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Form follows function: actin-binding proteins as critical regulators of excitatory synapses

  • Review article
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e-Neuroforum

Abstract

Actin filaments (F-actin) are the major structural component of excitatory synapses. In excitatory synapses, F-actin is enriched in presynaptic terminals and in dendritic spines, and actin dynamics—the spatiotemporally controlled assembly and disassembly of F-actin—have been implicated in pre- and postsynaptic physiology. Hence, actin-binding proteins that control actin dynamics emerged as important regulators of excitatory synapses linking synaptic function and structure, and therefore they are of vital importance for behavior. By the analyses of gene-targeted mice and by loss- and gain-of-function approaches in acute brain slices or dissociated neuronal cultures, studies from the last decade, including studies from our own labs, unraveled the versatile synaptic functions for members of two important families of actin dynamics regulating proteins, namely ADF/cofilin and profilin. After a short introduction into chemical synapses and actin dynamics, we will summarize and discuss recent findings on the synaptic functions of ADF/cofilin and profilin in this review article, and we will outline future directions and perspectives in the field.

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References

  1. Cingolani LA, Goda Y (2008) Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 9:344–356

    Article  CAS  PubMed  Google Scholar 

  2. Rust MB, Maritzen T (2015) Relevance of presynaptic actin dynamics for synapse function and mouse behavior. Exp Cell Res 335:165–171

    Article  CAS  PubMed  Google Scholar 

  3. Sala C, Segal M (2014) Dendritic spines: the locus of structural and functional plasticity. Physiol Rev 94:141–188

    Article  CAS  PubMed  Google Scholar 

  4. Reeve SP, Bassetto L, Genova GK, Kleyner Y, Leyssen M, Jackson FR, Hassan BA (2005) The Drosophila fragile X mental retardation protein controls actin dynamics by directly regulating profilin in the brain. Curr Biol 15:1156–1163

    Article  CAS  PubMed  Google Scholar 

  5. Won H, Mah W, Kim E, Kim JW, Hahm EK, Kim MH, Cho S, Kim J, Jang H, Cho SC, Kim BN, Shin MS, Seo J, Jeong J, Choi SY, Kim D, Kang C, Kim E (2011) GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice. Nat Med 17:566–572

    Article  CAS  PubMed  Google Scholar 

  6. Duffney LJ, Wei J, Cheng J, Liu W, Smith KR, Kittler JT, Yan Z (2013) Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism. J Neurosci 33:15767–15778

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Steinecke A, Gampe C, Nitzsche F Bolz J (2014) DISC1 knockdown impairs the tangential migration of cortical interneurons by affecting the actin cytoskeleton. Front Cell Neurosci 8:190

    Article  PubMed Central  PubMed  Google Scholar 

  8. Hild G, Kalmar L, Kardos R, Nyitrai M, Bugyi B (2014) The other side of the coin: functional and structural versatility of ADF/cofilins. Eur J Cell Biol 93:238–251

    Article  CAS  PubMed  Google Scholar 

  9. Bellenchi GC, Gurniak CB, Perlas E, Middei S, Ammassari-Teule M, Witke W (2007) N-cofilin is associated with neuronal migration disorders and cell cycle control in the cerebral cortex. Genes Dev 21:2347–2357

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Racz B, Weinberg RJ (2006) Spatial organization of cofilin in dendritic spines. Neuroscience 138:447–456

    Article  CAS  PubMed  Google Scholar 

  11. Rust MB, Gurniak CB, Renner M, Vara H, Morando L, Gorlich A, Sassoe-Pognetto M, Banchaabouchi MA, Giustetto M, Triller A, Choquet D, Witke W (2010) Learning AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics. EMBO J 29:1889–1902

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Herde MK, Friauf E, Rust MB (2010) Developmental expression of the actin depolymerizing factor ADF in the mouse inner ear and spiral ganglia. J Comp Neurol 518:1724–1741

    Article  CAS  PubMed  Google Scholar 

  13. Görlich A, Wolf M, Zimmermann AM, Gurniak CB, Al Banchaabouchi M, Sassoè-Pognetto M, Witke W, Friauf E, Rust MB (2011) N-Cofilin can compensate for the loss of ADF in excitatory synapses. PLoS One 6:e26789

    Article  PubMed Central  PubMed  Google Scholar 

  14. Bernstein BW, Bamburg JR (2010) ADF/cofilin: a functional node in cell biology. Trend Cell Biol 20:187–195

    Article  CAS  Google Scholar 

  15. Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, Jia Z (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121–133

    Article  CAS  PubMed  Google Scholar 

  16. Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K Inokuchi K (2003) Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 38:447–460

    Article  CAS  PubMed  Google Scholar 

  17. Zhou Q, Homma KJ, Poo MM (2004) Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44:749–757

    Article  CAS  PubMed  Google Scholar 

  18. Hotulainen P, Llano O, Smirnov S, Tanhuanpää K, Faix J, Rivera C, Lappalainen P (2009) Defining mechanisms of actin polymerization and depolymerization during dendritic spine morphogenesis. J Cell Biol 185:323–339

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Gu J, Lee CW, Fan Y, Komlos D, Tang X, Sun C, Yu K, Hartzell HC, Chen G, Bamburg JR, Zheng JQ (2010) ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nat Neurosci 13:1208–1215

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Pontrello CG, Sun MY, Lin A, Fiacco TA, DeFea KA, Ethell IM (2012) Cofilin under control of beta-arrestin-2 in NMDA-dependent dendritic spine plasticity, long-term depression (LTD), and learning. Proc Natl Acad Sci USA 109:E442–E451

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Bosch M, Castro J, Saneyoshi T, Matsuno H, Sur M, Hayashi Y (2014) Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron 82:444–459

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Rust MB (2015) ADF/cofilin: a crucial regulator of synapse physiology and behavior. Cell Mol Life Sci 72:3521–3529

    Article  CAS  PubMed  Google Scholar 

  23. Flynn KC, Hellal F, Neukirchen D, Jacob S, Tahirovic S, Dupraz S, Stern S, Garvalov BK, Gurniak C, Shaw AE, Meyn L, Wedlich-Söldner R, Bamburg JR, Small JV, Witke W, Bradke F (2012) ADF/cofilin-mediated actin retrograde flow directs neurite formation in the developing brain. Neuron 76:1091–1107

    Article  CAS  PubMed  Google Scholar 

  24. Wolf M, Zimmermann AM, Görlich A, Gurniak CB, Sassoè-Pognetto M, Friauf E, Witke W, Rust MB (2015) ADF/cofilin controls synaptic actin dynamics and regulates synaptic vesicle mobilization and exocytosis. Cereb Cortex 25:2863–2875

    Article  PubMed  Google Scholar 

  25. Goodson M, Rust MB, Witke W, Bannerman D, Mott R, Ponting CP, Flint J (2012) Cofilin-1: a modulator of anxiety in mice. PLos Genet 8:e1002970

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Zimmermann AM, Jene T, Wolf M, Görlich A, Gurniak CB, Sassoè-Pognetto M, Witke W, Friauf E, Rust MB (2015) Attention-deficit/hyperactivity disorder-like phenotype in a mouse model with impaired actin dynamics. Biol Psychiatry 78:95–106

    Article  CAS  PubMed  Google Scholar 

  27. Witke W (2004) The role of profilin complexes in cell motility and other cellular processes. Trend Cell Biol 14:461–469

    Article  CAS  Google Scholar 

  28. Jockusch BM, Murk K, Rothkegel M (2007) The profile of profilins. Rev Physiol Biochem Pharmacol 159:131–149

    CAS  PubMed  Google Scholar 

  29. Carlsson L, Nyström LE, Sundkvist I, Markey F, Lindberg U (1977) Actin polymerizability is influenced by profilin, a low molecular weight protein in non-muscle cells. J Mol Biol 115:465–483

    Article  CAS  PubMed  Google Scholar 

  30. Kang F, Purich DL, Southwick FS (1999) Profilin promotes barbed-end actin filament assembly without lowering the critical concentration. J Biol Chem 274:36963–36972

    Article  CAS  PubMed  Google Scholar 

  31. Haarer BK, Lillie SH, Adams AE, Magdolen V, Bandlow W, Brown SS (1990) Purification of profilin from Saccharomyces cerevisiae and analysis of profilin-deficient cells. J Cell Biol 110:105–114

    Article  CAS  PubMed  Google Scholar 

  32. Staiger CJ, Goodbody KC, Hussey PJ, Valenta R, Drøbak BK, Lloyd CW (1993) The profilin multigene family of maize: differential expression of three isoforms. Plant J 4:631–641

    Article  CAS  PubMed  Google Scholar 

  33. Witke W, Podtelejnikov AV, Di Nardo A, Sutherland JD, Gurniak CB, Dotti C, Mann M (1998) In mouse brain profilin I and profilin II associate with regulators of the endocytic pathway and actin assembly. EMBO J 17:967–976

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Witke W, Sutherland JD, Sharpe A, Arai M, Kwiatkowski DJ (2001) Profilin I is essential for cell survival and cell division in early mouse development. Proc Natl Acad Sci USA 98:3832–3836

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Pilo Boyl P, Di Nardo A, Mulle C, Sassoè-Pognetto M, Panzanelli P, Mele A, Kneussel M, Costantini V, Perlas E, Massimi M, Vara H, Giustetto M Witke W (2007) Profilin2 contributes to synaptic vesicle exocytosis, neuronal excitability, and novelty-seeking behavior. EMBO J 26:2991–3002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Murk K, Wittenmayer N, Michaelsen-Preusse K, Dresbach T, Schoenenberger CA, Korte M, Jockusch BM, Rothkegel M (2012) Neuronal profilin isoforms are addressed by different signalling pathways. PLoS One 7:e34167

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Ackermann M, Matus A (2003) Activity-induced targeting of profilin and stabilization of dendritic spine morphology. Nat Neurosci 6:1194–1200

    Article  CAS  PubMed  Google Scholar 

  38. Neuhoff H, Sassoè-Pognetto M, Panzanelli P, Maas C, Witke W, Kneussel M (2005) The actin-binding protein profilin I is localized at synaptic sites in an activity-regulated manner. Eur J Neurosci 21:15–25

    Article  PubMed  Google Scholar 

  39. Lamprecht R, Farb CR, Rodrigues SM, LeDoux JE (2006) Fear conditioning drives profilin into amygdala dendritic spines. Nat Neurosci 9:481–483

    Article  CAS  PubMed  Google Scholar 

  40. Schubert V, Da Silva JS, Dotti CG (2006) Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner. J Cell Biol 172:453–467

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Michaelsen K, Murk K, Zagrebelsky M, Dreznjak A, Jockusch BM, Rothkegel M, Korte M (2010) Fine-tuning of neuronal architecture requires two profilin isoforms. Proc Natl Acad Sci USA 107:15780–15785

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Görlich A, Zimmermann AM, Schober D, Böttcher RT, Sassoè-Pognetto M, Friauf E, Witke W, Rust MB (2012) Preserved morphology and physiology of excitatory synapses in profilin1-deficient mice. PLoS One 7:e30068

    Article  PubMed Central  PubMed  Google Scholar 

  43. Fischer M, Kaech S, Knutti D, Matus A (1998) Rapid actin-based plasticity in dendritic spines. Neuron 20:847–854

    Article  CAS  PubMed  Google Scholar 

  44. Star EN, Kwiatkowski DJ, Murthy VN (2002) Rapid turnover of actin in dendritic spines and its regulation by activity. Nat Neurosci 5:239–246

    Article  CAS  PubMed  Google Scholar 

  45. Blanpied TA, Ehlers MD (2004) Microanatomy of dendritic spines: emerging principles of synaptic pathology in psychiatric and neurological disease. Biol Psychiatry 55:1121–1127

    Article  PubMed  Google Scholar 

  46. Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14:285–293

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Bhakar AL, Dölen G, Bear MF (2012) The pathophysiology of fragile X (and what it teaches us about synapses). Annu Rev Neurosci 35:417–443

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Drs. Martin Korte and Walter Witke for supporting our research projects.

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Correspondence to Marco B. Rust.

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Rust, M.B., Michaelsen-Preusse, K. Form follows function: actin-binding proteins as critical regulators of excitatory synapses. e-Neuroforum 7, 7–12 (2016). https://doi.org/10.1007/s13295-015-0019-6

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