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Phase separation at the synapse


Emerging evidence indicates that liquid–liquid phase separation, the formation of a condensed molecular assembly within another diluted aqueous solution, is a means for cells to organize highly condensed biological assemblies (also known as biological condensates or membraneless compartments) with very broad functions and regulatory properties in different subcellular regions. Molecular machineries dictating synaptic transmissions in both presynaptic boutons and postsynaptic densities of neuronal synapses may be such biological condensates. Here we review recent developments showing how phase separation can build dense synaptic molecular clusters, highlight unique features of such condensed clusters in the context of synaptic development and signaling, discuss how aberrant phase-separation-mediated synaptic assembly formation may contribute to dysfunctional signaling in psychiatric disorders, and present some challenges and opportunities of phase separation in synaptic biology.

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Fig. 1: Basic principles of phase separation illustrated by a simple two-component system.
Fig. 2: Phase separation in neurons.
Fig. 3: Phase-separation-mediated formation of PSD assemblies.
Fig. 4: Phase separation in presynaptic boutons.
Fig. 5: Mutual exclusion of excitatory and inhibitory PSD condensates.


  1. 1.

    Ramon y Cajal, S. Un sencillo metodo de coloracion selectiva del reticulo protoplasmatico y sus efectos en los diversos organos nerviosos de vertebrados e invertebrados. Trab. Lab. Invest. Biol. Univ. Madrid 2, 129–221 (1903).

    Google Scholar 

  2. 2.

    Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    CAS  PubMed  Google Scholar 

  3. 3.

    Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).

    PubMed  Google Scholar 

  4. 4.

    Hyman, A. A., Weber, C. A. & Jülicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39–58 (2014).

    CAS  PubMed  Google Scholar 

  5. 5.

    Van Treeck, B. & Parker, R. Emerging roles for intermolecular RNA-RNA interactions in RNP assemblies. Cell 174, 791–802 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Harris, K. M. & Weinberg, R. J. Ultrastructure of synapses in the mammalian brain. Cold Spring Harb. Perspect. Biol. 4, a005587 (2012).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Chen, X. et al. Organization of the core structure of the postsynaptic density. Proc. Natl Acad. Sci. USA 105, 4453–4458 (2008).

    CAS  PubMed  Google Scholar 

  8. 8.

    Blomberg, F., Cohen, R. S. & Siekevitz, P. The structure of postsynaptic densities isolated from dog cerebral cortex. II. Characterization and arrangement of some of the major proteins within the structure. J. Cell Biol. 74, 204–225 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Couteaux, R. & Pécot-Dechavassine, M. [Synaptic vesicles and pouches at the level of “active zones” of the neuromuscular junction]. C. R. Acad. Sci. Hebd. Seances Acad. Sci. D 271, 2346–2349 (1970).

    CAS  PubMed  Google Scholar 

  10. 10.

    Südhof, T. C. The presynaptic active zone. Neuron 75, 11–25 (2012).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Biederer, T., Kaeser, P. S. & Blanpied, T. A. Transcellular nanoalignment of synaptic function. Neuron 96, 680–696 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Rizzoli, S. O. & Betz, W. J. Synaptic vesicle pools. Nat. Rev. Neurosci. 6, 57–69 (2005).

    CAS  PubMed  Google Scholar 

  13. 13.

    Alabi, A. A. & Tsien, R. W. Synaptic vesicle pools and dynamics. Cold Spring Harb. Perspect. Biol. 4, a013680 (2012).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Zeng, M. et al. Phase transition in postsynaptic densities underlies formation of synaptic complexes and synaptic plasticity. Cell 166, 1163–1175.e12 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Zeng, M. et al. Reconstituted postsynaptic density as a molecular platform for understanding synapse formation and plasticity. Cell 174, 1172–1187.e16 (2018).

    CAS  PubMed  Google Scholar 

  16. 16.

    Milovanovic, D., Wu, Y., Bian, X. & De Camilli, P. A liquid phase of synapsin and lipid vesicles. Science 361, 604–607 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wu, X. et al. RIM and RIM-BP form presynaptic active-zone-like condensates via phase separation. Mol. Cell 73, 971–984.e5 (2019).

    CAS  PubMed  Google Scholar 

  18. 18.

    Nedelsky, N. B. & Taylor, J. P. Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease. Nat. Rev. Neurol. 15, 272–286 (2019).

    PubMed  Google Scholar 

  19. 19.

    Elbaum-Garfinkle, S. Matter over mind: liquid phase separation and neurodegeneration. J. Biol. Chem. 294, 7160–7168 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Taylor, J. P., Brown, R. H. Jr. & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature 539, 197–206 (2016).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Palay, S. L. Synapses in the central nervous system. J. Biophys. Biochem. Cytol. 2(Suppl), 193–202 (1956).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Gray, E. G. Axo-somatic and axo-dendritic synapses of the cerebral cortex: an electron microscope study. J. Anat. 93, 420–433 (1959).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Banker, G., Churchill, L. & Cotman, C. W. Proteins of the postsynaptic density. J. Cell Biol. 63, 456–465 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Cheng, D. et al. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum. Mol. Cell. Proteomics 5, 1158–1170 (2006).

    CAS  PubMed  Google Scholar 

  25. 25.

    Roy, M. et al. Proteomic analysis of postsynaptic proteins in regions of the human neocortex. Nat. Neurosci. 21, 130–138 (2018).

    CAS  PubMed  Google Scholar 

  26. 26.

    Wilson, R. S. et al. Development of targeted mass spectrometry-based approaches for quantitation of proteins enriched in the postsynaptic density (PSD). Proteomes 7, 12 (2019).

    CAS  PubMed Central  Google Scholar 

  27. 27.

    Kennedy, M. B. The postsynaptic density at glutamatergic synapses. Trends Neurosci. 20, 264–268 (1997).

    CAS  PubMed  Google Scholar 

  28. 28.

    Sheng, M. & Hoogenraad, C. C. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76, 823–847 (2007).

    CAS  PubMed  Google Scholar 

  29. 29.

    Li, J. et al. Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders. Nat. Neurosci. 20, 1150–1161 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Cohen, R. S., Blomberg, F., Berzins, K. & Siekevitz, P. The structure of postsynaptic densities isolated from dog cerebral cortex. I. Overall morphology and protein composition. J. Cell Biol. 74, 181–203 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Kornau, H. C., Schenker, L. T., Kennedy, M. B. & Seeburg, P. H. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269, 1737–1740 (1995).

    CAS  PubMed  Google Scholar 

  32. 32.

    Kim, E. et al. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. J. Cell Biol. 136, 669–678 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    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).

    CAS  PubMed  Google Scholar 

  34. 34.

    Xiao, B. et al. Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins. Neuron 21, 707–716 (1998).

    CAS  PubMed  Google Scholar 

  35. 35.

    Berry, K. P. & Nedivi, E. Spine dynamics: are they all the same? Neuron 96, 43–55 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Nishiyama, J. & Yasuda, R. Biochemical computation for spine structural plasticity. Neuron 87, 63–75 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Harris, K. M., Jensen, F. E. & Tsao, B. Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J. Neurosci. 12, 2685–2705 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Huganir, R. L. & Nicoll, R. A. AMPARs and synaptic plasticity: the last 25 years. Neuron 80, 704–717 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Borgdorff, A. J. & Choquet, D. Regulation of AMPA receptor lateral movements. Nature 417, 649–653 (2002).

    CAS  PubMed  Google Scholar 

  40. 40.

    Heine, M. et al. Surface mobility of postsynaptic AMPARs tunes synaptic transmission. Science 320, 201–205 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Makino, H. & Malinow, R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64, 381–390 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Blanpied, T. A., Kerr, J. M. & Ehlers, M. D. Structural plasticity with preserved topology in the postsynaptic protein network. Proc. Natl Acad. Sci. USA 105, 12587–12592 (2008).

    CAS  PubMed  Google Scholar 

  44. 44.

    Nair, D. et al. Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J. Neurosci. 33, 13204–13224 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Bosch, M. et al. Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron 82, 444–459 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Kuriu, T., Inoue, A., Bito, H., Sobue, K. & Okabe, S. Differential control of postsynaptic density scaffolds via actin-dependent and -independent mechanisms. J. Neurosci. 26, 7693–7706 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Kim, J. H., Liao, D., Lau, L. F. & Huganir, R. L. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 20, 683–691 (1998).

    CAS  PubMed  Google Scholar 

  48. 48.

    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).

    CAS  PubMed  Google Scholar 

  49. 49.

    Araki, Y., Zeng, M., Zhang, M. & Huganir, R. L. Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron 85, 173–189 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Pena, V. et al. The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction. EMBO Rep. 9, 350–355 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Vazquez, L. E., Chen, H.-J., Sokolova, I., Knuesel, I. & Kennedy, M. B. SynGAP regulates spine formation. J. Neurosci. 24, 8862–8872 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Zeng, M., Bai, G. & Zhang, M. Anchoring high concentrations of SynGAP at postsynaptic densities via liquid-liquid phase separation. Small GTPases 10, 296–304 (2017).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Clement, J. P. et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151, 709–723 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Kilinc, M. et al. Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders. Mol. Cell. Neurosci. 91, 140–150 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Zeng, M., Ye, F., Xu, J. & Zhang, M. PDZ ligand binding-induced conformational coupling of the PDZ-SH3-GK tandems in PSD-95 family MAGUKs. J. Mol. Biol. 430, 69–86 (2018).

    CAS  PubMed  Google Scholar 

  56. 56.

    McGee, A. W. et al. Structure of the SH3-guanylate kinase module from PSD-95 suggests a mechanism for regulated assembly of MAGUK scaffolding proteins. Mol. Cell 8, 1291–1301 (2001).

    CAS  PubMed  Google Scholar 

  57. 57.

    Li, P. et al. Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336–340 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Walkup, W. G. et al. A model for regulation by SynGAP-alpha1 of binding of synaptic proteins to PDZ-domain ‘Slots’ in the postsynaptic density. eLife 5, e16813 (2016).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Petralia, R. S., Sans, N., Wang, Y. X. & Wenthold, R. J. Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol. Cell. Neurosci. 29, 436–452 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Valtschanoff, J. G. & Weinberg, R. J. Laminar organization of the NMDA receptor complex within the postsynaptic density. J. Neurosci. 21, 1211–1217 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Dosemeci, A., Weinberg, R. J., Reese, T. S. & Tao-Cheng, J. H. The postsynaptic density: there is more than meets the eye. Front. Synaptic Neurosci. 8, 23 (2016).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Lowenthal, M. S., Markey, S. P. & Dosemeci, A. Quantitative mass spectrometry measurements reveal stoichiometry of principal postsynaptic density proteins. J. Proteome Res. 14, 2528–2538 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Ting, J. T., Peça, J. & Feng, G. Functional consequences of mutations in postsynaptic scaffolding proteins and relevance to psychiatric disorders. Annu. Rev. Neurosci. 35, 49–71 (2012).

    CAS  PubMed  Google Scholar 

  64. 64.

    Zhu, J., Shang, Y. & Zhang, M. Mechanistic basis of MAGUK-organized complexes in synaptic development and signalling. Nat. Rev. Neurosci. 17, 209–223 (2016).

    CAS  PubMed  Google Scholar 

  65. 65.

    Feng, W. & Zhang, M. Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density. Nat. Rev. Neurosci. 10, 87–99 (2009).

    CAS  PubMed  Google Scholar 

  66. 66.

    Zeng, M. et al. Phase separation-mediated TARP/MAGUK complex condensation and AMPA receptor synaptic transmission. Neuron 104, 529–543.e6 (2019).

    CAS  PubMed  Google Scholar 

  67. 67.

    Landis, D. M. D., Hall, A. K., Weinstein, L. A. & Reese, T. S. The organization of cytoplasm at the presynaptic active zone of a central nervous system synapse. Neuron 1, 201–209 (1988).

    CAS  PubMed  Google Scholar 

  68. 68.

    Rosahl, T. W. et al. Essential functions of synapsins I and II in synaptic vesicle regulation. Nature 375, 488–493 (1995).

    CAS  PubMed  Google Scholar 

  69. 69.

    Pieribone, V. A. et al. Distinct pools of synaptic vesicles in neurotransmitter release. Nature 375, 493–497 (1995).

    CAS  PubMed  Google Scholar 

  70. 70.

    Milovanovic, D. & De Camilli, P. Synaptic vesicle clusters at synapses: a distinct liquid phase? Neuron 93, 995–1002 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Siksou, L. et al. Three-dimensional architecture of presynaptic terminal cytomatrix. J. Neurosci. 27, 6868–6877 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Acuna, C., Liu, X. & Südhof, T. C. How to make an active zone: unexpected universal functional redundancy between RIMs and RIM-BPs. Neuron 91, 792–807 (2016).

    CAS  PubMed  Google Scholar 

  73. 73.

    Wang, S. S. H. et al. Fusion competent synaptic vesicles persist upon active zone disruption and loss of vesicle docking. Neuron 91, 777–791 (2016).

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Benfenati, F., Bähler, M., Jahn, R. & Greengard, P. Interactions of synapsin I with small synaptic vesicles: distinct sites in synapsin I bind to vesicle phospholipids and vesicle proteins. J. Cell Biol. 108, 1863–1872 (1989).

    CAS  PubMed  Google Scholar 

  75. 75.

    Südhof, T. C. et al. Synapsins: mosaics of shared and individual domains in a family of synaptic vesicle phosphoproteins. Science 245, 1474–1480 (1989).

    PubMed  Google Scholar 

  76. 76.

    Shupliakov, O., Haucke, V. & Pechstein, A. How synapsin I may cluster synaptic vesicles. Semin. Cell Dev. Biol. 22, 393–399 (2011).

    CAS  PubMed  Google Scholar 

  77. 77.

    Esser, L. et al. Synapsin I is structurally similar to ATP-utilizing enzymes. EMBO J. 17, 977–984 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Hosaka, M. & Südhof, T. C. Homo- and heterodimerization of synapsins. J. Biol. Chem. 274, 16747–16753 (1999).

    CAS  PubMed  Google Scholar 

  79. 79.

    Hosaka, M., Hammer, R. E. & Südhof, T. C. A phospho-switch controls the dynamic association of synapsins with synaptic vesicles. Neuron 24, 377–387 (1999).

    CAS  PubMed  Google Scholar 

  80. 80.

    Cheetham, J. J. et al. Identification of synapsin I peptides that insert into lipid membranes. Biochem. J. 354, 57–66 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    De Camilli, P., Harris, S. M. Jr., Huttner, W. B. & Greengard, P. Synapsin I (Protein I), a nerve terminal-specific phosphoprotein. II. Its specific association with synaptic vesicles demonstrated by immunocytochemistry in agarose-embedded synaptosomes. J. Cell Biol. 96, 1355–1373 (1983).

    PubMed  Google Scholar 

  82. 82.

    Chi, P., Greengard, P. & Ryan, T. A. Synapsin dispersion and reclustering during synaptic activity. Nat. Neurosci. 4, 1187–1193 (2001).

    CAS  PubMed  Google Scholar 

  83. 83.

    Benfenati, F. et al. Synaptic vesicle-associated Ca2+/calmodulin-dependent protein kinase II is a binding protein for synapsin I. Nature 359, 417–420 (1992).

    CAS  PubMed  Google Scholar 

  84. 84.

    Zhai, R. G. & Bellen, H. J. The architecture of the active zone in the presynaptic nerve terminal. Physiology (Bethesda) 19, 262–270 (2004).

    Google Scholar 

  85. 85.

    Tang, A. H. et al. A trans-synaptic nanocolumn aligns neurotransmitter release to receptors. Nature 536, 210–214 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Miki, T. et al. Numbers of presynaptic Ca2+ channel clusters match those of functionally defined vesicular docking sites in single central synapses. Proc. Natl Acad. Sci. USA 114, E5246–E5255 (2017).

    CAS  PubMed  Google Scholar 

  87. 87.

    Nakamura, Y. et al. Nanoscale distribution of presynaptic Ca(2+) channels and its impact on vesicular release during development. Neuron 85, 145–158 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Eggermann, E., Bucurenciu, I., Goswami, S. P. & Jonas, P. Nanodomain coupling between Ca2+ channels and sensors of exocytosis at fast mammalian synapses. Nat. Rev. Neurosci. 13, 7–21 (2011).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Südhof, T. C. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80, 675–690 (2013).

    PubMed  Google Scholar 

  90. 90.

    Kaeser, P. S. et al. RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction. Cell 144, 282–295 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Acuna, C., Liu, X., Gonzalez, A. & Südhof, T. C. RIM-BPs mediate tight coupling of action potentials to Ca(2+)-triggered neurotransmitter release. Neuron 87, 1234–1247 (2015).

    CAS  PubMed  Google Scholar 

  92. 92.

    Wilhelm, B. G. et al. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344, 1023–1028 (2014).

    CAS  PubMed  Google Scholar 

  93. 93.

    Galkin, O., Chen, K., Nagel, R. L., Hirsch, R. E. & Vekilov, P. G. Liquid-liquid separation in solutions of normal and sickle cell hemoglobin. Proc. Natl Acad. Sci. USA 99, 8479–8483 (2002).

    CAS  PubMed  Google Scholar 

  94. 94.

    Brangwynne, C. P. et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324, 1729–1732 (2009).

    CAS  PubMed  Google Scholar 

  95. 95.

    Zhu, J. et al. Synaptic targeting and function of SAPAPs mediated by phosphorylation-dependent binding to PSD-95 MAGUKs. Cell Rep. 21, 3781–3793 (2017).

    CAS  PubMed  Google Scholar 

  96. 96.

    Xiao, B., Tu, J. C. & Worley, P. F. Homer: a link between neural activity and glutamate receptor function. Curr. Opin. Neurobiol. 10, 370–374 (2000).

    CAS  PubMed  Google Scholar 

  97. 97.

    Sala, C. et al. Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a. J. Neurosci. 23, 6327–6337 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Diering, G. H. et al. Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science 355, 511–515 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    de Vivo, L. et al. Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science 355, 507–510 (2017).

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    Kubota, Y., Hatada, S., Kondo, S., Karube, F. & Kawaguchi, Y. Neocortical inhibitory terminals innervate dendritic spines targeted by thalamocortical afferents. J. Neurosci. 27, 1139–1150 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Villa, K. L. et al. Inhibitory synapses are repeatedly assembled and removed at persistent sites in vivo. Neuron 89, 756–769 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Toretsky, J. A. & Wright, P. E. Assemblages: functional units formed by cellular phase separation. J. Cell Biol. 206, 579–588 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Jiang, H. et al. Phase transition of spindle-associated protein regulate spindle apparatus assembly. Cell 163, 108–122 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Molliex, A. et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163, 123–133 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).

    CAS  PubMed  Google Scholar 

  108. 108.

    Wang, J. et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174, 688–699.e16 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Baldan, A. Progress in Ostwald ripening theories and their applications to nickel-base superalloys. J. Mater. Sci. 37, 2171–2202 (2002).

    CAS  Google Scholar 

  110. 110.

    Guo, L. et al. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173, 677–692.e20 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Qamar, S. et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions. Cell 173, 720–734.e15 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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Work in our laboratory is supported by grants from RGC of Hong Kong (AoE-M09-12 and C6004-17G) and a grant from Simons Foundation for Autism Research (510178). M.Z. receives support from a Kerry Holdings Professorship of Science and a Senior Fellowship of IAS at HKUST.

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Chen, X., Wu, X., Wu, H. et al. Phase separation at the synapse. Nat Neurosci 23, 301–310 (2020).

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