Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

References

  1. 1

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 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. 12

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 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. 14

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 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.

    CAS  Article  Google Scholar 

  17. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

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

    Article  Google Scholar 

  22. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 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).

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 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).

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

  31. 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).

    CAS  Article  Google Scholar 

  32. 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  Google Scholar 

  33. 33

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

    CAS  Article  Google Scholar 

  34. 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).

    CAS  Article  Google Scholar 

  35. 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. 36

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

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

    CAS  Article  Google Scholar 

  38. 38

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 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).

    CAS  Article  Google Scholar 

  40. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 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. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 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).

    CAS  Article  Google Scholar 

  44. 44

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

    CAS  Article  Google Scholar 

  45. 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. 46

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 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).

    CAS  Article  Google Scholar 

  48. 48

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

    CAS  Article  Google Scholar 

  49. 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).

    CAS  Article  Google Scholar 

  50. 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).

    CAS  Article  Google Scholar 

  51. 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).

    CAS  Article  Google Scholar 

  52. 52

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

    CAS  Article  Google Scholar 

  53. 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).

    CAS  Article  Google Scholar 

  54. 54

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

    CAS  Article  Google Scholar 

  55. 55

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

    CAS  Article  Google Scholar 

  56. 56

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

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

    CAS  Article  Google Scholar 

  58. 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  Google Scholar 

  59. 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  Google Scholar 

  60. 60

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

    Article  Google Scholar 

  61. 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. 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. 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. 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  Google Scholar 

  65. 65

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 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. 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  Google Scholar 

  68. 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

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

    CAS  Article  Google Scholar 

  70. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 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. 72

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 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).

    CAS  Article  Google Scholar 

  75. 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).

    CAS  Article  Google Scholar 

  76. 76

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

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

    CAS  Article  Google Scholar 

  78. 78

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 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. 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  Google Scholar 

  81. 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).

    CAS  Article  Google Scholar 

  82. 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  Google Scholar 

  83. 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.

    CAS  Article  Google Scholar 

  84. 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).

    CAS  Article  Google Scholar 

  85. 85

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

    CAS  Article  Google Scholar 

  86. 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  Google Scholar 

  87. 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).

    CAS  Article  Google Scholar 

  88. 88

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

    Article  Google Scholar 

  89. 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  PubMed Central  Google Scholar 

  90. 90

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 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  Google Scholar 

  92. 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. 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).

    CAS  Article  Google Scholar 

  94. 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. 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. 96

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 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. 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. 99

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

    CAS  Article  Google Scholar 

  100. 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.

    CAS  Article  Google Scholar 

  101. 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. 102

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

    CAS  Article  Google Scholar 

  103. 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).

    CAS  Article  Google Scholar 

  104. 104

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

    CAS  Article  Google Scholar 

  105. 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).

    CAS  Article  Google Scholar 

  106. 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. 107

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

    CAS  Article  Google Scholar 

  108. 108

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

    CAS  Article  Google Scholar 

  109. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 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. 111

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 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. 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).

    CAS  Article  Google Scholar 

  114. 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).

    CAS  Article  Google Scholar 

  115. 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).

    CAS  Article  Google Scholar 

  116. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 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).

    CAS  Article  Google Scholar 

  118. 118

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

    CAS  Article  Google Scholar 

  119. 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).

    CAS  Article  Google Scholar 

  120. 120

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 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).

    CAS  Article  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

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.

Topographic mappings

Ordered projections of a sensory surface, such as the retina, to one or more structures of the central nervous system (such as the lateral geniculate nucleus and the visual cortex).

Climbing fibres

Axons of inferior olivary neurons that form excitatory synapses with Purkinje cells in the cerebellum.

Bergmann glia

Radial astrocytes in the cerebellar cortex that are involved in early cerebellar development, glutamate diffusion control, synaptogenesis and synaptic pruning.

Minocycline

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing