Precise connectivity in neuronal circuits is a prerequisite for proper brain function. The dauntingly complex environment encountered by axons and dendrites, even after navigation to their target area, prompts the question of how specificity of synaptic connections arises during development. We review developmental strategies and molecular mechanisms that are used by neurons to ensure their precise matching of pre- and postsynaptic elements. The emerging theme is that each circuit uses a combination of simple mechanisms to achieve its refined, often complex connectivity pattern. At increasing levels of resolution, from lamina choice to subcellular targeting, similar signaling concepts are reemployed to narrow the choice of potential matches. Temporal control over synapse development and synapse elimination further ensures the specificity of connections in the nervous system.


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Literature Cited

  1. Ango F, di Cristo G, Higashiyama H, Bennett V, Wu P, Huang ZJ. 2004. Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment. Cell 119:257–72 [Google Scholar]
  2. Ango F, Wu C, Van der Want JJ, Wu P, Schachner M, Huang ZJ. 2008. Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites. PLOS Biol. 6:e103 [Google Scholar]
  3. Ashrafi S, Betley JN, Comer JD, Brenner-Morton S, Bar V. et al. 2014. Neuronal Ig/Caspr recognition promotes the formation of axoaxonic synapses in mouse spinal cord. Neuron 81:120–29 [Google Scholar]
  4. Bagri A, Cheng HJ, Yaron A, Pleasure SJ, Tessier-Lavigne M. 2003. Stereotyped pruning of long hippocampal axon branches triggered by retraction inducers of the semaphorin family. Cell 113:285–99 [Google Scholar]
  5. Betley JN, Wright CV, Kawaguchi Y, Erdelyi F, Szabo G. et al. 2009. Stringent specificity in the construction of a GABAergic presynaptic inhibitory circuit. Cell 139:161–74 [Google Scholar]
  6. Bloodgood BL, Sharma N, Browne HA, Trepman AZ, Greenberg ME. 2013. The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 503:121–25 [Google Scholar]
  7. Buffelli M, Burgess RW, Feng G, Lobe CG, Lichtman JW, Sanes JR. 2003. Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition. Nature 424:430–34 [Google Scholar]
  8. Busetto G, Buffelli M, Tognana E, Bellico F, Cangiano A. 2000. Hebbian mechanisms revealed by electrical stimulation at developing rat neuromuscular junctions. J. Neurosci. 20:685–95 [Google Scholar]
  9. Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB. 1998. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20:895–904 [Google Scholar]
  10. Chen PL, Clandinin TR. 2008. The cadherin Flamingo mediates level-dependent interactions that guide photoreceptor target choice in Drosophila. Neuron 58:26–33 [Google Scholar]
  11. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW. et al. 2005. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–33 [Google Scholar]
  12. Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A. et al. 2013. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504:394–400 [Google Scholar]
  13. Clandinin TR, Zipursky SL. 2000. Afferent growth cone interactions control synaptic specificity in the Drosophila visual system. Neuron 28:427–36 [Google Scholar]
  14. Clandinin TR, Zipursky SL. 2002. Making connections in the fly visual system. Neuron 35:827–41 [Google Scholar]
  15. Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y. et al. 2012. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151:709–23 [Google Scholar]
  16. Colman H, Nabekura J, Lichtman JW. 1997. Alterations in synaptic strength preceding axon withdrawal. Science 275:356–61 [Google Scholar]
  17. Colón-Ramos DA, Margeta MA, Shen K. 2007. Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans. Science 318:103–6 [Google Scholar]
  18. Crepel F, Mariani J, Delhaye-Bouchaud N. 1976. Evidence for a multiple innervation of Purkinje cells by climbing fibers in the immature rat cerebellum. J. Neurobiol. 7:567–78 [Google Scholar]
  19. Deguchi Y, Donato F, Galimberti I, Cabuy E, Caroni P. 2011. Temporally matched subpopulations of selectively interconnected principal neurons in the hippocampus. Nat. Neurosci. 14:495–504 [Google Scholar]
  20. Di Cristo G, Wu C, Chattopadhyaya B, Ango F, Knott G. et al. 2004. Subcellular domain-restricted GABAergic innervation in primary visual cortex in the absence of sensory and thalamic inputs. Nat. Neurosci. 7:1184–86 [Google Scholar]
  21. Ding JB, Oh WJ, Sabatini BL, Gu C. 2012. Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum. Nat. Neurosci. 15:215–23 [Google Scholar]
  22. Ding M, Chao D, Wang G, Shen K. 2007. Spatial regulation of an E3 ubiquitin ligase directs selective synapse elimination. Science 317:947–51 [Google Scholar]
  23. Flavell SW, Cowan CW, Kim TK, Greer PL, Lin Y. et al. 2006. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311:1008–12 [Google Scholar]
  24. Forster E, Zhao S, Frotscher M. 2006. Laminating the hippocampus. Nat. Rev. 7:259–67 [Google Scholar]
  25. Fukuhara K, Imai F, Ladle DR, Katayama K, Leslie JR. et al. 2013. Specificity of monosynaptic sensory-motor connections imposed by repellent Sema3E-PlexinD1 signaling. Cell Rep. 5:748–58 [Google Scholar]
  26. Ghosh A, Antonini A, McConnell SK, Shatz CJ. 1990. Requirement for subplate neurons in the formation of thalamocortical connections. Nature 347:179–81 [Google Scholar]
  27. Ghosh A, Shatz CJ. 1992. Involvement of subplate neurons in the formation of ocular dominance columns. Science 255:1441–43 [Google Scholar]
  28. Hadjieconomou D, Timofeev K, Salecker I. 2011. A step-by-step guide to visual circuit assembly in Drosophila. Curr. Opin. Neurobiol. 21:76–84 [Google Scholar]
  29. Hallam SJ, Jin Y. 1998. lin-14 regulates the timing of synaptic remodelling in Caenorhabditis elegans. Nature 395:78–82 [Google Scholar]
  30. Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y. et al. 2009. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N. Engl. J. Med. 360:599–605 [Google Scholar]
  31. Hamos JE, Van Horn SC, Raczkowski D, Sherman SM. 1987. Synaptic circuits involving an individual retinogeniculate axon in the cat. J. Comp. Neurol. 259:165–92 [Google Scholar]
  32. Hiesinger PR, Zhai RG, Zhou Y, Koh TW, Mehta SQ. et al. 2006. Activity-independent prespecification of synaptic partners in the visual map of Drosophila. Curr. Biol. 16:1835–43 [Google Scholar]
  33. Hong W, Luo L. 2014. Genetic control of wiring specificity in the fly olfactory system. Genetics 196:17–29 [Google Scholar]
  34. Hong W, Mosca TJ, Luo L. 2012. Teneurins instruct synaptic partner matching in an olfactory map. Nature 484:201–7 [Google Scholar]
  35. Hooks BM, Chen C. 2006. Distinct roles for spontaneous and visual activity in remodeling of the retinogeniculate synapse. Neuron 52:281–91 [Google Scholar]
  36. Hubel DH, Wiesel TN, LeVay S. 1977. Plasticity of ocular dominance columns in monkey striate cortex. Philos. Trans. R. Soc. Lond. 278:377–409 [Google Scholar]
  37. Imamura F, Ayoub AE, Rakic P, Greer CA. 2011. Timing of neurogenesis is a determinant of olfactory circuitry. Nat. Neurosci. 14:331–37 [Google Scholar]
  38. Inaki M, Yoshikawa S, Thomas JB, Aburatani H, Nose A. 2007. Wnt4 is a local repulsive cue that determines synaptic target specificity. Curr. Biol. 17:1574–79 [Google Scholar]
  39. Isshiki T, Pearson B, Holbrook S, Doe CQ. 2001. Drosophila neuroblasts sequentially express transcription factors which specify the temporal identity of their neuronal progeny. Cell 106:511–21 [Google Scholar]
  40. Je HS, Yang F, Ji Y, Potluri S, Fu XQ. et al. 2013. ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions. J. Neurosci. 33:9957–62 [Google Scholar]
  41. Kanold PO, Kara P, Reid RC, Shatz CJ. 2003. Role of subplate neurons in functional maturation of visual cortical columns. Science 301:521–25 [Google Scholar]
  42. Kim JH, Liao D, Lau LF, Huganir RL. 1998. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 20:683–91 [Google Scholar]
  43. Klassen MP, Shen K. 2007. Wnt signaling positions neuromuscular connectivity by inhibiting synapse formation in C. elegans. Cell 130:704–16 [Google Scholar]
  44. Koles K, Budnik V. 2012. Wnt signaling in neuromuscular junction development. Cold Spring Harb. Perspect. Biol. 4:a008045 [Google Scholar]
  45. Kolodkin AL, Tessier-Lavigne M. 2011. Mechanisms and molecules of neuronal wiring: a primer. Cold Spring Harb. Perspect. Biol. 3:a001727 [Google Scholar]
  46. Komiyama T, Sweeney LB, Schuldiner O, Garcia KC, Luo L. 2007. Graded expression of semaphorin-1a cell-autonomously directs dendritic targeting of olfactory projection neurons. Cell 128:399–410 [Google Scholar]
  47. Krepischi AC, Rosenberg C, Costa SS, Crolla JA, Huang S, Vianna-Morgante AM. 2010. A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation. Am. J. Med. Genet. 152A:2376–78 [Google Scholar]
  48. Langley JN. 1895. Note on regeneration of prae-ganglionic fibres of the sympathetic. J. Physiol. 18:280–84 [Google Scholar]
  49. Lee CH, Herman T, Clandinin TR, Lee R, Zipursky SL. 2001. N-cadherin regulates target specificity in the Drosophila visual system. Neuron 30:437–50 [Google Scholar]
  50. Lee RC, Clandinin TR, Lee CH, Chen PL, Meinertzhagen IA, Zipursky SL. 2003. The protocadherin Flamingo is required for axon target selection in the Drosophila visual system. Nat. Neurosci. 6:557–63 [Google Scholar]
  51. Lin Y, Bloodgood BL, Hauser JL, Lapan AD, Koon AC. et al. 2008. Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 455:1198–204 [Google Scholar]
  52. Liu XB, Low LK, Jones EG, Cheng HJ. 2005. Stereotyped axon pruning via plexin signaling is associated with synaptic complex elimination in the hippocampus. J. Neurosci. 25:9124–34 [Google Scholar]
  53. Maro GS, Shen K, Cheng HJ. 2009. Deal breaker: semaphorin and specificity in the spinal stretch reflex circuit. Neuron 63:8–11 [Google Scholar]
  54. Matsuoka RL, Chivatakarn O, Badea TC, Samuels IS, Cahill H. et al. 2011a. Class 5 transmembrane semaphorins control selective mammalian retinal lamination and function. Neuron 71:460–73 [Google Scholar]
  55. Matsuoka RL, Nguyen-Ba-Charvet KT, Parray A, Badea TC, Chedotal A, Kolodkin AL. 2011b. Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina. Nature 470:259–63 [Google Scholar]
  56. Meinertzhagen IA, O'Neil SD. 1991. Synaptic organization of columnar elements in the lamina of the wild type in Drosophila melanogaster. J. Comp. Neurol. 305:232–63 [Google Scholar]
  57. Miles R, Tóth K, Gulyás AI, Hájos N, Freund TF. 1996. Differences between somatic and dendritic inhibition in the hippocampus. Neuron 16:815–23 [Google Scholar]
  58. Millard SS, Flanagan JJ, Pappu KS, Wu W, Zipursky SL. 2007. Dscam2 mediates axonal tiling in the Drosophila visual system. Nature 447:720–24 [Google Scholar]
  59. Millard SS, Lu Z, Zipursky SL, Meinertzhagen IA. 2010. Drosophila Dscam proteins regulate postsynaptic specificity at multiple-contact synapses. Neuron 67:761–68 [Google Scholar]
  60. Mizumoto K, Shen K. 2013a. Interaxonal interaction defines tiled presynaptic innervation in C. elegans. Neuron 77:655–66 [Google Scholar]
  61. Mizumoto K, Shen K. 2013b. Two Wnts instruct topographic synaptic innervation in C. elegans. Cell Rep. 5:389–96 [Google Scholar]
  62. Packard M, Koo ES, Gorczyca M, Sharpe J, Cumberledge S, Budnik V. 2002. The Drosophila Wnt, wingless, provides an essential signal for pre- and postsynaptic differentiation. Cell 111:319–30 [Google Scholar]
  63. Pecho-Vrieseling E, Sigrist M, Yoshida Y, Jessell TM, Arber S. 2009. Specificity of sensory-motor connections encoded by Sema3e-Plxnd1 recognition. Nature 459:842–46 [Google Scholar]
  64. Pecot MY, Tadros W, Nern A, Bader M, Chen Y, Zipursky SL. 2013. Multiple interactions control synaptic layer specificity in the Drosophila visual system. Neuron 77:299–310 [Google Scholar]
  65. Petrovic M, Hummel T. 2008. Temporal identity in axonal target layer recognition. Nature 456:800–3 [Google Scholar]
  66. Pfeiffer BE, Zang T, Wilkerson JR, Taniguchi M, Maksimova MA. et al. 2010. Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66:191–97 [Google Scholar]
  67. Poon VY, Klassen MP, Shen K. 2008. UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites. Nature 455:669–73 [Google Scholar]
  68. Pouille F, Scanziani M. 2004. Routing of spike series by dynamic circuits in the hippocampus. Nature 429:717–23 [Google Scholar]
  69. Sala C, Segal M. 2014. Dendritic spines: the locus of structural and functional plasticity. Physiol. Rev. 94:141–88 [Google Scholar]
  70. Sanes JR, Lichtman JW. 1999. Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22:389–442 [Google Scholar]
  71. Sanes JR, Yamagata M. 2009. Many paths to synaptic specificity. Annu. Rev. Cell Dev. Biol. 25:161–95 [Google Scholar]
  72. Sanes JR, Zipursky SL. 2010. Design principles of insect and vertebrate visual systems. Neuron 66:15–36 [Google Scholar]
  73. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR. et al. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705 [Google Scholar]
  74. Schwabe T, Neuert H, Clandinin TR. 2013. A network of cadherin-mediated interactions polarizes growth cones to determine targeting specificity. Cell 154:351–64 [Google Scholar]
  75. Shen K, Bargmann CI. 2003. The immunoglobulin superfamily protein SYG-1 determines the location of specific synapses in C. elegans. Cell 112:619–30 [Google Scholar]
  76. Shen K, Fetter RD, Bargmann CI. 2004. Synaptic specificity is generated by the synaptic guidepost protein SYG-2 and its receptor, SYG-1. Cell 116:869–81 [Google Scholar]
  77. Sperry RW. 1963. Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc. Natl. Acad. Sci. USA 50:703–10 [Google Scholar]
  78. Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA. et al. 2013. A dramatic increase of C1q protein in the CNS during normal aging. J. Neurosci. 33:13460–74 [Google Scholar]
  79. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS. et al. 2007. The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–78 [Google Scholar]
  80. Sun LO, Jiang Z, Rivlin-Etzion M, Hand R, Brady CM. et al. 2013. On and off retinal circuit assembly by divergent molecular mechanisms. Science 342:1241974 [Google Scholar]
  81. Sweeney LB, Chou YH, Wu Z, Joo W, Komiyama T. et al. 2011. Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting. Neuron 72:734–47 [Google Scholar]
  82. Thompson-Peer KL, Bai J, Hu Z, Kaplan JM. 2012. HBL-1 patterns synaptic remodeling in C. elegans. Neuron 73:453–65 [Google Scholar]
  83. Tran TS, Rubio ME, Clem RL, Johnson D, Case L. et al. 2009. Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 462:1065–69 [Google Scholar]
  84. Tripodi M, Stepien AE, Arber S. 2011. Motor antagonism exposed by spatial segregation and timing of neurogenesis. Nature 479:61–66 [Google Scholar]
  85. Tsai NP, Wilkerson JR, Guo W, Maksimova MA, DeMartino GN. et al. 2012. Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 151:1581–94 [Google Scholar]
  86. Waddington CH. 1959. Canalization of development and genetic assimilation of acquired characters. Nature 183:1654–55 [Google Scholar]
  87. Wang Y, He H, Srivastava N, Vikarunnessa S, Chen YB. et al. 2012. Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Sci. Signal. 5:ra6 [Google Scholar]
  88. White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans. Philos. Trans. R. Soc. Lond. 314:1–340 [Google Scholar]
  89. Williams ME, Wilke SA, Daggett A, Davis E, Otto S. et al. 2011. Cadherin-9 regulates synapse-specific differentiation in the developing hippocampus. Neuron 71:640–55 [Google Scholar]
  90. Yamagata M, Sanes JR. 2008. Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina. Nature 451:465–69 [Google Scholar]
  91. Yamagata M, Sanes JR. 2012. Expanding the Ig superfamily code for laminar specificity in retina: expression and role of contactins. J. Neurosci. 32:14402–14 [Google Scholar]
  92. Yamagata M, Weiner JA, Sanes JR. 2002. Sidekicks: synaptic adhesion molecules that promote lamina-specific connectivity in the retina. Cell 110:649–60 [Google Scholar]
  93. Yu X, Wang G, Gilmore A, Yee AX, Li X. et al. 2013. Accelerated experience-dependent pruning of cortical synapses in ephrin-A2 knockout mice. Neuron 80:64–71 [Google Scholar]
  94. Zipursky SL, Grueber WB. 2013. The molecular basis of self-avoidance. Annu. Rev. Neurosci. 36:547–68 [Google Scholar]

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