Key Points
-
Cytoskeletal structure is the main stabilizing determinant in dendritic spines and dendrite shafts.
-
Actin cytoskeletal regulators are essential for dendritic spine maintenance.
-
Adhesion receptor and neurotrophin receptor signalling to the cytoskeleton confers long-term dendritic spine stability.
-
Microtubules and their organizing proteins are key controllers of dendrite arbor stabilization.
-
Specific signalling mechanisms mediate crosstalk between dendritic spine and dendrite stabilization pathways.
-
Pathological events target dendritic spines and dendrite branch stabilization mechanisms.
Abstract
In the developing brain, dendrite branches and dendritic spines form and turn over dynamically. By contrast, most dendrite arbors and dendritic spines in the adult brain are stable for months, years and possibly even decades. Emerging evidence reveals that dendritic spine and dendrite arbor stability have crucial roles in the correct functioning of the adult brain and that loss of stability is associated with psychiatric disorders and neurodegenerative diseases. Recent findings have provided insights into the molecular mechanisms that underlie long-term dendrite stabilization, how these mechanisms differ from those used to mediate structural plasticity and how they are disrupted in disease.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dailey, M. E. & Smith, S. J. The dynamics of dendritic structure in developing hippocampal slices. J. Neurosci. 16, 2983–2994 (1996).
Wong, W. T., Faulkner-Jones, B. E., Sanes, J. R. & Wong, R. O. Rapid dendritic remodeling in the developing retina: dependence on neurotransmission and reciprocal regulation by Rac and Rho. J. Neurosci. 20, 5024–5036 (2000).
Wong, W. T. & Wong, R. O. Rapid dendritic movements during synapse formation and rearrangement. Curr. Opin. Neurobiol. 10, 118–124 (2000).
Wu, G. Y., Zou, D. J., Rajan, I. & Cline, H. Dendritic dynamics in vivo change during neuronal maturation. J. Neurosci. 19, 4472–4483 (1999).
Clark, W. L. Inquiries into the anatomical basis of olfactory discrimination. Proc. R. Soc. Lond. B 146, 299–319 (1957).
Cline, H. & Haas, K. The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: a review of the synaptotrophic hypothesis. J. Physiol. 586, 1509–1517 (2008).
Coleman, P. D. & Riesen, A. H. Evironmental effects on cortical dendritic fields. I. Rearing in the dark. J. Anat. 102, 363–374 (1968).
Jones, W. H. & Thomas, D. B. Changes in the dendritic organization of neurons in the cerebral cortex following deafferentation. J. Anat. 96, 375–381 (1962).
Matthews, M. R. & Powell, T. P. Some observations on transneuronal cell degeneration in the olfactory bulb of the rabbit. J. Anat. 96, 89–102 (1962).
Wiesel, T. N. & Hubel, D. H. Effects of visual deprivation on morphology and physiology of cells in the cats lateral geniculate body. J. Neurophysiol. 26, 978–993 (1963).
Rajan, I., Witte, S. & Cline, H. T. NMDA receptor activity stabilizes presynaptic retinotectal axons and postsynaptic optic tectal cell dendrites in vivo. J. Neurobiol. 38, 357–368 (1999).
Niell, C. M., Meyer, M. P. & Smith, S. J. In vivo imaging of synapse formation on a growing dendritic arbor. Nature Neurosci. 7, 254–260 (2004).
Vaughn, J. E. Fine structure of synaptogenesis in the vertebrate central nervous system. Synapse 3, 255–285 (1989).
Oray, S., Majewska, A. & Sur, M. Dendritic spine dynamics are regulated by monocular deprivation and extracellular matrix degradation. Neuron 44, 1021–1030 (2004).
Majewska, A. K., Newton, J. R. & Sur, M. Remodeling of synaptic structure in sensory cortical areas in vivo. J. Neurosci. 26, 3021–3029 (2006).
Holtmaat, A., Wilbrecht, L., Knott, G. W., Welker, E. & Svoboda, K. Experience-dependent and cell-type-specific spine growth in the neocortex. Nature 441, 979–983 (2006).
Holtmaat, A. J. et al. Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45, 279–291 (2005).
Trachtenberg, J. T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794 (2002).
Zuo, Y., Yang, G., Kwon, E. & Gan, W. B. Long-term sensory deprivation prevents dendritic spine loss in primary somatosensory cortex. Nature 436, 261–265 (2005).
Yang, G., Pan, F. & Gan, W. B. Stably maintained dendritic spines are associated with lifelong memories. Nature 462, 920–924 (2009). The landmark studies described in references 14–20 use live imaging to describe and characterize dendrite arbor and dendritic spine dynamics in living brain tissue over periods ranging from hours to many months and assess how dynamics are affected by developmental periods and sensory inputs.
Huttenlocher, P. R. Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Res. 163, 195–205 (1979).
Huttenlocher, P. R. Morphometric study of human cerebral cortex development. Neuropsychologia 28, 517–527 (1990).
Rakic, P., Bourgeois, J. P., Eckenhoff, M. F., Zecevic, N. & Goldman-Rakic, P. S. Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science 232, 232–235 (1986).
Rakic, P., Bourgeois, J. P. & Goldman-Rakic, P. S. Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness. Prog. Brain Res. 102, 227–243 (1994).
Markus, E. J. & Petit, T. L. Neocortical synaptogenesis, aging, and behavior: lifespan development in the motor-sensory system of the rat. Exp. Neurol. 96, 262–278 (1987).
Gourley, S. L., Olevska, A., Warren, M. S., Taylor, J. R. & Koleske, A. J. Arg kinase regulates prefrontal dendritic spine refinement and cocaine-induced plasticity. J. Neurosci. 32, 2314–2323 (2012).
Zuo, Y., Lin, A., Chang, P. & Gan, W. B. Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181–189 (2005). This study associates the formation and stabilization of new spines with learning of new tasks, supporting the idea that spines may help to encode memories.
Kulkarni, V. A. & Firestein, B. L. The dendritic tree and brain disorders. Mol. Cell. Neurosci. 50, 10–20 (2012).
Harris, K. M. Structure, development, and plasticity of dendritic spines. Curr. Opin. Neurobiol. 9, 343–348 (1999).
Bourne, J. & Harris, K. M. Do thin spines learn to be mushroom spines that remember? Curr. Opin. Neurobiol. 17, 381–386 (2007).
Izeddin, I. et al. Super-resolution dynamic imaging of dendritic spines using a low-affinity photoconvertible actin probe. PLoS ONE 6, e15611 (2011).
Tashiro, A. & Yuste, R. Structure and molecular organization of dendritic spines. Histol. Histopathol. 18, 617–634 (2003).
Fifkova, E. & Delay, R. J. Cytoplasmic actin in neuronal processes as a possible mediator of synaptic plasticity. J. Cell Biol. 95, 345–350 (1982).
Matus, A., Ackermann, M., Pehling, G., Byers, H. R. & Fujiwara, K. High actin concentrations in brain dendritic spines and postsynaptic densities. Proc. Natl Acad. Sci. USA 79, 7590–7594 (1982).
Fischer, M., Kaech, S., Knutti, D. & Matus, A. Rapid actin-based plasticity in dendritic spines. Neuron 20, 847–854 (1998).
Star, E. N., Kwiatkowski, D. J. & Murthy, V. N. Rapid turnover of actin in dendritic spines and its regulation by activity. Nature Neurosci. 5, 239–246 (2002).
Hotulainen, P. & Hoogenraad, C. C. Actin in dendritic spines: connecting dynamics to function. J. Cell Biol. 189, 619–629 (2010).
Racz, B. & Weinberg, R. J. Microdomains in forebrain spines: an ultrastructural perspective. Mol. Neurobiol. 47, 77–89 (2012).
Korobova, F. & Svitkina, T. Molecular architecture of synaptic actin cytoskeleton in hippocampal neurons reveals a mechanism of dendritic spine morphogenesis. Mol. Biol. Cell 21, 165–176 (2010). This paper uses platinum replica electron microscopy to reveal the cytoskeletal ultrastructure in dendritic spines.
Okamoto, K., Nagai, T., Miyawaki, A. & Hayashi, Y. Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nature Neurosci. 7, 1104–1112 (2004).
Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).
Zhou, Q., Homma, K. J. & Poo, M. M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749–757 (2004).
Honkura, N., Matsuzaki, M., Noguchi, J., Ellis-Davies, G. C. & Kasai, H. The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron 57, 719–729 (2008). This study uses photoactivation of green fluorescent protein-tagged actin to demonstrate that dendritic spines contain a more stable F-actin core and a dynamic pool of F-actin at the periphery.
Tatavarty, V., Kim, E. J., Rodionov, V. & Yu, J. Investigating sub-spine actin dynamics in rat hippocampal neurons with super-resolution optical imaging. PLoS ONE 4, e7724 (2009). This study uses single-molecule photoactivation combined with total internal reflection fluorescence microscopy to monitor the dynamics of single actin molecules in dendritic spines.
Racz, B. & Weinberg, R. J. The subcellular organization of cortactin in hippocampus. J. Neurosci. 24, 10310–10317 (2004).
Racz, B. & Weinberg, R. J. Spatial organization of cofilin in dendritic spines. Neuroscience 138, 447–456 (2006).
Conde, C. & Caceres, A. Microtubule assembly, organization and dynamics in axons and dendrites. Nature Rev. Neurosci. 10, 319–332 (2009).
Baas, P. W., Deitch, J. S., Black, M. M. & Banker, G. A. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc. Natl Acad. Sci. USA 85, 8335–8339 (1988).
Burton, P. R. Dendrites of mitral cell neurons contain microtubules of opposite polarity. Brain Res. 473, 107–115 (1988).
Kwan, A. C., Dombeck, D. A. & Webb, W. W. Polarized microtubule arrays in apical dendrites and axons. Proc. Natl Acad. Sci. USA 105, 11370–11375 (2008).
Sasaki, S., Stevens, J. K. & Bodick, N. Serial reconstruction of microtubular arrays within dendrites of the cat retinal ganglion cell: the cytoskeleton of a vertebrate dendrite. Brain Res. 259, 193–206 (1983).
Okabe, S. & Hirokawa, N. Turnover of fluorescently labelled tubulin and actin in the axon. Nature 343, 479–482 (1990).
Edson, K. J., Lim, S. S., Borisy, G. G. & Letourneau, P. C. FRAP analysis of the stability of the microtubule population along the neurites of chick sensory neurons. Cell Motil. Cytoskeleton 25, 59–72 (1993).
Racz, B. & Weinberg, R. J. Organization of the Arp2/3 complex in hippocampal spines. J. Neurosci. 28, 5654–5659 (2008).
Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).
Kim, I. H. et al. Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities. J. Neurosci. 33, 6081–6092 (2013). This interesting paper shows that inactivation of the ARP2/3 complex in mature neurons leads to loss of plasticity-associated spine enlargement and gradual spine shrinkage and loss.
De Camilli, P., Miller, P. E., Navone, F., Theurkauf, W. E. & Vallee, R. B. Distribution of microtubule-associated protein 2 in the nervous system of the rat studied by immunofluorescence. Neuroscience 11, 817–846 (1984).
Huber, G. & Matus, A. Differences in the cellular distributions of two microtubule-associated proteins, MAP1 and MAP2, in rat brain. J. Neurosci. 4, 151–160 (1984).
Bloom, G. S., Schoenfeld, T. A. & Vallee, R. B. Widespread distribution of the major polypeptide component of MAP 1 (microtubule-associated protein 1) in the nervous system. J. Cell Biol. 98, 320–330 (1984).
Vaillant, A. R. et al. Signaling mechanisms underlying reversible, activity-dependent dendrite formation. Neuron 34, 985–998 (2002).
Szebenyi, G. et al. Activity-driven dendritic remodeling requires microtubule-associated protein 1A. Curr. Biol. 15, 1820–1826 (2005). This very elegant study demonstrates that activity-dependent dendrite elaboration depends critically on MAP1A.
Teng, J. et al. Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization. J. Cell Biol. 155, 65–76 (2001).
Harada, A., Teng, J., Takei, Y., Oguchi, K. & Hirokawa, N. MAP2 is required for dendrite elongation, PKA anchoring in dendrites, and proper PKA signal transduction. J. Cell Biol. 158, 541–549 (2002).
Sudo, H. & Baas, P. W. Acetylation of microtubules influences their sensitivity to severing by katanin in neurons and fibroblasts. J. Neurosci. 30, 7215–7226 (2010).
Peris, L. et al. Motor-dependent microtubule disassembly driven by tubulin tyrosination. J. Cell Biol. 185, 1159–1166 (2009).
Govek, E. E., Newey, S. E. & Van Aelst, L. The role of the Rho GTPases in neuronal development. Genes Dev. 19, 1–49 (2005).
Murakoshi, H., Wang, H. & Yasuda, R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472, 100–104 (2011). This landmark paper uses fluorescence resonance energy transfer-based probes and genetic knockdown to implicate RHO and CDC42 in activity-based spine head enlargement.
Nakayama, A. Y., Harms, M. B. & Luo, L. Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci. 20, 5329–5338 (2000).
Kim, Y. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006).
Soderling, S. H. et al. A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. J. Neurosci. 27, 355–365 (2007). References 69 and 70 implicate WAVE1 as a critical downstream target of RAC1 in the control of dendritic spine formation and stability.
Tashiro, A., Minden, A. & Yuste, R. Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb. Cortex 10, 927–938 (2000).
Xing, L., Yao, X., Williams, K. R. & Bassell, G. J. Negative regulation of RhoA translation and signaling by hnRNP-Q1 affects cellular morphogenesis. Mol. Biol. Cell 23, 1500–1509 (2012).
Kang, M. G., Guo, Y. & Huganir, R. L. AMPA receptor and GEF-H1/Lfc complex regulates dendritic spine development through RhoA signaling cascade. Proc. Natl Acad. Sci. USA 106, 3549–3554 (2009).
Yang, N. et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393, 809–812 (1998).
Arber, S. et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 805–809 (1998).
Lin, Y. C., Yeckel, M. F. & Koleske, A. J. Abl2/Arg controls dendritic spine and dendrite arbor stability via distinct cytoskeletal control pathways. J. Neurosci. 33, 1846–1857 (2013). This paper demonstrates that ARG dampens activity-dependent disruption of cortactin localization to stabilize dendritic spines and independently attenuates RHO activity to stabilize dendrite arbors.
Sfakianos, M. K. et al. Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior. J. Neurosci. 27, 10982–10992 (2007).
Calabrese, B. & Halpain, S. Essential role for the PKC target MARCKS in maintaining dendritic spine morphology. Neuron 48, 77–90 (2005).
Shirao, T., Inoue, H. K., Kano, Y. & Obata, K. Localization of a developmentally regulated neuron-specific protein S54 in dendrites as revealed by immunoelectron microscopy. Brain Res. 413, 374–378 (1987).
Yamazaki, H., Takahashi, H., Aoki, T. & Shirao, T. Molecular cloning and dendritic localization of rat SH3P7. Eur. J. Neurosci. 14, 998–1008 (2001).
Matsuoka, Y., Li, X. & Bennett, V. Adducin is an in vivo substrate for protein kinase C: phosphorylation in the MARCKS-related domain inhibits activity in promoting spectrin-actin complexes and occurs in many cells, including dendritic spines of neurons. J. Cell Biol. 142, 485–497 (1998).
Tanokashira, D. et al. Glucocorticoid suppresses dendritic spine development mediated by down-regulation of caldesmon expression. J. Neurosci. 32, 14583–14591 (2012).
Macgrath, S. M. & Koleske, A. J. Cortactin in cell migration and cancer at a glance. J. Cell Sci. 125, 1621–1626 (2012).
Iki, J., Inoue, A., Bito, H. & Okabe, S. Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity. Eur. J. Neurosci. 22, 2985–2994 (2005).
Jaworski, J. et al. Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron 61, 85–100 (2009). This study, along with references 156–158, indicates that microtubule targeting to dendritic spines can be regulated by activity and by BDNF and that this targeting stabilizes spines by promoting the accumulation of key spine stabilizing proteins.
Naisbitt, S. et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23, 569–582 (1999).
Du, Y., Weed, S. A., Xiong, W. C., Marshall, T. D. & Parsons, J. T. Identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons. Mol. Cell. Biol. 18, 5838–5851 (1998).
Chen, Y. K. & Hsueh, Y. P. Cortactin-binding protein 2 modulates the mobility of cortactin and regulates dendritic spine formation and maintenance. J. Neurosci. 32, 1043–1055 (2012).
Hering, H. & Sheng, M. Activity-dependent redistribution and essential role of cortactin in dendritic spine morphogenesis. J. Neurosci. 23, 11759–11769 (2003).
Seese, R. R. et al. LTP induction translocates cortactin at distant synapses in wild-type but not Fmr1 knock-out mice. J. Neurosci. 32, 7403–7413 (2012).
Takahashi, H. et al. Drebrin-dependent actin clustering in dendritic filopodia governs synaptic targeting of postsynaptic density-95 and dendritic spine morphogenesis. J. Neurosci. 23, 6586–6595 (2003).
Haeckel, A., Ahuja, R., Gundelfinger, E. D., Qualmann, B. & Kessels, M. M. The actin-binding protein Abp1 controls dendritic spine morphology and is important for spine head and synapse formation. J. Neurosci. 28, 10031–10044 (2008).
Malenka, R. C. & Bear, M. F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).
Larsson, C. Protein kinase C and the regulation of the actin cytoskeleton. Cell. Signal. 18, 276–284 (2006).
Hartwig, J. H. et al. MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium-calmodulin. Nature 356, 618–622 (1992).
Bednarek, E. & Caroni, P. β-Adducin is required for stable assembly of new synapses and improved memory upon environmental enrichment. Neuron 69, 1132–1146 (2011). This paper shows the critical importance of β-adducin in controlling new synapse formation upon environmental enrichment.
Jung, Y., Mulholland, P. J., Wiseman, S. L., Judson Chandler, L. & Picciotto, M. R. Constitutive knockout of the membrane cytoskeleton protein β adducin decreases mushroom spine density in the nucleus accumbens but does not prevent spine remodeling in response to cocaine. Eur. J. Neurosci. 37, 1–9 (2012).
Shi, Y., Pontrello, C. G., DeFea, K. A., Reichardt, L. F. & Ethell, I. M. Focal adhesion kinase acts downstream of EphB receptors to maintain mature dendritic spines by regulating cofilin activity. J. Neurosci. 29, 8129–8142 (2009). This study describes an important role for FAK as an intermediary between EPHB signalling and cofilin phosphorylation in the control of dendritic spine stability.
Tomar, A. & Schlaepfer, D. D. Focal adhesion kinase: switching between GAPs and GEFs in the regulation of cell motility. Curr. Opin. Cell Biol. 21, 676–683 (2009).
Babus, L. W. et al. Decreased dendritic spine density and abnormal spine morphology in Fyn knockout mice. Brain Res. 1415, 96–102 (2011).
Bourgin, C., Murai, K. K., Richter, M. & Pasquale, E. B. The EphA4 receptor regulates dendritic spine remodeling by affecting β1-integrin signaling pathways. J. Cell Biol. 178, 1295–1307 (2007).
Hartmann, M., Heumann, R. & Lessmann, V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J. 20, 5887–5897 (2001).
Kohara, K., Kitamura, A., Morishima, M. & Tsumoto, T. Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons. Science 291, 2419–2423 (2001).
Kojima, M. et al. Biological characterization and optical imaging of brain-derived neurotrophic factor-green fluorescent protein suggest an activity-dependent local release of brain-derived neurotrophic factor in neurites of cultured hippocampal neurons. J. Neurosci. Res. 64, 1–10 (2001).
Hu, B., Nikolakopoulou, A. M. & Cohen-Cory, S. BDNF stabilizes synapses and maintains the structural complexity of optic axons in vivo. Development 132, 4285–4298 (2005).
Marshak, S., Nikolakopoulou, A. M., Dirks, R., Martens, G. J. & Cohen-Cory, S. Cell-autonomous TrkB signaling in presynaptic retinal ganglion cells mediates axon arbor growth and synapse maturation during the establishment of retinotectal synaptic connectivity. J. Neurosci. 27, 2444–2456 (2007).
Yasuda, R. et al. Supersensitive Ras activation in dendrites and spines revealed by two-photon fluorescence lifetime imaging. Nature Neurosci. 9, 283–291 (2006).
Rex, C. S. et al. Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J. Neurosci. 27, 3017–3029 (2007).
Pinkstaff, J. K., Detterich, J., Lynch, G. & Gall, C. Integrin subunit gene expression is regionally differentiated in adult brain. J. Neurosci. 19, 1541–1556 (1999).
Mortillo, S. et al. Compensatory redistribution of neuroligins and N-cadherin following deletion of synaptic β1-integrin. J. Comp. Neurol. 520, 2041–2052 (2012).
Kramar, E. A., Bernard, J. A., Gall, C. M. & Lynch, G. α3 integrin receptors contribute to the consolidation of long-term potentiation. Neuroscience 110, 29–39 (2002).
Chan, C. S. et al. α3-integrins are required for hippocampal long-term potentiation and working memory. Learn. Mem. 14, 606–615 (2007).
Chan, C. S., Weeber, E. J., Kurup, S., Sweatt, J. D. & Davis, R. L. Integrin requirement for hippocampal synaptic plasticity and spatial memory. J. Neurosci. 23, 7107–7116 (2003).
Warren, M. S. et al. Integrin β1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior. J. Neurosci. 32, 2824–2834 (2012).
Kerrisk, M. E., Greer, C. A. & Koleske, A. J. Integrin a3 is required for late postnatal stability of dendrite arbors, dendritic spines and synapses, and mouse behavior. J. Neurosci. I33, 6742–6752 (2013). References 114 and 115 describe key roles for integrin α3β1 in the control of dendrite and dendritic spine stability.
Stanco, A. et al. Netrin-1–α3β1 integrin interactions regulate the migration of interneurons through the cortical marginal zone. Proc. Natl Acad. Sci. USA 106, 7595–7600 (2009).
Yebra, M. et al. Recognition of the neural chemoattractant Netrin-1 by integrins α6β4 and α3β1 regulates epithelial cell adhesion and migration. Dev. Cell 5, 695–707 (2003).
Dulabon, L. et al. Reelin binds α3β1 integrin and inhibits neuronal migration. Neuron 27, 33–44 (2000).
DeFreitas, M. F. et al. Identification of integrin α3β1 as a neuronal thrombospondin receptor mediating neurite outgrowth. Neuron 15, 333–343 (1995).
Bradley, W. D. & Koleske, A. J. Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts. J. Cell Sci. 122, 3441–3454 (2009).
Koleske, A. J. et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 21, 1259–1272 (1998).
Moresco, E. M., Scheetz, A. J., Bornmann, W. G., Koleske, A. J. & Fitzsimonds, R. M. Abl family nonreceptor tyrosine kinases modulate short-term synaptic plasticity. J. Neurophysiol. 89, 1678–1687 (2003).
Gourley, S. L., Koleske, A. J. & Taylor, J. R. Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine. Proc. Natl Acad. Sci. USA 106, 16859–16864 (2009).
Wang, Y., Miller, A. L., Mooseker, M. S. & Koleske, A. J. The Abl-related gene (Arg) nonreceptor tyrosine kinase uses two F-actin-binding domains to bundle F-actin. Proc. Natl Acad. Sci. USA 98, 14865–14870 (2001).
Macgrath, S. M. & Koleske, A. J. Arg/Abl2 modulates the affinity and stoichiometry of binding of cortactin to f-actin. Biochemistry 51, 6644–6653 (2012).
Galkin, V. E., Orlova, A., Koleske, A. J. & Egelman, E. H. The Arg non-receptor tyrosine kinase modifies F-actin structure. J. Mol. Biol. 346, 565–575 (2005).
Lau, L. F. & Huganir, R. L. Differential tyrosine phosphorylation of N-methyl-D-aspartate receptor subunits. J. Biol. Chem. 270, 20036–20041 (1995).
Moon, I. S. Relative extent of tyrosine phosphorylation of the NR2A and NR2B subunits in the rat forebrain postsynaptic density fraction. Mol. Cells 16, 28–33 (2003).
Prybylowski, K. et al. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron 47, 845–857 (2005).
Williams, D. W. & Truman, J. W. Cellular mechanisms of dendrite pruning in Drosophila: insights from in vivo time-lapse of remodeling dendritic arborizing sensory neurons. Development 132, 3631–3642 (2005).
Lee, H. H., Jan, L. Y. & Jan, Y. N. Drosophila IKK-related kinase Ik2 and Katanin p60-like 1 regulate dendrite pruning of sensory neuron during metamorphosis. Proc. Natl Acad. Sci. USA 106, 6363–6368 (2009).
Bodick, N., Stevens, J. K., Sasaki, S. & Purpura, D. P. Microtubular disarray in cortical dendrites and neurobehavioral failure. II. Computer reconstruction of perturbed microtubular arrays. Brain Res. 281, 299–309 (1982).
Purpura, D. P., Bodick, N., Suzuki, K., Rapin, I. & Wurzelmann, S. Microtubule disarray in cortical dendrites and neurobehavioral failure. I. Golgi and electron microscopic studies. Brain Res. 281, 287–297 (1982).
Horton, A. C. et al. Polarized secretory trafficking directs cargo for asymmetric dendrite growth and morphogenesis. Neuron 48, 757–771 (2005).
Ori-McKenney, K. M., Jan, L. Y. & Jan, Y. N. Golgi outposts shape dendrite morphology by functioning as sites of acentrosomal microtubule nucleation in neurons. Neuron 76, 921–930 (2012).
Satoh, D. et al. Spatial control of branching within dendritic arbors by dynein-dependent transport of Rab5-endosomes. Nature Cell Biol. 10, 1164–1171 (2008).
Zheng, Y. et al. Dynein is required for polarized dendritic transport and uniform microtubule orientation in axons. Nature Cell Biol. 10, 1172–1180 (2008).
Ultanir, S. K. et al. Chemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 Uncovers their roles in dendrite arborization and spine development. Neuron 73, 1127–1142 (2012). This study uses the most cutting edge chemical genetic approach to identify several targets of the NDR1 and NDR2 in the control of dendrite formation and stability.
Wu, G. Y. & Cline, H. T. Stabilization of dendritic arbor structure in vivo by CaMKII. Science 279, 222–226 (1998).
Gorski, J. A., Zeiler, S. R., Tamowski, S. & Jones, K. R. Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites. J. Neurosci. 23, 6856–6865 (2003).
Xu, B. et al. Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of the receptor TrkB. Neuron 26, 233–245 (2000).
Akum, B. F. et al. Cypin regulates dendrite patterning in hippocampal neurons by promoting microtubule assembly. Nature Neurosci. 7, 145–152 (2004).
Kwon, M., Fernandez, J. R., Zegarek, G. F., Lo, S. B. & Firestein, B. L. BDNF-promoted increases in proximal dendrites occur via CREB-dependent transcriptional regulation of cypin. J. Neurosci. 31, 9735–9745 (2011). This study shows that BDNF can induce transcription of the microtubule- and dendrite-stabilizing protein cypin.
Moresco, E. M., Donaldson, S., Williamson, A. & Koleske, A. J. Integrin-mediated dendrite branch maintenance requires Abelson (Abl) family kinases. J. Neurosci. 25, 6105–6118 (2005).
Hernandez, S. E., Settleman, J. & Koleske, A. J. Adhesion-dependent regulation of p190RhoGAP in the developing brain by the Abl-related gene tyrosine kinase. Curr. Biol. 14, 691–696 (2004).
Bradley, W. D., Hernandez, S. E., Settleman, J. & Koleske, A. J. Integrin signaling through Arg activates p190RhoGAP by promoting its binding to p120RasGAP and recruitment to the membrane. Mol. Biol. Cell 17, 4827–4836 (2006).
Li, Z., Aizenman, C. D. & Cline, H. T. Regulation of rho GTPases by crosstalk and neuronal activity in vivo. Neuron 33, 741–750 (2002).
Li, Z., Van Aelst, L. & Cline, H. T. Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo. Nature Neurosci. 3, 217–225 (2000).
Ruchhoeft, M. L., Ohnuma, S., McNeill, L., Holt, C. E. & Harris, W. A. The neuronal architecture of Xenopus retinal ganglion cells is sculpted by rho-family GTPases in vivo. J. Neurosci. 19, 8454–8463 (1999).
Lee, T., Winter, C., Marticke, S. S., Lee, A. & Luo, L. Essential roles of Drosophila RhoA in the regulation of neuroblast proliferation and dendritic but not axonal morphogenesis. Neuron 25, 307–316 (2000).
Chen, H. & Firestein, B. L. RhoA regulates dendrite branching in hippocampal neurons by decreasing cypin protein levels. J. Neurosci. 27, 8378–8386 (2007).
Hirose, M. et al. Molecular dissection of the Rho-associated protein kinase (p160ROCK)-regulated neurite remodeling in neuroblastoma N1E-115 cells. J. Cell Biol. 141, 1625–1636 (1998).
Amano, M. et al. Identification of Tau and MAP2 as novel substrates of Rho-kinase and myosin phosphatase. J. Neurochem. 87, 780–790 (2003).
Murthy, A. S. & Flavin, M. Microtubule assembly using the microtubule-associated protein MAP-2 prepared in defined states of phosphorylation with protein kinase and phosphatase. Eur. J. Biochem. 137, 37–46 (1983).
Yamamoto, H., Fukunaga, K., Tanaka, E. & Miyamoto, E. Ca2+- and calmodulin-dependent phosphorylation of microtubule-associated protein 2 and tau factor, and inhibition of microtubule assembly. J. Neurochem. 41, 1119–1125 (1983).
Gu, J., Firestein, B. L. & Zheng, J. Q. Microtubules in dendritic spine development. J. Neurosci. 28, 12120–12124 (2008).
Hu, X. et al. BDNF-induced increase of PSD-95 in dendritic spines requires dynamic microtubule invasions. J. Neurosci. 31, 15597–15603 (2011).
Hu, X., Viesselmann, C., Nam, S., Merriam, E. & Dent, E. W. Activity-dependent dynamic microtubule invasion of dendritic spines. J. Neurosci. 28, 13094–13105 (2008). References 156–158, along with reference 85, indicate that microtubule targeting to dendritic spines can be regulated by activity and by BDNF and that this targeting stabilizes spines by promoting the accumulation of key spine stabilizing proteins.
von Bohlen und Halbach, O., Minichiello, L. & Unsicker, K. Haploinsufficiency in trkB and/or trkC neurotrophin receptors causes structural alterations in the aged hippocampus and amygdala. Eur. J. Neurosci. 18, 2319–2325 (2003).
Kapitein, L. C. et al. NMDA receptor activation suppresses microtubule growth and spine entry. J. Neurosci. 31, 8194–8209 (2011).
Le Gros Clark, W. Inquiries into the anatomical basis of olfactory discrimination. Proc. R. Soc. Lond. B 146, 299–319 (1957).
Fleming, I. N., Elliott, C. M., Buchanan, F. G., Downes, C. P. & Exton, J. H. Ca2+/calmodulin-dependent protein kinase II regulates Tiam1 by reversible protein phosphorylation. J. Biol. Chem. 274, 12753–12758 (1999).
Xie, Z. et al. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron 56, 640–656 (2007).
Chen, H. J., Rojas-Soto, M., Oguni, A. & Kennedy, M. B. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20, 895–904 (1998).
Takemoto-Kimura, S. et al. Differential roles for CaM kinases in mediating excitation-morphogenesis coupling during formation and maturation of neuronal circuits. Eur. J. Neurosci. 32, 224–230 (2010).
Lemieux, M. et al. Translocation of CaMKII to dendritic microtubules supports the plasticity of local synapses. J. Cell Biol. 198, 1055–1073 (2012).
Lin, Y. C. & Koleske, A. J. Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders. Annu. Rev. Neurosci. 33, 349–378 (2010).
Flood, D. G. Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease. II. Subiculum. Brain Res. 540, 83–95 (1991).
Flood, D. G., Buell, S. J., Horwitz, G. J. & Coleman, P. D. Dendritic extent in human dentate gyrus granule cells in normal aging and senile dementia. Brain Res. 402, 205–216 (1987).
Flood, D. G., Guarnaccia, M. & Coleman, P. D. Dendritic extent in human CA2-3 hippocampal pyramidal neurons in normal aging and senile dementia. Brain Res. 409, 88–96 (1987).
Anderton, B. H. et al. Dendritic changes in Alzheimer's disease and factors that may underlie these changes. Prog. Neurobiol. 55, 595–609 (1998).
Falke, E. et al. Subicular dendritic arborization in Alzheimer's disease correlates with neurofibrillary tangle density. Am. J. Pathol. 163, 1615–1621 (2003).
Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).
Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007).
Lacor, P. N. et al. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J. Neurosci. 27, 796–807 (2007).
Shankar, G. M. et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007).
Calabrese, B. et al. Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein. Mol. Cell. Neurosci. 35, 183–193 (2007).
Um, J. W. et al. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nature Neurosci. 15, 1227–1235 (2012). References 175–178 describe the destabilizing effects of ADDLs on dendritic spine stability and the involvement of FYN and the NMDAR in this process.
Wu, H. Y. et al. Amyloid β induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J. Neurosci. 30, 2636–2649 (2010).
Wang, Y., Shibasaki, F. & Mizuno, K. Calcium signal-induced cofilin dephosphorylation is mediated by Slingshot via calcineurin. J. Biol. Chem. 280, 12683–12689 (2005).
Zempel, H., Thies, E., Mandelkow, E. & Mandelkow, E. M. Aβ oligomers cause localized Ca2+ elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30, 11938–11950 (2010).
Larson, M. et al. The complex. PrPc-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease. J. Neurosci. 32, 16857–16871 (2012).
Ittner, L. M. et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 142, 387–397 (2010).
Hoover, B. R. et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68, 1067–1081 (2010). References 181–184 elaborate on the effects of ADDLs on tau phosphorylation and redistribution and the ensuing destabilization of dendrite arbors.
Kang, H. J. et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nature Med. 18, 1413–1417 (2012). This landmark study documents synapse loss in MDD and identifies a genetic regulatory network that underlies synapse and dendrite arbor destablization.
Drevets, W. C. et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386, 824–827 (1997).
Drevets, W. C. Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog. Brain Res. 126, 413–431 (2000).
Cotter, D. et al. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb. Cortex 12, 386–394 (2002).
Cotter, D., Mackay, D., Landau, S., Kerwin, R. & Everall, I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch. Gen. Psychiatry 58, 545–553 (2001).
Smith, M. A., Makino, S., Kvetnansky, R. & Post, R. M. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15, 1768–1777 (1995).
Nibuya, M., Takahashi, M., Russell, D. S. & Duman, R. S. Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci. Lett. 267, 81–84 (1999).
Gourley, S. L., Kedves, A. T., Olausson, P. & Taylor, J. R. A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology 34, 707–716 (2009).
Gourley, S. L. et al. Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding. Proc. Natl Acad. Sci. USA 109, 20714–20719 (2012).
Ray, B. et al. Restraint stress and repeated corticotrophin-releasing factor receptor activation in the amygdala both increase amyloid-β precursor protein and amyloid-β peptide but have divergent effects on brain-derived neurotrophic factor and pre-synaptic proteins in the prefrontal cortex of rats. Neuroscience 184, 139–150 (2011).
Schmidt, H. D. & Duman, R. S. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav. Pharmacol. 18, 391–418 (2007).
Brown, C. E., Boyd, J. D. & Murphy, T. H. Longitudinal in vivo imaging reveals balanced and branch-specific remodeling of mature cortical pyramidal dendritic arbors after stroke. J. Cereb. Blood Flow Metab. 30, 783–791 (2010).
Kalia, L. V., Kalia, S. K. & Salter, M. W. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 7, 742–755 (2008).
Halpain, S., Hipolito, A. & Saffer, L. Regulation of F-actin stability in dendritic spines by glutamate receptors and calcineurin. J. Neurosci. 18, 9835–9844 (1998).
Hasbani, M. J., Schlief, M. L., Fisher, D. A. & Goldberg, M. P. Dendritic spines lost during glutamate receptor activation reemerge at original sites of synaptic contact. J. Neurosci. 21, 2393–2403 (2001).
Tseng, C. Y. & Firestein, B. L. The role of PSD-95 and cypin in morphological changes in dendrites following sublethal NMDA exposure. J. Neurosci. 31, 15468–15480 (2011).
Hasbani, M. J., Hyrc, K. L., Faddis, B. T., Romano, C. & Goldberg, M. P. Distinct roles for sodium, chloride, and calcium in excitotoxic dendritic injury and recovery. Exp. Neurol. 154, 241–258 (1998).
Kitaoka, Y. et al. Involvement of RhoA and possible neuroprotective effect of fasudil, a Rho kinase inhibitor, in NMDA-induced neurotoxicity in the rat retina. Brain Res. 1018, 111–118 (2004).
Graber, S., Maiti, S. & Halpain, S. Cathepsin B-like proteolysis and MARCKS degradation in sub-lethal NMDA-induced collapse of dendritic spines. Neuropharmacology 47, 706–713 (2004).
Sweet, E. S. et al. PSD-95 alters microtubule dynamics via an association with EB3. J. Neurosci. 31, 1038–1047 (2011).
Morales-Medina, J. C., Sanchez, F., Flores, G., Dumont, Y. & Quirion, R. Morphological reorganization after repeated corticosterone administration in the hippocampus, nucleus accumbens and amygdala in the rat. J. Chem. Neuroanat. 38, 266–272 (2009).
Woolley, C. S., Gould, E. & McEwen, B. S. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 531, 225–231 (1990).
Wellman, C. L. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J. Neurobiol. 49, 245–253 (2001).
Gourley, S. L., Swanson, A. M. & Koleske, A. J. Corticosteroid-induced neural remodeling predicts behavioral vulnerability and resilience. J. Neurosci. 33, 3107–3112 (2013).
Acknowledgements
I apologize to those whose excellent work I could not cite owing to word and reference limits. I am grateful to members of my laboratory, especially M. Kerrisk, A. Levy, M. Omar and Y-C. Lin for critical feedback, and to three anonymous reviewers for helpful suggestions on content. Work in my laboratory is supported by US National Institutes of Health grants NS39475, CA133346, and multi-PI grant GM100411 (joint with T. Boggon).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Glossary
- Golgi outposts
-
Clusters of Golgi-like cisternae that reside in neuronal processes and act as local trafficking centres for membrane-bound vesicles.
Rights and permissions
About this article
Cite this article
Koleske, A. Molecular mechanisms of dendrite stability. Nat Rev Neurosci 14, 536–550 (2013). https://doi.org/10.1038/nrn3486
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrn3486
This article is cited by
-
Chronic low-dose Δ9-tetrahydrocannabinol (THC) treatment stabilizes dendritic spines in 18-month-old mice
Scientific Reports (2023)
-
Aberrant somatic calcium channel function in cNurr1 and LRRK2-G2019S mice
npj Parkinson's Disease (2023)
-
Patchouli alcohol as a selective estrogen receptor β agonist ameliorates AD-like pathology of APP/PS1 model mice
Acta Pharmacologica Sinica (2022)
-
Protocadherin 15 suppresses oligodendrocyte progenitor cell proliferation and promotes motility through distinct signalling pathways
Communications Biology (2022)