Abstract
Specificity of molecular mechanisms for synaptic weight regulation is critical for understanding the cellular basis of learning and memory. Thus, while we have known for decades that protein synthesis is involved in long-term memory (Flexner et al., 1963; Hy-den et al., 1965; Agranoff et al., 1966; Matthies, 1989; Van der Zee et al., 1992; Nelson and Alkon, 1992; see Kandel, this volume), protein synthesis is also necessary for so many cellular functions that its direct contribution to memory function remains obscure. Here, however, we describe a new signalling protein, Calexcitin, which powerfully and specifically regulates synaptic weight as well as synaptic sign and is activated by a molecular cascade more directly implicated in associative learning of diverse molluscan and mammalian species . This cascade begins when temporally related training stimuli (e.g. an auditory tone and a touch stimulus to the cornea) elicit temporally related synaptic signals that in turn elicit temporally related second messengers such as Ca++, DAG (diacyl-glycerol), and AA (arachidonic acid). Temporally associated second messengers activate protein kinase C (PKC) through its translocation to the inner surface of neuronal membranes (and possibly membranes of subcellular organelles such as the ER). Membrane-associated PKC, now sensitive to low levels of Ca++ (0.1–1.0 uM), phosphorylates critical signaling proteins such as the recently sequenced cp20 (now called “Calexcitin”), the first known protein to bind both Ca++ and GTP. Calexcitin, shown to be a high affinity substrate of Ca++-dependent isozymes of PKC (particularly the α-isozyme), when phosphorylated during learning, also becomes membrane associated and inactivates voltage-dependent K+ channels (such as IA, IC etc.). Recent experiments (Weh et al., in press) also implicate Calexcitin in the regulation of Ca++ release from the endoplasmic reticulum and thus further Ca++-mediated transformations of synaptic weight and perhaps structure. Still other recent experiments (Cavallero et al., Soc.for Neuroscience, Abstract, in press) showed increased activation of the gene responsible for ryanodine receptor expression after spatial maze learning.
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References
Acosta-Urquidi J., Alkon D. L., Neary J. T. (1984) Ca2+-calmodulin-dependent protein kinase injection in a photoreceptor mimics biophysical effects of associative learning in Hermissenda. Science 224, 1254–1257.
Agranoff B.W., Davis R. E., and Brink J. J. (1966) Chemical studies on memory fixation in goldfish. Brain Res. 1, 303–309.
Alkon D. L. (1983) Learning in a marine snail. Sci. Amer. 249, 70–84.
Alkon, D. L. (1984) Calcium-mediated reduction of ionic currents: A biophysical memory trace. Science 226, 1037–1045.
Alkon D. L. (1989) Memory storage and neural systems. Sc. Amer. 260, 42–50.
Alkon D. L., Blackwell K. T., Barbour G. S., Werness S. A., and Vogl T. P. (1994) Biological plausibility of synaptic associative memory models. Neural Networks 7, 1005–1017.
Alkon D. L., Sanchez-Andres J. V., Ito E., Oka K., Yoshioka T. and Collin C. (1992) Long-term transformation of an inhibitory into an excitatory GABA-ergic synaptic response. Proc. Nat. Acad. of Sci. USA 89, 11862–11866.
Bank B., DeWeer A., Kuzirian A. M, Rasmussen H. and Alkon D. L. (1988) Classical conditioning induces long-term translocation of protein kinase C in rabbit hippocampal CA1 cells. Proc. Natl. Acad. Sci. USA 85, 1988–1992.
Bondy B., Hofmann M., Muller-Spahn F., Witzko M., and Hock C. (1996) The PHA-induced calcium signal in lymphocytes is altered after blockade of K+-channeIs in Alzheimer’s disease. J. Psych. Res. 30, 217–227.
Colin C., Devan, W. A., Dahl D., Lee C. J., Axelrod J. and Alkon D. L. (1995) Long-term synaptic transformation of hippocampal Caly-aminobutyric acid synapses and the effect of anadamide. Proc. Nat. Acad. of Sci. USA 92, 10167–10171.
Dahl D., Arrowood J. L., Olds J. L., McPhie D. L. and Alkon D. L. (1997) Chohnergic transformation of GABAergic inhibition into excitation: heterosynaptic receptor interaction in the hipocampus. J. Neuropy-hysiology, (in press).
Davies H. R. and Squire L. R. Protein synthesis and memory: a review. (1984) Psychol. Bull. 96, 518–559.
Disterhoft J. F., Coulter D. A. and Alkon D. L. (1986) Conditioning-specific membrane changes of rabbit hippocampal neurons measured in vitro.Proc. Natl. Acad. Sci. USA 83, 2733–2737.
Etcheberrigaray R., Ito E., Kim S., and Alkon D. L. (1994) Soluble ß-amyloid induction of Alzheimer’s phenotype for human fibroblast K+ channels. Science 264, 276–279.
Flexner J. B., Flexner L. B., Stellar E. (1963) Science 141, 57.
Furukawa K., Barger S. W., Blalock E. M., and Mattson M. P. (1996) Activation of K channels and suppression of neuronal activity by secreted ß-amyloid-precursor protein. Nature 379, 74–78.
Glomset J.A., Gelb M.H., and Farnsworth C.C. (1990) Prenyl proteins in eukaryotic cells: a new type of membrane anchor. Trends in Biochem. Sci. 15. 139–142
Good T.A., Smith D.O. and Murphy R.M. (1996) ß-amyloid peptide blocks the fast-inactivating K current in rat hippocampal neurons. Biophysical Journal 70, 296–304.
Hyden H., Lange P.W. (1965) A differential RNA response in neurons early and late during learning. Proc. Natl. Acad. Sci. USA 53. 946–952.
Katz B. (1966) Nerve. Muscle, and Synapse. New York: McGraw Hill.
Kretsinger R.H. (1987) Calcium coordination and the calmodulin fold: divergent versus convergent evolution. Cold Spring Harbor Symp. Quant. Biol. 52. 499–510
Kuffler S.W., Nicholls J.G. and Martin A.R. (1984) From Neuron to Brain (2nd edition) Sunderland. MA, Sinauver.
Linden D.J. and Connor J.A. (1995) Long-term synaptic depression. Ann. Rev. Neurosci. 18, 319–357.
LoTurco J. L., Coulter D. A. and Alkon D. L. (1988) Enhancement of synaptic potentials in rabbit CA1 pyramidal neurons following classical conditioning. Proc. Natl. Acad. Sci. USA 85, 1672–1676.
Lowy D., and Willumsen B. (1989) Protein modification: new clue to Ras lipid glue. Nature 341, 384–385.
Matthies H. (1989) In search of cellular mechanisms of memory. Prog. Neurobiol 32, 277–349.
McPhie DL, Matzel LD, Olds JL, Lester DS, Kuzirian AM, Alkon DL. (1993) Cell specficity of molecular changes during memory storage. J Neurochem 60, 646–651.
Meiri N., Ghelardini C., Tesco G., Galeotti N., Dahl D., Tomsic D., Cavallaro S., Quattrone A., Capaccioli S., Bartolini A. and Alkon D. (1997) Antisense inhibition of the rodent Shaker-like potassium channel Kvl.l: disruption of memory without effects on LTP. Proc. Natl. Acad. Sci. USA (in press ).
Migliore M., Coo E. P., Jaffe D. B., Turner D. A., and Johnston D. (1995) Computer simulations of morphologically reconstructed CA3 hippocampal neurons. J. Neurophysiol. 73, 1157–1168.
Musil L., Carr C., Cohe, J., and Merlie J. (1988) Acetylcholine receptor-associated 43K protein contains covalently bound myristate. J. Cell Biol., 107,: 1113–1121.
Nelson T. and Alkon D.L. (1990) Specific high-molecular weight mRNAs induced by associative learning in Hermissemla. Proc. Natl. Acad. Sci. USA 87, 195–200.
Nelson T. J., Cavalaro S., Yi C.-L., McPhie D., Schreurs B. G., Gusev P. A., Favit A., Zohar O., Kim J., Beuschausen S., Ascoli G., Olds J., Neve R., and Alkon D. L. (1996) Calexcitin. a signaling protein that binds calcium, inhibits potassium channels, and enhances membrane excitability. Proc. Nat. Acad. Sci. USA 93, 13808–13813
Nelson T., Collin C. and Alkon D. L. (1990) Isolation of a G protein that is modified by learning and reduces potassium currents in Hermissenda. Science 247, 1479–1483.
Nelson T. J., Yoshioka T., Toyoshima S., Han Y-F., and Alkon D.L. (1994) Characterization of a GTP-binding protein implicated in both memory storage and interorganelle vesicle transport. Proc. Nat. Acad. Sci. USA 91, 9287–9291.
Nosten-Bertrand M., Errington M.L., Murphy K.P., Tokugawa Y., Barboni E., Kozlova E., Michalovich D., Morris R.G., Silver J., Stewart C.L., Bliss T.V., and Morris R.J. (1996) Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1. Nature 379, 826–829.
Olds J. L., Anderson M., McPhie D. L., Staten L., Alkon D. L., (1989) Imaging memory-specific changes in the distribution of protein kinase c within the hippocampus. Science; 245, 866–869.
Olds JL, Bahalla US, McPhie DL, Lester DS, Bower JM, Alkon DL. (1994) Lateralization of membrane-associated protein kinase C in rat piriform cortex: specific to operant training cues in the olfactory modality. Beh Brain Res 61: 37–46.
Olds JL, Golski S, McPhie DL, Olton D. Mishkin M and Alkon DL. (1990) Discrimination learning alters the distribution of protein kinase C in the hippocampus of rats. J. Neurosci. 10, 3707–3713.
Sakakibara M., Alkon D. L., Neary J. T., Heldman E., and Gould R.: (1986) Inositol trisphosphate regulation of photoreceptor membrane currents. Biophys. J. 50, 797–803.
Sakakibara M., Ikeno H., Usui, S., Collin C., Alkon, D. L. (1993) Reconstruction of ionic currents in a molluscan photoreceptor. Biophys J 65, 519–527.
Schachter, J., Lester, D., and Alkon, D.L. (1996) Synergistic activation of protein kinase C by arachidonic acid and diacylglycerols in vitro: generation of a stable membrane. Biochemica Biophysica Acta.
Schreurs B. G., Tomsic D., Gusev P. A., and Alkon D. L. (1997) Dendritic excitability microzones and occluded long-term depression after classical conditioning of the rabbit’s nictating membrane response. J. Neuro-physiology, 75 1051–1060.
Thomson R. F. (1986) The neurobiology of learning and memory. Science Wash. DC 233, 941–947.
Tonegawa S. (1994) Gene Targeting: A new approach for the analysis of mammalian memory and learning. In: Molecular Neurobiology: Mechanisms Common to Brain, Skin, and Immune System, Wiley-Liss, Inc. pp. 5–18.
Turner R.S., Kemp B., Su H.-D., and Kuo J.F. (1985) Substrate specficity of phospholipoid/Ca2- dependent protein kinase as probed with synthetic peptide fragments of the bovine myelin basic protein. J. Biol. Chem. 260, 11503–11507.
Walker J.E., Saraste M., Runswick M.J., and Gay N.J. (1982) Distantly related sequences of the alpha-and beta-subunits of ATP synthase, myosin, kinase. and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1. 945–951.
Wickman K. and Clapham D. E. (1995) Ion channel regulation by G proteins. Physiol. Rev. 75: 865–885.
Usherwood P. N. R. (1993) Memories are made of this. Trends in Neuroscience 93, 427–429.
Van der Zee E.A., Compaan J.C., de Boer M., Luiten P.G.M. (1992) Changes in PKC immunoreactivity in mouse hippocampus induced by spatial discrimination learning. J. Neurosci. 12,: 4808–4815, 1992.
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Alkon, D.L. (1998). Molecular Specificity of Synaptic Changes Responsible for Associative Memory. In: Ehrlich, Y.H. (eds) Molecular and Cellular Mechanisms of Neuronal Plasticity. Advances in Experimental Medicine and Biology, vol 446. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4869-0_1
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