Professor, Department of Physiology, Graduate School of Medicine, Keio University
Michisuke Yuzaki, MD, PhD
Mechanisms underlying synapse formation and maintenance in the adult brain
Recent studies have provided evidence suggesting that synapses are dynamically generated and eliminated throughout adulthood. An understanding of the mechanisms by which neurons form correct synapses in the adult brain is crucial to the use of regenerative medicine using stem cell-derived neurons. Although many molecules have been shown to be essential for synapse formation during development, their requirement for the maintenance of synapses or the formation of new synapses in the adult CNS in vivo remains largely unknown. The goal of this project is to characterize the molecular mechanisms underlying synapse formation and maintenance in the adult cerebellum, focusing on the recently identified synapse organizer Cbln1 and related molecules. More specifically, at first, the effect of Cbln1 on synapse formation and functional recovery of cerebellar circuits will be studied by transplanting stem cell-derived neurons together with recombinant Cbln1. In a subsequent study, since endogenous Cbln1 is constitutively expressed and stabilizes synapses, the mechanisms determining gene expression of Cbln1 will be investigated with the aim of modulating the expression levels of endogenous Cbln1. The results of these studies are expected to pave the way for new and better therapeutic application of stem cells to the treatment of certain brain disorders.
Cbln1 as a new and potent synapse organizer in the mature brain
Cbln1, which belongs to the C1q/tumor necrosis factor (TNF) superfamily, is one of the most recently identified proteins capable of inducing synapse formation in the CNS. In the cerebellum, Cbln1 is produced and secreted from the granule cells and plays a crucial role in the formation of excitatory synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells during development; mice with a disrupted cbln1 gene (cbln1 KO) display severe ataxia and reduction in the number of PF Purkinje cell synapses (Nature Neurosci, '05). Furthermore, a single application of recombinant Cbln1 rapidly, but transiently, restored the PF synapses in mature cbln1 KO Purkinje cells, both in vitro and in vivo (J Neurosci, '08). We also found that the orphan glutamate receptor GluRδ2, predominantly expressed in PF Purkinje cell postsynapses, and Cbln1, expressed mainly in granule cell presynapses, are involved in a common signaling pathway crucial for synapse formation and maintenance. Since proteins related to Cbln1 and GluRδ2 are expressed in various brain regions of adult mice, proteins of these families are likely to be generally involved in the mechanisms responsible for synapse formation/maintenance in the adult brain.
Fig.1 Cbln1 and the δ2 glutamate receptor (δ2 receptor).
Cbln1, secreted from presynaptic parallel fibers (PF; axons of cerebellar granule cells), and the δ2receptor,expressed at post-synaptic Purkinjecells,
together regulatePF-Purkinjecell synapse formation.
Fig.2 Cbln1 rapidly and potently induce synapse formation in adult cerebellum.
A single injection of recombinant Cbln1 into the subarachnoidal space above the cerebellar vermis of adult cbln1-null mice completely restored parallel fiber-Purkinje cell synapses and motor coordination.
- Ito-Ishida A., Miura E., Emi K., Matsuda K, Iijima T, Kondo T, Kohda K, Watanabe M, Yuzaki M. Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo. J. Neurosci. 28:5920-30, 2008.
- Matsuda S, Matsuda K, Kakegawa W, Miura E, Kohda K, Watanabe M, Yuzaki M. Polarized sorting of AMPA receptors to the somatodendritic domain is regulated by adaptor protein AP-4. Neuron. 57:730-45, 2008.
- Kakegawa W, Miyazaki T, Emi K, Matsuda K, Kohda K, Motohashi J, Mishina, M, Kawahara S, Watanabe M, Yuzaki M. Differential regulation of synaptic plasticity and cerebellar motor learning by the c-terminal pdz-binding motif of GluRδ2. J Neurosci. 28:1460-8, 2008.
- Kakegawa, W., Yuzaki, M. Novel mechanism underlying AMPA receptor trafficking during cerebellar long-term potentiation. Proc Natl Acad Sci USA. 102:17846 51, 2005.
- Hirai, H., Pang, Z., Bao, D., Miyazaki, T., Li, L., Miura, E., Parris, J., Rong, Y., Watanabe, W., Yuzaki, M.*, Morgan, JI. Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nature Neurosci. 8:1534-41, 2005. (*co-corresponding author)
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