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Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders

Nature Reviews Neuroscience volume 18, pages 658–670 (2017)Cite this article

Subjects

Key Points

  • Brain development is associated with the formation of excessive synapses that have to be removed in a controlled and timely manner to achieve refined mature circuitry.

  • Glial cells, including microglia and astrocytes, are the effectors of synaptic pruning, identifying and eliminating superfluous synapses.

  • Synaptic pruning depends on various molecules, including those controlling glial chemotaxis, target recognition and phagocytosis.

  • Autism spectrum disorders are associated with excessive synapses, autophagy and dysregulated microglial function.

  • Schizophrenia is linked to exaggerated synaptic pruning owing to elevated levels of complement proteins and microglial activation.

  • Epilepsy is thought to arise owing to immature circuitry that was not refined via synaptic pruning. This initial epileptiform activity is followed by microglial activation and upregulation of complement components.

Abstract

The final stage of brain development is associated with the generation and maturation of neuronal synapses. However, the same period is also associated with a peak in synapse elimination — a process known as synaptic pruning — that has been proposed to be crucial for the maturation of remaining synaptic connections. Recent studies have pointed to a key role for glial cells in synaptic pruning in various parts of the nervous system and have identified a set of critical signalling pathways between glia and neurons. At the same time, brain imaging and post-mortem anatomical studies suggest that insufficient or excessive synaptic pruning may underlie several neurodevelopmental disorders, including autism, schizophrenia and epilepsy. Here, we review current data on the cellular, physiological and molecular mechanisms of glial-cell-dependent synaptic pruning and outline their potential contribution to neurodevelopmental disorders.

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Figure 1: Molecular mechanisms of synaptic pruning by glial cells.
Figure 2: Putative molecular components of aberrant synaptic pruning by glia in disease.

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References

  1. Riccomagno, M. M. & Kolodkin, A. L. Sculpting neural circuits by axon and dendrite pruning. Annu. Rev. Cell Dev. Biol. 31, 779–805 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Innocenti, G. M. & Price, D. J. Exuberance in the development of cortical networks. Nat. Rev. Neurosci. 6, 955–965 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Johnson, M. H. Functional brain development in humans. Nat. Rev. Neurosci. 2, 475–483 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Darabid, H., Perez-Gonzalez, A. P. & Robitaille, R. Neuromuscular synaptogenesis: coordinating partners with multiple functions. Nat. Rev. Neurosci. 15, 703–718 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Hashimoto, K. & Kano, M. Synapse elimination in the developing cerebellum. Cell. Mol. Life Sci. 70, 4667–4680 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Huberman, A. D. Mechanisms of eye-specific visual circuit development. Curr. Opin. Neurobiol. 17, 73–80 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).This was the first study to demonstrate that microglial cells are required for synaptic pruning.

    Article  CAS  PubMed  Google Scholar 

  9. Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).This study presented the first molecular mechanism by which microglia prune superfluous synapses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chung, W. S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).This study introduced astrocytes as cells capable of synaptic pruning and described astrocytic receptors involved in the process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chung, W. S. et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc. Natl Acad. Sci. USA (2016).

  12. Sipe, G. O. et al. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat. Commun. 7, 10905 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schafer, D. P. & Stevens, B. Microglia function in central nervous system development and plasticity. Cold Spring Harb. Perspect. Biol. 7, a020545 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Clarke, L. E. & Barres, B. A. Emerging roles of astrocytes in neural circuit development. Nat. Rev. Neurosci. 14, 311–321 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Darabid, H., Arbour, D. & Robitaille, R. Glial cells decipher synaptic competition at the mammalian neuromuscular junction. J. Neurosci. 33, 1297–1313 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Berbel, P. & Innocenti, G. M. The development of the corpus callosum in cats: a light- and electron-microscopic study. J. Comp. Neurol. 276, 132–156 (1988).This classic study was the first to indicate that glial cells are involved in synaptic pruning.

    Article  CAS  PubMed  Google Scholar 

  17. Hoshiko, M., Arnoux, I., Avignone, E., Yamamoto, N. & Audinat, E. Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J. Neurosci. 32, 15106–15111 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Ichikawa, R. et al. Developmental switching of perisomatic innervation from climbing fibers to basket cell fibers in cerebellar Purkinje cells. J. Neurosci. 31, 16916–16927 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).This study described upregulated C4 as a risk factor for schizophrenia, linking aberrant synaptic pruning to the pathology of the disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Blakemore, S. J. Development of the social brain during adolescence. Q. J. Exp. Psychol. (Hove) 61, 40–49 (2008).

    Article  Google Scholar 

  22. Smith, I. W., Mikesh, M., Lee, Y. & Thompson, W. J. Terminal Schwann cells participate in the competition underlying neuromuscular synapse elimination. J. Neurosci. 33, 17724–17736 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tapia, J. C. et al. Pervasive synaptic branch removal in the mammalian neuromuscular system at birth. Neuron 74, 816–829 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Bishop, D. L., Misgeld, T., Walsh, M. K., Gan, W. B. & Lichtman, J. W. Axon branch removal at developing synapses by axosome shedding. Neuron 44, 651–661 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Song, J. W. et al. Lysosomal activity associated with developmental axon pruning. J. Neurosci. 28, 8993–9001 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee, Y. I. et al. Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions. Proc. Natl Acad. Sci. USA 113, E479–E487 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, J. Y. et al. Caspase-3 cleavage of dishevelled induces elimination of postsynaptic structures. Dev. Cell 28, 670–684 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Todd, K. J., Darabid, H. & Robitaille, R. Perisynaptic glia discriminate patterns of motor nerve activity and influence plasticity at the neuromuscular junction. J. Neurosci. 30, 11870–11882 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Carrillo, J., Nishiyama, N. & Nishiyama, H. Dendritic translocation establishes the winner in cerebellar climbing fiber synapse elimination. J. Neurosci. 33, 7641–7653 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hashimoto, K. & Kano, M. Functional differentiation of multiple climbing fiber inputs during synapse elimination in the developing cerebellum. Neuron 38, 785–796 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Andjus, P. R., Zhu, L., Cesa, R., Carulli, D. & Strata, P. A change in the pattern of activity affects the developmental regression of the Purkinje cell polyinnervation by climbing fibers in the rat cerebellum. Neuroscience 121, 563–572 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Sugihara, I. Microzonal projection and climbing fiber remodeling in single olivocerebellar axons of newborn rats at postnatal days 4–7. J. Comp. Neurol. 487, 93–106 (2005).

    Article  PubMed  Google Scholar 

  33. Iino, M. et al. Glia–synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Kakegawa, W. et al. Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. Neuron 85, 316–329 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Ballesteros, J. M., Van Der List, D. A. & Chalupa, L. M. Formation of eye-specific retinogeniculate projections occurs prior to the innervation of the dorsal lateral geniculate nucleus by cholinergic fibers. Thalamus Relat. Syst. 3, 157–163 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hong, Y. K. et al. Refinement of the retinogeniculate synapse by bouton clustering. Neuron 84, 332–339 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Perry, V. H. & O'Connor, V. C1q: the perfect complement for a synaptic feast? Nat. Rev. Neurosci. 9, 807–811 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Hajishengallis, G. & Lambris, J. D. Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 31, 154–163 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Le Cabec, V., Carreno, S., Moisand, A., Bordier, C. & Maridonneau-Parini, I. Complement receptor 3 (CD11b/CD18) mediates type I and type II phagocytosis during nonopsonic and opsonic phagocytosis, respectively. J. Immunol. 169, 2003–2009 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Linnartz, B., Kopatz, J., Tenner, A. J. & Neumann, H. Sialic acid on the neuronal glycocalyx prevents complement C1 binding and complement receptor-3-mediated removal by microglia. J. Neurosci. 32, 946–952 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schafer, D. P. et al. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. Elife 5, e15224 (2016).This report linked microglial synaptic pruning to the progression of Rett syndrome.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cahoy, J. D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Low, L. K., Liu, X. B., Faulkner, R. L., Coble, J. & Cheng, H. J. Plexin signaling selectively regulates the stereotyped pruning of corticospinal axons from visual cortex. Proc. Natl Acad. Sci. USA 105, 8136–8141 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Faulkner, R. L., Low, L. K. & Cheng, H. J. Axon pruning in the developing vertebrate hippocampus. Dev. Neurosci. 29, 6–13 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Tremblay, M. E., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).This was the first study to present live microglial-cell–synapse interactions in the brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Espinosa, J. S. & Stryker, M. P. Development and plasticity of the primary visual cortex. Neuron 75, 230–249 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sieger, D., Moritz, C., Ziegenhals, T., Prykhozhij, S. & Peri, F. Long-range Ca2+ waves transmit brain-damage signals to microglia. Dev. Cell 22, 1138–1148 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Haynes, S. E. et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci. 9, 1512–1519 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Sasaki, T. et al. Developmental expression profiles of axon guidance signaling and the immune system in the marmoset cortex: potential molecular mechanisms of pruning of dendritic spines during primate synapse formation in late infancy and prepuberty (I). Biochem. Biophys. Res. Commun. 444, 302–306 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Sasaki, T. et al. Developmental genetic profiles of glutamate receptor system, neuromodulator system, protector of normal tissue and mitochondria, and reelin in marmoset cortex: potential molecular mechanisms of pruning phase of spines in primate synaptic formation process during the end of infancy and prepuberty (II). Biochem. Biophys. Res. Commun. 444, 307–310 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. LaMantia, A. S. & Rakic, P. Axon overproduction and elimination in the corpus callosum of the developing rhesus monkey. J. Neurosci. 10, 2156–2175 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bourgeois, J. P., Goldman-Rakic, P. S. & Rakic, P. Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb. Cortex 4, 78–96 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Perry, V. H., Hume, D. A. & Gordon, S. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15, 313–326 (1985).

    Article  CAS  PubMed  Google Scholar 

  54. Mody, M. et al. Genome-wide gene expression profiles of the developing mouse hippocampus. Proc. Natl Acad. Sci. USA 98, 8862–8867 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Block, M., Zecca, L. & Hong, J. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57–69 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. van Loo, K. M. & Martens, G. J. Genetic and environmental factors in complex neurodevelopmental disorders. Curr. Genomics 8, 429–444 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pierce, K. Early functional brain development in autism and the promise of sleep fMRI. Brain Res. 1380, 162–174 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Sacco, R., Gabriele, S. & Persico, A. M. Head circumference and brain size in autism spectrum disorder: a systematic review and meta-analysis. Psychiatry Res. 234, 239–251 (2015).

    Article  PubMed  Google Scholar 

  59. Redcay, E. & Courchesne, E. When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol. Psychiatry 58, 1–9 (2005).

    Article  PubMed  Google Scholar 

  60. Suzuki, K. et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70, 49–58 (2013).

    Article  PubMed  Google Scholar 

  61. Dinstein, I., Haar, S., Atsmon, S. & Schtaerman, H. No evidence of early head circumference enlargements in children later diagnosed with autism in Israel. Mol. Autism 8, 15 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Raznahan, A. et al. Compared to what? Early brain overgrowth in autism and the perils of population norms. Biol. Psychiatry 74, 563–575 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lewis, J. D., Theilmann, R. J., Townsend, J. & Evans, A. C. Network efficiency in autism spectrum disorder and its relation to brain overgrowth. Front. Hum. Neurosci. 7, 845 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Lewis, J. D. et al. Callosal fiber length and interhemispheric connectivity in adults with autism: brain overgrowth and underconnectivity. Hum. Brain Mapp. 34, 1685–1695 (2013).

    Article  PubMed  Google Scholar 

  65. Dinstein, I. et al. Disrupted neural synchronization in toddlers with autism. Neuron 70, 1218–1225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dichter, G. S. Functional magnetic resonance imaging of autism spectrum disorders. Dialogues Clin. Neurosci. 14, 319–351 (2012).

    PubMed  PubMed Central  Google Scholar 

  67. Barttfeld, P. et al. A big-world network in ASD: dynamical connectivity analysis reflects a deficit in long-range connections and an excess of short-range connections. Neuropsychologia 49, 254–263 (2011).

    Article  PubMed  Google Scholar 

  68. Tang, G. et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83, 1131–1143 (2014).This study revealed excessive synapses in autistic brains and presented a druggable target that is involved in synaptic pruning.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hutsler, J. J. & Zhang, H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 1309, 83–94 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Piochon, C. et al. Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat. Commun. 5, 5586 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Kim, H. J. et al. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol. Psychiatry https://dx.doi.org/10.1038/mp.2016.103 (2016).

  72. Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nardone, S. et al. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry 4, e433 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Miyazaki, S., Hiraoka, Y., Hidema, S. & Nishimori, K. Prenatal minocycline treatment alters synaptic protein expression, and rescues reduced mother call rate in oxytocin receptor-knockout mice. Biochem. Biophys. Res. Commun. 472, 319–323 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Selemon, L. D. & Zecevic, N. Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry 5, e623 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Casey, B. J., Jones, R. M. & Hare, T. A. The adolescent brain. Ann. NY Acad. Sci. 1124, 111–126 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Zhang, Y. et al. Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation. Transl Psychiatry 6, e982 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tomasi, D. & Volkow, N. D. Mapping small-world properties through development in the human brain: disruption in schizophrenia. PLoS ONE 9, e96176 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Alexander-Bloch, A. F. et al. The anatomical distance of functional connections predicts brain network topology in health and schizophrenia. Cereb. Cortex 23, 127–138 (2013).

    Article  PubMed  Google Scholar 

  81. Glantz, L. A. & Lewis, D. A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Kolluri, N., Sun, Z., Sampson, A. R. & Lewis, D. A. Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am. J. Psychiatry 162, 1200–1202 (2005).

    Article  PubMed  Google Scholar 

  83. 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).This classical study revealed that brain development is associated with the formation of superfluous excitatory synapses that are subsequently eliminated.

    Article  CAS  PubMed  Google Scholar 

  84. Bourgeois, J. P. & Rakic, P. Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage. J. Neurosci. 13, 2801–2820 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cocchi, E., Drago, A. & Serretti, A. Hippocampal pruning as a new theory of schizophrenia etiopathogenesis. Mol. Neurobiol. 53, 2065–2081 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. Calabro, M., Drago, A., Sidoti, A., Serretti, A. & Crisafulli, C. Genes involved in pruning and inflammation are enriched in a large mega-sample of patients affected by schizophrenia and bipolar disorder and controls. Psychiatry Res. 228, 945–949 (2015).

    Article  PubMed  Google Scholar 

  87. Bayer, T. A., Buslei, R., Havas, L. & Falkai, P. Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci. Lett. 271, 126–128 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Doorduin, J. et al. Neuroinflammation in schizophrenia-related psychosis: a PET study. J. Nucl. Med. 50, 1801–1807 (2009).

    Article  PubMed  Google Scholar 

  89. Inta, D., Lang, U. E., Borgwardt, S., Meyer-Lindenberg, A. & Gass, P. Microglia activation and schizophrenia: lessons from the effects of minocycline on postnatal neurogenesis, neuronal survival and synaptic pruning. Schizophr. Bull. 43, 493–496 (2016).

    PubMed Central  Google Scholar 

  90. Mayilyan, K. R., Weinberger, D. R. & Sim, R. B. The complement system in schizophrenia. Drug News Perspect. 21, 200–210 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mayilyan, K. R., Dodds, A. W., Boyajyan, A. S., Soghoyan, A. F. & Sim, R. B. Complement C4B protein in schizophrenia. World J. Biol. Psychiatry 9, 225–230 (2008).

    Article  PubMed  Google Scholar 

  92. Severance, E. G., Gressitt, K. L., Buka, S. L., Cannon, T. D. & Yolken, R. H. Maternal complement C1q and increased odds for psychosis in adult offspring. Schizophr. Res. 159, 14–19 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Fananas, L., Moral, P., Panadero, M. A. & Bertranpetit, J. Complement genetic markers in schizophrenia: C3, BF and C6 polymorphisms. Hum. Hered. 42, 162–167 (1992).

    Article  CAS  PubMed  Google Scholar 

  94. Myers, C. T. & Mefford, H. C. Advancing epilepsy genetics in the genomic era. Genome Med. 7, 91 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Eyo, U. B., Murugan, M. & Wu, L. J. Microglia–neuron communication in epilepsy. Glia 65, 5–18 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Zhou, Y. D. et al. Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy. Nat. Med. 15, 1208–1214 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhou, Y. D. et al. Epilepsy gene LGI1 regulates postnatal developmental remodeling of retinogeniculate synapses. J. Neurosci. 32, 903–910 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. van Campen, J. S. et al. Sensory modulation disorders in childhood epilepsy. J. Neurodev Disord. 7, 34 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Head, K. et al. Defining the expression pattern of the LGI1 gene in BAC transgenic mice. Mamm. Genome 18, 328–337 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Chu, Y. et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc. Natl Acad. Sci. USA 107, 7975–7980 (2010).This study demonstrated that impairment of developmental synaptic pruning leads to an epileptic phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ma, Y., Ramachandran, A., Ford, N., Parada, I. & Prince, D. A. Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy. Epilepsia 54, 1232–1239 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Aronica, E. et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiol. Dis. 26, 497–511 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Xu, Y. et al. Altered expression of CX3CL1 in patients with epilepsy and in a rat model. Am. J. Pathol. 180, 1950–1962 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Roseti, C. et al. Fractalkine/CX3CL1 modulates GABAA currents in human temporal lobe epilepsy. Epilepsia 54, 1834–1844 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Ali, I., Chugh, D. & Ekdahl, C. T. Role of fractalkine–CX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain. Neurobiol. Dis. 74, 194–203 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Neher, J. J., Neniskyte, U. & Brown, G. C. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Front. Pharmacol. 3, 27 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tremblay, M. E., Zettel, M. L., Ison, J. R., Allen, P. D. & Majewska, A. K. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60, 541–558 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Arnoux, I. & Audinat, E. Fractalkine signaling and microglia functions in the developing brain. Neural Plast. http://dx.doi.org/10.1155/2015/689404 (2015).

  113. Erturk, A., Wang, Y. & Sheng, M. Local pruning of dendrites and spines by caspase-3-dependent and proteasome-limited mechanisms. J. Neurosci. 34, 1672–1688 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Awasaki, T. & Ito, K. Engulfing action of glial cells is required for programmed axon pruning during Drosophila metamorphosis. Curr. Biol. 14, 668–677 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Marin, E. C., Watts, R. J., Tanaka, N. K., Ito, K. & Luo, L. Developmentally programmed remodeling of the Drosophila olfactory circuit. Development 132, 725–737 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Tasdemir-Yilmaz, O. E. & Freeman, M. R. Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons. Genes Dev. 28, 20–33 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Awasaki, T. et al. Essential role of the apoptotic cell engulfment genes draper and ced-6 in programmed axon pruning during Drosophila metamorphosis. Neuron 50, 855–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Milior, G. et al. Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress. Brain Behav. Immun. 55, 114–125 (2016).

    Article  CAS  PubMed  Google Scholar 

  119. Spiga, S. et al. Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats. Proc. Natl Acad. Sci. USA 111, E3745–E3754 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Shi, Q. et al. Complement C3-deficient mice fail to display age-related hippocampal decline. J. Neurosci. 35, 13029–13042 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Vasek, M. J. et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Iram, T. et al. Megf10 is a receptor for C1Q that mediates clearance of apoptotic cells by astrocytes. J. Neurosci. 36, 5185–5192 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Beisiegel, U., Weber, W., Ihrke, G., Herz, J. & Stanley, K. K. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature 341, 162–164 (1989).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

U.N. has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 705452, International Brain Research Organization Return Home Fellowship, and L'ORÉAL Baltic “For Women In Science” fellowship with the support of the Lithuanian National Commission for the United Nations Educational, Scientific and Cultural Organization (UNESCO) and the Lithuanian Academy of Sciences.

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Authors and Affiliations

  1. Department of Neurobiology and Biophysics, Life Science Center, Vilnius University, Sauletekio al. 7, Vilnius, LT-10257, Lithuania

    Urte Neniskyte

  2. Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), Via Ramarini 32, Monterotondo, 00015, Italy

    Cornelius T. Gross

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  1. Urte Neniskyte
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Contributions

U.N. and C.T.G. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Cornelius T. Gross.

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Neuromuscular junction

(NMJ). A peripheral synapse between one or more motor neurons and the motor endplate on a skeletal muscle fibre.

Receptive fields

Particular regions of a sensory space, such as the visual field, in which a stimulus will modify the firing of an individual sensory neuron.

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A tetracycline antibiotic that has been shown to inhibit inflammatory activation of microglia by blocking the nuclear translocation of the pro-inflammatory transcription factor nuclear factor-κB.

Retinal waves

Spontaneous bursts of action potentials that propagate in a wave-like fashion across the developing retina.

Apolipoprotein E

(APOE). A major cholesterol carrier that is also hypothesized to serve as an opsonin. The APOE*4 allele is a major genetic risk factor for Alzheimer disease.

Opsonin

A protein, such as an antibody or complement protein, that binds to a phagocytic target (such as a pathogen), thus rendering it more susceptible to phagocytosis, in a process known as opsonization.

Archicortex

A phylogenetically old part of the cerebral cortex that constitutes the hippocampal formation.

Synaptic multiplicity

A feature of mature circuits in which afferent inputs make more than one synapse onto a single target neuron.

Window-on-the-brain technology

A technique in which the skull is thinned or opened and capped with a transparent implant to allow two-photon or near-infrared in vivo imaging of cortical function.

Autism spectrum disorder

(ASD). A group of neurodevelopmental conditions characterized by social deficits, impaired language development, intellectual disability, increased repetitive or restrictive behaviours and motor abnormalities.

Peripheral benzodiazepine receptor

Translocator protein (TSPO) of the outer mitochondrial membrane that modulates bursts of reactive oxygen species in macrophages, including microglia, and is therefore used as a marker of inflammation.

Penetrant

Of a mutation, producing expression of associated phenotypic traits in a large proportion of individuals carrying the mutation.

Autophagy

An intracellular self-degradative process for orderly degradation and recycling of cellular components and balancing sources of energy at critical periods.

Microgliosis

An intense inflammatory activation of microglia in response to insults to the CNS (such as infection, trauma or neuronal damage).

Ocular dominance index

The difference between contralateral response and ipsilateral response divided by the sum of contralateral and ipsilateral responses.

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Neniskyte, U., Gross, C. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci 18, 658–670 (2017). https://doi.org/10.1038/nrn.2017.110

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