Dataset Information

Control of cortical axon elongation by a GABA-driven Ca2+/calmodulin-dependent protein kinase cascade.

ABSTRACT: Ca(2+) signaling plays important roles during both axonal and dendritic growth. Yet whether and how Ca(2+) rises may trigger and contribute to the development of long-range cortical connections remains mostly unknown. Here, we demonstrate that two separate limbs of the Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK)-CaMKI cascades, CaMKK-CaMKIalpha and CaMKK-CaMKIgamma, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphological phenotype required a diffuse cytoplasmic localization and a strikingly alpha-isoform-specific kinase activity of CaMKI. Unexpectedly, treatment with muscimol, a GABA(A) receptor agonist, selectively stimulated elongation of axons but not of dendrites, and the CaMKK-CaMKIalpha cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKIalpha significantly impaired the terminal axonal extension and thereby perturbed the refinement of the interhemispheric callosal projections into the contralateral cortices. Our findings thus indicate a novel role for the GABA-driven CaMKK-CaMKIalpha cascade as a mechanism critical for accurate cortical axon pathfinding, an essential process that may contribute to fine-tuning the formation of interhemispheric connectivity during the perinatal development of the CNS.

SUBMITTER: Ageta-Ishihara N

PROVIDER: S-EPMC2796271 | biostudies-other | 2009 Oct

REPOSITORIES: biostudies-other

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Publications

Control of cortical axon elongation by a GABA-driven Ca2+/calmodulin-dependent protein kinase cascade.

Ageta-Ishihara Natsumi N Takemoto-Kimura Sayaka S Nonaka Mio M Adachi-Morishima Aki A Suzuki Kanzo K Kamijo Satoshi S Fujii Hajime H Mano Tatsuo T Blaeser Frank F Chatila Talal A TA Mizuno Hidenobu H Hirano Tomoo T Tagawa Yoshiaki Y Okuno Hiroyuki H Bito Haruhiko H

The Journal of neuroscience : the official journal of the Society for Neuroscience 20091001 43

Ca(2+) signaling plays important roles during both axonal and dendritic growth. Yet whether and how Ca(2+) rises may trigger and contribute to the development of long-range cortical connections remains mostly unknown. Here, we demonstrate that two separate limbs of the Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK)-CaMKI cascades, CaMKK-CaMKIalpha and CaMKK-CaMKIgamma, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphol ...[more]

PMID: 19864584

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Project description:During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning.

Dataset Information

Control of cortical axon elongation by a GABA-driven Ca2+/calmodulin-dependent protein kinase cascade.

Publications

Control of cortical axon elongation by a GABA-driven Ca2+/calmodulin-dependent protein kinase cascade.

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