Review

Activity-dependent neuronal signalling and autism spectrum disorder

Received:
Accepted:
Published online:

Abstract

Neuronal activity induces the post-translational modification of synaptic molecules, promotes localized protein synthesis within dendrites and activates gene transcription, thereby regulating synaptic function and allowing neuronal circuits to respond dynamically to experience. Evidence indicates that many of the genes that are mutated in autism spectrum disorder are crucial components of the activity-dependent signalling networks that regulate synapse development and plasticity. Dysregulation of activity-dependent signalling pathways in neurons may, therefore, have a key role in the aetiology of autism spectrum disorder.

  • Subscribe to Nature for full access:

    $199

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    et al. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 368, 210–215 (2006).

  2. 2.

    & Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4, a009886 (2012).

  3. 3.

    & Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563–590 (2008).

  4. 4.

    & Advances in autism genetics: on the threshold of a new neurobiology. Nature Rev. Genet. 9, 341–355 (2008).

  5. 5.

    & The conundrums of understanding genetic risks for autism spectrum disorders. Nature Neurosci. 14, 1499–1506 (2011).

  6. 6.

    & CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148, 1223–1241 (2012).

  7. 7.

    et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).

  8. 8.

    et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).

  9. 9.

    et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genet. 43, 585–589 (2011).

  10. 10.

    et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012). References 7–10 demonstrate the ability of new sequencing technologies to significantly advance our understanding of the genetic basis of ASD.

  11. 11.

    The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

  12. 12.

    & From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59, 846–860 (2008).

  13. 13.

    & The autistic neuron: troubled translation? Cell 135, 401–406 (2008).

  14. 14.

    Postnatal development of the visual cortex and the influence of environment. Nature 299, 583–591 (1982).

  15. 15.

    & Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Annu. Rev. Cell Dev. Biol. 24, 183–209 (2008).

  16. 16.

    , & Synaptic cell adhesion. Cold Spring Harb. Perspect. Biol. 4, a005694 (2012).

  17. 17.

    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).

  18. 18.

    et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001).

  19. 19.

    & The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 3, a005678 (2011).

  20. 20.

    & NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb. Perspect. Biol. 4, a005710 (2012).

  21. 21.

    , & A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication. Nature Neurosci. 4, 565–566 (2001).

  22. 22.

    & LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

  23. 23.

    , & The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012).

  24. 24.

    , & Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. Science 260, 181–186 (1993).

  25. 25.

    , , , & Signaling to the nucleus by an L-type calcium channel–calmodulin complex through the MAP kinase pathway. Science 294, 333–339 (2001).

  26. 26.

    et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012 (2006).

  27. 27.

    , & Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science 234, 80–83 (1986).

  28. 28.

    et al. Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 455, 1198–1204 (2008).

  29. 29.

    et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60, 1022–1038 (2008).

  30. 30.

    , & A biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition. Neuron 60, 610–624 (2008).

  31. 31.

    et al. CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004).

  32. 32.

    et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011).

  33. 33.

    et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).

  34. 34.

    et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008). This paper provides evidence for the hypothesis that genetic mutations associated with ASD may disrupt activity-dependent gene expression programs.

  35. 35.

    et al. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet. 8, e1002635 (2012).

  36. 36.

    et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).

  37. 37.

    Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008).

  38. 38.

    et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007).

  39. 39.

    , , , & An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. 30, 2908–2919 (2011).

  40. 40.

    , , & Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl Acad. Sci. USA 106, 17998–18003 (2009).

  41. 41.

    et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54, 919–931 (2007). This study reports the crucial role for neuroligins in activity-dependent synapse maturation and how this pathway is dysregulated by ASD-associated mutations in neuroligin.

  42. 42.

    et al. Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals. Proc. Natl Acad. Sci. USA 105, 9087–9092 (2008).

  43. 43.

    et al. Neurexin-neuroligin transsynaptic interaction mediates learning-related synaptic remodeling and long-term facilitation in Aplysia. Neuron 70, 468–481 (2011). Using the Aplysia model, this study demonstrates that the neurexin–neuroligin interaction regulates activity-dependent synaptic development and plasticity, a process that is dysregulated by an ASD-associated mutation in neuroligin.

  44. 44.

    & Imaging activity-dependent regulation of neurexin-neuroligin interactions using trans-synaptic enzymatic biotinylation. Cell 143, 456–469 (2010).

  45. 45.

    et al. SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell 147, 1601–1614 (2011).

  46. 46.

    et al. SHANK1 deletions in males with autism spectrum disorder. Am. J. Hum. Genet. 90, 879–887 (2012).

  47. 47.

    et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011).

  48. 48.

    et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012).

  49. 49.

    et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 (2012). References 47–49 demonstrate the role of Shanks in regulating excitatory neurotransmission.

  50. 50.

    Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nature Neurosci. 6, 231–242 (2003).

  51. 51.

    & Deconstruction for reconstruction: the role of proteolysis in neural plasticity and disease. Neuron 69, 22–32 (2011).

  52. 52.

    , , & Degradation of postsynaptic scaffold GKAP and regulation of dendritic spine morphology by the TRIM3 ubiquitin ligase in rat hippocampal neurons. PLoS ONE 5, e9842 (2010).

  53. 53.

    et al. Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319, 1253–1256 (2008).

  54. 54.

    et al. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112, 317–327 (2003).

  55. 55.

    , , & Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746–7750 (2002).

  56. 56.

    , & The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004).

  57. 57.

    , , & Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J. Neurosci. 30, 15616–15627 (2010).

  58. 58.

    et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007).

  59. 59.

    et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59, 70–83 (2008).

  60. 60.

    , , , & Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 59, 84–97 (2008).

  61. 61.

    , & Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression. J. Neurosci. 32, 5924–5936 (2012).

  62. 62.

    et al. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron 51, 441–454 (2006).

  63. 63.

    et al. Critical period plasticity is disrupted in the barrel cortex of Fmr1 knockout mice. Neuron 65, 385–398 (2010).

  64. 64.

    et al. Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66, 191–197 (2010).

  65. 65.

    et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc. Natl Acad. Sci. USA 105, 9391–9396 (2008).

  66. 66.

    et al. Cocaine regulates MEF2 to control synaptic and behavioral plasticity. Neuron 59, 621–633 (2008).

  67. 67.

    & TSC1/TSC2 signaling in the CNS. FEBS Lett. 585, 973–980 (2011).

  68. 68.

    & A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273, 1402–1406 (1996).

  69. 69.

    et al. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nature Med. 14, 843–848 (2008).

  70. 70.

    & PTEN signaling in autism spectrum disorders. Curr. Opin. Neurobiol. 22, 873–879 (2012).

  71. 71.

    , & Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011). This paper shows that loss of function of either TSC1–TSC2 or FMRP disrupts activity-regulated mRNA translation and synaptic plasticity in opposite directions.

  72. 72.

    , , , & Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J. Neurosci. 31, 8862–8869 (2011).

  73. 73.

    et al. Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum. Mol. Genet. 12, 3295–3305 (2003).

  74. 74.

    et al. FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A. J. Neurosci. 27, 14349–14357 (2007).

  75. 75.

    et al. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Mol. Cell 42, 673–688 (2011).

  76. 76.

    et al. CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Prog. Neurobiol. 99, 1–14 (2012).

  77. 77.

    & The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels. Proc. Natl Acad. Sci. USA 105, 2157–2162 (2008).

  78. 78.

    et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nature Med. 17, 1657–1662 (2011).

  79. 79.

    et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010).

  80. 80.

    et al. Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72, 72–85 (2011). This paper demonstrates the importance of activity-dependent regulation of MECP2 in the control of synapse development and behaviour.

  81. 81.

    et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003).

  82. 82.

    et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269 (2006).

  83. 83.

    et al. MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants. Nature Neurosci. 13, 1128–1136 (2010).

  84. 84.

    , , , & Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory. Nature Neurosci. 14, 1001–1008 (2011).

  85. 85.

    , , , & Experience-dependent retinogeniculate synapse remodeling is abnormal in MeCP2-deficient mice. Neuron 70, 35–42 (2011).

  86. 86.

    et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 102, 12560–12565 (2005).

  87. 87.

    , & MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65 (2007).

  88. 88.

    et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319–327 (2006).

  89. 89.

    et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc. Cell 140, 704–716 (2010). This study provides insight into the molecular mechanisms underlying Angelman syndrome and the role of neuronal activity in regulating UBE3A and its targets.

  90. 90.

    et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21, 799–811 (1998).

  91. 91.

    et al. Ube3a is required for experience-dependent maturation of the neocortex. Nature Neurosci. 12, 777–783 (2009).

  92. 92.

    , , & Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects. Neuron 74, 793–800 (2012).

  93. 93.

    et al. High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. PLoS ONE 7, e35003 (2012).

  94. 94.

    et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010).

  95. 95.

    , , , & Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004).

  96. 96.

    , , , & Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007).

  97. 97.

    , , & Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc. Natl Acad. Sci. USA 104, 1931–1936 (2007).

  98. 98.

    et al. Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of αCaMKII inhibitory phosphorylation. Nature Neurosci. 10, 280–282 (2007).

Download references

Acknowledgements

M.E.G. is supported by NIH grant RO1NS048276 and the Rett Syndrome Research Trust. D.H.E. is supported by NIH grant K08MH90306.

Author information

Affiliations

  1. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Daniel H. Ebert
    •  & Michael E. Greenberg
  2. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Daniel H. Ebert

Authors

  1. Search for Daniel H. Ebert in:

  2. Search for Michael E. Greenberg in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael E. Greenberg.

Reprints and permissions information is available at www.nature.com/reprints.