama, T., Kishimoto, Y., Sakai, I., Miyazawa, T., Kishio, M., Inoue, H., Nakao, K., Ikeda, M., Kawahara, S., Kirino, Y., Katsuki, M., Horie, H., Ishikawa, Y., & Yoshioka, T. (2001). Phospholipase cbeta4 and protein kinase calpha and/or protein kinase cbetai are involved in the induction of long term depression in cerebellar purkinje cells.J Biol Chem, 276, 45236–42.

    Article  PubMed  Google Scholar 

  • Holmes, W. R. (2000). Models of calmodulin trapping and CaM kinase I activation in a dendritic spine.J. Comput. Neurosci, 8, 65–85.

    Article  PubMed  Google Scholar 

  • Ivkovich, D., Paczkowski, C. M., & Stanton, M. E. (2000). Ontogeny of delay versus trace eyeblink conditioning in the rat.Dev Psychobiol, 36, 148–60.

    Article  PubMed  Google Scholar 

  • Jafri, M. S. & Keizer, J. (1997). Agonist-induced calcium waves in oscillatory cells: a biological example of Burgers' equation.Bull Math Biol, 59, 1125–1144.

    Article  PubMed  Google Scholar 

  • Kaftan, E. J., Ehrlich, B. E., & Watras, J. (1997). Inositol 1,4,5-trisphosphate (insp3) and calcium interact to increase the dynamic range of insp3 receptor-dependent calcium signaling.J Gen Physiol, 110, 529–538.

    Article  PubMed  Google Scholar 

  • Kano, M., Garaschuk, O., Verkhratsky, A., & Konnerth, A. (1995). Ryanodine receptormediated intracellular calcium release in rat cerebellar purkinje neurones.J. Physiol. 487, 1–16.

    PubMed  Google Scholar 

  • Karachot, L., Kado, R. T., & Ito M. (1994). Stimulus parameters for induction of long-term depression in in vitro rat Purkinje cells.Neurosci. Res, 21, 161–168.

    Article  PubMed  Google Scholar 

  • Katz, D. B. & Steinmetz, J. E. (1997). Single-unit evidence for eye-blink conditioning in cerebellar cortex is altered, but not eliminated, by interpositus nucleus lesions.Learn Mem, 4, 88–104.

    Article  PubMed  Google Scholar 

  • Kawasaki, H., Fujii, H., Gotoh, Y., Shimohama, S., Nishida, E., & Hirano, T. (1999). Requirement for mitogen-activated protein kinase in cerebellar long term depression.J Biol Chem, 487, 13498–13502.

    Article  Google Scholar 

  • Khodakhah, K. & Ogden, D. (1995). Fast activation and inactivation of inositol trisphosphate evokedCa 2+ release in rat cerebellar Purkinje neurones.J. Physiol., 487, 343–358.

    PubMed  Google Scholar 

  • Kuroda, S., Schweighofer, N., & Kawato, M. (2001). Exploration of signal transduction pathways in cerebellar long-term depression by kinetic simulation.J. Neurosci, 21, 5693–702.

    PubMed  Google Scholar 

  • Lang, E. J., Sugihara, I., Welsh, J. P., & Llinas, R. (1999). Patterns of spontaneous Purkinje cell complex activity in the awake rat.J Neurosci., 1, 2728–2739.

    Google Scholar 

  • Leslie, C. C. & Channon, J. Y. (1990). Anionic phospholipids stimulate an arachidonoyl-hydrolyzing phospholipase A2 from macrophages and reduce the calcium requirement for activity.Biochimica et Biophysica Acta, 1045, 261–270.

    PubMed  Google Scholar 

  • Lester, D. S. & Bramham, C. R. (1993). Persistent, membrane-associated protein kinase C: from model membranes to synaptic long-term potentiation.Cell Signal, 5, 695–708.

    Article  PubMed  Google Scholar 

  • Levenes, C., Daniel, H., & Crepel, F. (1998). Long-term depression of synaptic transmission in the cerebellum: cellular and molecular mechanisms revisited.Progress in Neurobiology, 55, 79–91.

    Article  PubMed  Google Scholar 

  • Li, Y.-X. & Rinzel, J. (1994). Equations for InsP3 receptor—mediated [Ca 2+]i oscillations derived from a detailed kinetic model: a Hodgkin-Huxley like formalism.J. Theor. Biol, 166, 461–473.

    Article  PubMed  Google Scholar 

  • Linden, D. J. (1995). Phospholipase A2 controls the induction of short-term versus long-term depression in the cerebellar Purkinje neuron in culture.Neuron, 15, 1393–1401.

    Article  PubMed  Google Scholar 

  • Lüscher, C., Nicoll, R. A., Malenka, R. C., & Muller, D. (2000). Synaptic plasticity and dynamic modulation of the postsynaptic membrane.Nat Neurosci, 3, 545–550.

    Article  PubMed  Google Scholar 

  • Maeda, H., Ellis-Davies, G. C., Ito, K., Miyashita, Y., & Kasai, H. (1999). SupralinearCa 2+ signaling by cooperative and mobileCa 2+ buffering in purkinje neurons.Neuron, 24, 989–1002.

    Article  PubMed  Google Scholar 

  • Marty, A. & Llano, I. (1995). Modulation of inhibitory synapses in the mammalian brain.Curr Opin Neurobiol, 5, 335–41.

    Article  PubMed  Google Scholar 

  • McCormick, D. A. & Thompson, R. F. (1984). Cerebellum: Essential involvement in the classically conditioned eyelid response.Science, 223, 296–299.

    Article  PubMed  Google Scholar 

  • Medina, J. F., Garcia, K. S., Nores, W. L., Taylor, N. M., & Mauk, M. D. (2000). Timing mechanisms in the cerebellum: testing predictions of a large-scale computer simulation.Neurosci, 41, 5516–5525.

    Google Scholar 

  • Medina, J. F. & Mauk, M. D. (2000). Computer simulation of cerebellar information processing.Nat Neurosci, 3, 1205–1211.

    Article  PubMed  Google Scholar 

  • Midtgaard, J. (1995). Spatial synaptic integration in purkinje cell dendrites.J. Physiol Paris, 89, 23–32.

    Article  PubMed  Google Scholar 

  • Miyakawa, H., Lev-Ram, V., Lasser-Ross, N., & Ross, W. N. (1992). Calcium transients evoked by climbing fiber and parallel fiber synaptic inputs in guinea pig cerebellar Purkinje neurons.J. Neurophysiol., 68, 1178–1189.

    PubMed  Google Scholar 

  • Miyata, M., Finch, E. A., Khiroug, L., Hashimoto, K., Hayasaka, S., Oda, S. I. Inouye, M., Takagishi, Y., Augustine, G. J., & Kano, M. (2000). Local calcium release in dendritic spines required for long-term synaptic depression.Neuron, 28, 233–244.

    Article  PubMed  Google Scholar 

  • Mukhopadhyay, S., & Ross, E. M. (1999). Rapid GTP binding and hydrolysis by G(q) promoted by receptor and GTPase-activating proteins.Proc. Natl. Acad. Sci., 96, 9539–9544.

    Article  PubMed  Google Scholar 

  • Nakamura, T., Barbara, J.-G., Nakamura, K., & Ross, W. N. (1999). Synergistics release ofCa 2+ fromIP 3-sensitive stores evoked by synaptic activation of mGluRs paired with backpropagating action potentials.Neuron, 24, 727–737.

    Article  PubMed  Google Scholar 

  • Narasimhan, K., Pessah, I. N., & Linden, D. J. (1998). Inositol-1,4,5-trisphosphate receptor mediated Ca mobilization is not required for cerebellar long-term depression in reduced preparationsJ Neurophysiol, 80, 2963–2974.

    PubMed  Google Scholar 

  • Netzeband, J. G., Parsons, K. L., Sweeney, D. D., & Gruol, D. L. (1997). Metabotropic glutamate receptor agonists, alter neuronal excitability and ca2+levels via the phospholipase c transduction pathway in cultured purkinje neurons.J Neurophysiol, 78, 63–75.

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Pete, M. J., & Exton, J. H. (1996). Purification of a lysophospholipase from bovine brain that, selectively decaylates arachidonyl-substituted lysophosphatidyl-choline.J. Biol. Chemistry, 271, 18114–18121.

    Article  Google Scholar 

  • Petit, K., De Block, J., & De Potter, W. (1995). Isolation and characterization of a cytosolic phospholipase A2 from bovine adrenal medulla.J. Neurochemistry, 41, 139–146.

    Google Scholar 

  • Qiu, Z.-H. & Leslie, C. C. (1994). Protein kinase C-dependent and-independent pathways of mitogen-activated protein kinase activation in macrophages by stimuli that activate phospholipase A2.J. Biol. Chem., 269, 19480–19487.

    PubMed  Google Scholar 

  • Reynolds, T., & Hartell, N. A. (2001). Roles for nitric oxide and arachidonic acid in the induction of heterosynaptic cerebellar LTD.Neuroreport, 12, 133–136.

    Article  PubMed  Google Scholar 

  • Ryon, J. W., Cho, S. Y., & Kim, H. T. (2001). Lesions of the entorhinal cortex impair acquisition of hippocampal-dependent trace conditioning.Neurobiol Learn Mem, 75, 121–7.

    Article  Google Scholar 

  • Sabatini, B. L., Maravall, M., & Svoboda, K. (2001). Ca2+ signaling in dendritic spines.Current Opinion in Neurobiology, 11, 349–356.

    Article  PubMed  Google Scholar 

  • Schacter, J. B., Lester, D. S., & Alkon, D. L. (1996). Synergistic activation of protein kinase C by arachidonic acid and diacylglycerol in vitro: generation of a stable membrane-bound, cofactor—independent state of protein kinase C activity.Biochimica et Biophysica Acta, 1291, 167–176.

    Google Scholar 

  • Schreurs, B. G. & Alkon, D. L. (1993). Rabbit cerebellar slice analysis of long-term depression and its role in classical conditioning.Brain Res, 631, 235–240.

    Article  PubMed  Google Scholar 

  • Schreurs, B. G., Oh, M. M., & Alkon, D. L. (1996). Pairing-specific long-term depression of Purkinje cell excitatory postsynaptic potentials results from a classical conditioning procedure in the rabbit cerebellar slice.J. Neurophysiol, 75, 1051–1060.

    PubMed  Google Scholar 

  • Schreurs, B. G., Tomsic, D., Gusev, P. A., & Alkon, D. L. (1997). Dendritic excitability microzones and occluded long-term depression after classical conditioning of the rabbit's nictitating membrane response.J. Neurophysiol, 77, 86–92.

    PubMed  Google Scholar 

  • Shinomura, T., Asaoka, Y., Oka, M., Yoshida, K., & Nishizuka, Y. (1991). Synergistic action of diacylglycerol and unsaturated fatty acid for protein kinase C activation: its possible implication.Proc. Natl. Acad. Sci., 88, 5149–5153.

    Article  PubMed  Google Scholar 

  • Shirai, Y., Kashiwagi, K., Yagi, K., Sakai, N., & Saito, N. (1998). Distinct effects of fatty acids on translocation of gamma—and epsilon-subspieces of protein kinase C.J. Cell Biol, 143, 511–521.

    Article  PubMed  Google Scholar 

  • Shirai, Y., Sakai, N., & Satir, N. (1998). Subspieces-specific targeting mechanism of protein kinase C.Jpn. J. Pharmacol, 78, 411–117.

    Article  PubMed  Google Scholar 

  • Smrcka, A. V., Hepler, J. R., Brown, K. O., & Sternweis, P. C. (1991). Regulation of polyphosphoinostitide-specific phospholipase C activity by purified Gq.Science, 251, 804–807.

    Article  PubMed  Google Scholar 

  • Southam, E., Morris, R., & Garthwaite, J. (1992). Sources and targets of nitric oxide in rat cerebellum.Neurosci Lett, 137, 241–244.

    Article  PubMed  Google Scholar 

  • Stanton, M. E. (2000). Multiple memory systems, development and conditioning.Behav Brain Res, 110, 25–37.

    Article  PubMed  Google Scholar 

  • Steinmetz, J. E. (2000). Brain substrates of classical eyeblink conditioning: a highly localized but also distributed system.Behav Brain Res, 110, 13–24.

    Article  PubMed  Google Scholar 

  • Stella, N., Pellerin, L., & Magistretti, B. J. (1995). Modulation of the glut amate-evoked release of arachidonic acid from mouse cortical neurons: involvement of a pH sensitive membrane phospholipase A2.J. Neurosci, 15, 3307–3317.

    PubMed  Google Scholar 

  • Striggow, F. & Ehrlich, B. E. (1997). Regulation of intracellular calcium release channel function by arachidonic acid and leukotriene B4.Biochern Biophys Res Commun, 237, 413–418.

    Article  Google Scholar 

  • Takechi, H., Eilers, J., & Konnerth, A. (1998). A new class of synaptic response involving calcium release in dendritic spines.Nature, 396, 757–760.

    Article  PubMed  Google Scholar 

  • Tempia, F., Miniaci, C., Anchisi, D., & Strata, P. (1998). Postsynaptic current mediated by metabotropic glutamate receptors in cerebellar Purkinje cells.J. Neurophysiol, 80, 520–528.

    PubMed  Google Scholar 

  • Thompson, R. F. (1986). The neurobiology of learning and memory.Science, 233, 941–947.

    Article  PubMed  Google Scholar 

  • Thompson, R. F., & Kim, J. J. (1996). Memory systems in the brain and localization of a memory.Proc. Natl. Acad. Sci. 93, 13438–13444.

    Article  PubMed  Google Scholar 

  • Thompson, R. F., & Krupa, D. J. (1994). Organization of memory traces in the mammalian brain.Ann. Rev. Neurosci., 17, 519–549.

    Article  PubMed  Google Scholar 

  • Wang, S. S., Alousi, A. A., & Thompson, S. H. (1995). The lifetime of inositol 1,4,5-trisphosphate in single cells.J Gen Physiol, 105, 149–171.

    Article  PubMed  Google Scholar 

  • Wang, S. S.-H., Denk, W., & Hausser, M. (2000). Coincidence detection in single dendritic spines mediated by calcium release.Nat Neurosci 3, 1266–1273.

    Article  PubMed  Google Scholar 

  • Wang, Y. T. & Linden, D. J. (2000). Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis.Neuron, 25, 635–647.

    Article  PubMed  Google Scholar 

  • Watras, J., Bezprozvanny, I., & Ehrlich, B. E. (1991). Inositol 1,4,5-trisphosphate-gated channels in cerebellum: presence of multiple conductance states.J. Neurosci, 1 3239–45.

    Google Scholar 

  • Watras, J., Orlando, R., & Moraru, I. I. (2000). An endogenous sulfated inhibitor of neuronal inositol trisphosphate receptors.Biochemistry, 39, 3452–60.

    Article  PubMed  Google Scholar 

  • Woodruff-Pak, D. S., Lavond, D. G., & Thompson, R. F. (1985). Trace conditioning: abolished by cerebelar nuclear lesions but not lateral cerebellar cortex aspiration.Brain Res., 348, 249–260.

    Article  PubMed  Google Scholar 

  • Yang, K., Hellgren Kotaleski, J., & Blackwell, K. T. (2000). The role of protein kinase C in the temporal specificity of purkinje cells.Soc. Neurosci. Abstr, 26, 718.

    Google Scholar 

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  1. Dept. of Numerical Analysis and Computing Science, Royal Institute of Technology, S-100 44, Stockholm, Sweden

    Jeanette Hellgren Kotaleski, David Lester & Kim T. Blackwell

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Kotaleski, J.H., Lester, D. & Blackwell, K.T. Subcellular interactions between parallel fibre and climbing fibre signals in purkinje cells predict sensitivity of classical conditioning to interstimulus interval. Integrative Physiological & Behavioral Science 37, 265–292 (2002). https://doi.org/10.1007/BF02734249

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