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Interrelationships Between Dendritic Protein Synthesis and the Efficacy and Structure of Synaptic Connections

P.W. Vanderklish, F. Smart, G.M. Edelman

Consolidation of memory requires the synthesis of new proteins and is correlated with changes in the shape and efficacy of synaptic connections. Several forms of activity-dependent synaptic plasticity share these and other features of memory formation and thus are considered a neurophysiologic basis of memory formation. The translation of dendritically localized mRNAs in particular is necessary for the stabilization of both long-term potentiation (LTP) and long-term depression (LTD). Local translation could affect plasticity in many ways, but because a change in synaptic efficacy can outlast the half-lives of proteins synthesized during its induction, most likely an important function of new proteins is the reorganization of synaptic structure. Currently, we are defining interrelationships between the synthesis of dendritic proteins and synaptic structure that could provide a basis for the longevity of LTP and LTD.

Recent results suggested a role for local translation in the changes in synaptic shape. First, pharmacologic stimulation of group I metabotropic glutamate receptors (mGluRs) in cultures of hippocampal neurons led to a rapid elongation of dendritic spines, the highly specialized, actin-rich protrusions of dendritic membrane that constitute the postsynaptic element at most glutamatergic synapses. Stimulation of mGluRs is necessary and, in some synaptic pathways, sufficient for the induction of LTD and results in protein synthesis. Importantly, treatment with an inhibitor of translation, a manipulation that reduces expression of LTD by preventing internalization of ionotropic receptors, blocked spine lengthening. Reports that longer, thinner spines have fewer ionotropic glutamate receptors suggest a potential link between structural changes induced by mGluR stimulation and the expression of LTD. Thus, LTD stabilization and mGluR-induced lengthening of dendritic spines may reflect the same protein synthesis­dependent processes. In accord with recent observations on the role of calcium in the regulation of spine length and translation, mGluR-induced spine elongation was also blocked by calcium chelators.

Our observations are also potentially informative about abnormalities in spine shape that occur in fragile X syndrome, a form of mental retardation caused by the underexpression of a translational suppressor and characterized by a preponderance of abnormally long and tortuous spines. We are using a mouse model for fragile X syndrome to characterize the relationship between spine morphology and protein synthesis.

A second line of evidence that local translation affects synaptic shape comes from studies on the regulation of a synaptic cytoskeletal protein. Using a synaptoneurosomal fraction enriched in resealed and functional presynaptic and postsynaptic endings, we found that brief incubation with brain-derived neurotrophic factor (BDNF) selectively enhanced the synthesis of the activity-regulated cytoskeletal protein Arc. Rapid transcription and dendritic transport of Arc mRNA are induced during learning and the induction of LTP, and inhibition of its translation causes decay in both memory and LTP. BDNF is released with synaptic activity patterns optimal for LTP induction, and signaling through its receptor, TrkB, is involved in LTP production. Compared with LTP, exogenously applied BDNF induces a more slowly developing form of synaptic potentiation that also depends on the synthesis of dendritic proteins. Although it remains to be established that BDNF-induced protein synthesis modifies synaptic structure during LTP, the actin-binding properties of locally synthesized Arc may contribute to synaptic reconfiguration.

Thus, rapid and dendritically localized synthesis of a cytoskeletal protein required for LTP stabilization is induced by a neurotrophin released during the induction of LTP. Interestingly, the effects of BDNF on Arc were attenuated by antagonists of N-methyl-d-aspartate­type glutamate receptors. Because localization of Arc mRNA to synapses undergoing plasticity requires the activity of these receptors, we are investigating the possibility that BDNF released during the brief induction period for LTP acts as a persistent cue or "tag" to coordinate translation of required proteins near activated synapses.

Currently, we are broadening our efforts to include characterizations of translational regulation in dendrites and reciprocal influences of synaptic structure on local protein synthesis. Multiple forms of plasticity that differ in valence, mechanisms of induction, and accompanying morphologic changes require dendritic translation for their persistence. We hypothesize that different plasticities require different proteins, and we are testing this hypothesis. In addition, we are testing the idea that newly elaborated cytoskeletal arrangements may provide a lasting regulatory influence on protein synthesis that affects the replacement of key proteins involved in the expression of synaptic plasticity.

PUBLICATIONS

Chappell, S.A., Owens, G.C., Mauro, V.P. A 5´ leader of Rbm3, a cold stress-induced mRNA, mediates internal initiation of translation with increased efficiency under conditions of mild hypothermia. J. Biol. Chem. 276:36917, 2001.

Edelman, G.M., Gally, J.A. Degeneracy and complexity in biological systems. Proc. Natl. Acad. Sci. U. S. A. 98:13763, 2001.

Mistry, S.K., Keefer, E.W., Cunningham, B.A., Edelman, G.M., Crossin, K.L. Cultured rat hippocampal neural progenitors generate spontaneously active neural networks. Proc. Natl. Acad. Sci. U. S. A. 99:1621, 2002.

Owens, G.C., Mistry, S., Edelman, G.M., Crossin, K.L. Efficient marking of neural stem cell-derived neurons with a modified murine embryonic stem cell virus, MESV2. Gene Ther. 9:1044, 2002.

Schmitt-Ulms, G., Legname, G., Baldwin, M.A., Ball, H.L., Bradon, N., Bosque, P.J., Crossin, K.L., Edelman, G.M., DeArmond, S.J., Cohen, F.E., Prusiner, S.B. Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein. J. Mol. Biol. 314:1209, 2001.

Vanderklish, P.W., Edelman, G.M. Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons. Proc. Natl. Acad. Sci. U. S. A. 99:1639, 2002.

Yin, Y., Edelman, G.M., Vanderklish, P.W. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc. Natl. Acad. Sci. U. S. A. 99:2368, 2002.