Failure of normal brain development leads to mental retardation or autism in about 3% of children. Many genes integral to pathways by which synaptic modification and the remodelling of neuronal networks mediate cognitive and social development have been identified, usually through loss of function. Evidence is accumulating, however, that either loss or gain of molecular functions can be deleterious to the nervous system. Copy-number variation, regulation of gene expression by non-coding RNAs and epigenetic changes are all mechanisms by which altered gene dosage can cause the failure of neuronal homeostasis.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Verkerk, A. J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).
Garber, K., Smith, K. T., Reines, D. & Warren, S. T. Transcription, translation and fragile X syndrome. Curr. Opin. Genet. Dev. 16, 270–275 (2006).
Comery, T. A. et al. Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc. Natl Acad. Sci. USA 94, 5401–5404 (1997).
Peier, A. M. et al. (Over) correction of FMR1 deficiency with YAC transgenics: behavioral and physical features. Hum. Mol. Genet. 9, 1145–1159 (2000).
Brown, V. et al. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107, 477–487 (2001).
Darnell, J. C. et al. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 107, 489–499 (2001).
Bear, M. F., Huber, K. M. & Warren, S. T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004).
Dolen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007). This paper provides genetic evidence that supports the mGluR theory of fragile X pathogenesis and proposes a potential therapeutic strategy.
Nakamoto, M. et al. Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proc. Natl Acad. Sci. USA 104, 15537–15542 (2007).
Muddashetty, R. S., Kelic, S., Gross, C., Xu, M. & Bassell, G. J. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. J. Neurosci. 27, 5338–5348 (2007). This paper provides a mechanism underlying abnormal AMPA-receptor surface expression in excitatory synapses in fragile X syndrome and suggests that the key principle responsible for fragile X syndrome is that synaptic activation cannot stimulate the additional local protein synthesis necessary for synaptic plasticity to occur.
Yan, Q. J., Rammal, M., Tranfaglia, M. & Bauchwitz, R. P. Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49, 1053–1066 (2005).
McBride, S. M. et al. Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron 45, 753–764 (2005).
Kobrynski, L. J. & Sullivan, K. E. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet 370, 1443–1452 (2007).
Gothelf, D. et al. Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am. J. Psychiatry 164, 663–669 (2007).
Lee, J. A. & Lupski, J. R. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52, 103–121 (2006).
Ensenauer, R. E. et al. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am. J. Hum. Genet. 73, 1027–1040 (2003).
Yobb, T. M. et al. Microduplication and triplication of 22q11.2: a highly variable syndrome. Am. J. Hum. Genet. 76, 865–876 (2005).
Paylor, R. et al. Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proc. Natl Acad. Sci. USA 103, 7729–7734 (2006).
Long, J. M. et al. Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. Neurogenetics 7, 247–257 (2006).
Yagi, H. et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 362, 1366–1373 (2003).
Hiroi, N. et al. A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice. Proc. Natl Acad. Sci. USA 102, 19132–19137 (2005).
Paterlini, M. et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nature Neurosci. 8, 1586–1594 (2005).
Stark, K. L. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nature Genet. 40, 751–760 (2008). This paper suggests a novel pathophysiological mechanism for the cognitive and psychiatric phenotypes observed in the human 22q11.2 deletion syndrome: abnormal miRNA biogenesis.
Lalande, M. & Calciano, M. A. Molecular epigenetics of Angelman syndrome. Cell Mol. Life Sci. 64, 947–960 (2007).
Battaglia A. The inv dup(15) or idic(15) syndrome: a clinically recognisable neurogenetic disorder. Brain Dev. 27, 365–369 (2005).
Sahoo, T. et al. Prader–Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nature Genet. 40, 719–721 (2008). This paper confirms the cause of PWS — deficiency of non-coding RNA molecules important for normal RNA processing — and suggests a novel role for snoRNAs in cognitive and psychiatric disease.
Miura, K. et al. Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiol. Dis. 9, 149–159 (2002).
Gallagher, R. C., Pils, B., Albalwi, M. & Francke, U. Evidence for the role of PWCR1/HBII-85 C/D box small nucleolar RNAs in Prader–Willi syndrome. Am. J. Hum. Genet. 71, 669–678 (2002).
Ding, F. et al. SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice. PLoS ONE 3, e1709 (2008).
Elsea, S. H. & Girirajan, S. Smith–Magenis syndrome. Eur. J. Hum. Genet. 16, 412–421 (2008).
Girirajan, S. et al. How much is too much? Phenotypic consequences of Rai1 overexpression in mice. Eur. J. Hum. Genet. 16, 941–954 (2008).
Smith, A. C. et al. Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am. J. Med. Genet. 24, 393–414 (1986).
Chen, K. S. et al. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nature Genet. 17, 154–163 (1997).
Slager, R. E., Newton, T. L., Vlangos, C. N., Finucane, B. & Elsea, S. H. Mutations in RAI1 associated with Smith–Magenis syndrome. Nature Genet. 33, 466–468 (2003).
Imai, Y. et al. Cloning of a retinoic acid-induced gene, GT1, in the embryonal carcinoma cell line P19: neuron-specific expression in the mouse brain. Brain Res. Mol. Brain Res. 31, 1–9 (1995).
Bi, W. et al. Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith–Magenis syndrome. Hum. Genet. 115, 515–524 (2004).
Bi, W. et al. Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith–Magenis syndrome. Hum. Mol. Genet. 14, 983–995 (2005).
Bi, W. et al. Rai1 deficiency in mice causes learning impairment and motor dysfunction, whereas Rai1 heterozygous mice display minimal behavioral phenotypes. Hum. Mol. Genet. 16, 1802–1813 (2007).
Potocki, L. et al. Molecular mechanism for duplication 17p11.2 — the homologous recombination reciprocal of the Smith–Magenis microdeletion. Nature Genet. 24, 84–87 (2000).
Potocki, L. et al. Characterization of Potocki–Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am. J. Hum. Genet. 80, 633–649 (2007).
Walz, K., Paylor, R., Yan, J., Bi, W. & Lupski, J. R. Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). J. Clin. Invest. 116, 3035–3041 (2006).
Moretti, P. & Zoghbi, H. Y. MeCP2 dysfunction in Rett syndrome and related disorders. Curr. Opin. Genet. Dev. 16, 276–281 (2006).
Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).
Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999).
del Gaudio, D. et al. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet. Med. 8, 784–792 (2006).
Van Esch, H. et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 77, 442–453 (2005).
Meins, M. et al. Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. J. Med. Genet. 42, e12 (2005).
Friez, M. J. et al. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics 118, e1687–e1695 (2006).
Smyk, M. et al. Different-sized duplications of Xq28, including MECP2, in three males with mental retardation, absent or delayed speech, and recurrent infections. Am. J. Med. Genet. B 147B, 799–806 (2008).
Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nature Genet. 27, 322–326 (2001).
Collins, A. L. et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum. Mol. Genet. 13, 2679–2689 (2004).
Samaco, R. C. et al. A partial loss of function allele of methyl-CpG-binding protein predicts a human neurodevelopmental syndrome. Hum. Mol. Genet. 17, 1718–1727 (2008).
Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).
Yasui, D. H. et al. Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc. Natl Acad. Sci. USA 104, 19416–19421 (2007).
Chao, H.-T., Zoghbi, H. & Rosenmund, C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65 (2007). This paper provides evidence that either loss or gain of MeCP2 alters excitatory synaptic function, leading to overlapping abnormal neurological phenotypes.
Zhou, Z. et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269 (2006).
Martinowich, K. et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302, 890–893 (2003).
McGill, B. E. et al. Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 103, 18267–18272 (2006).
Bourgeron, T. The possible interplay of synaptic and clock genes in autism spectrum disorders. Cold Spring Harb. Symp. Quant. Biol. 72, 645–654 (2007).
Berg, J. S. et al. Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams–Beuren syndrome region. Genet. Med. 9, 427–441 (2007).
Somerville, M. J. et al. Severe expressive-language delay related to duplication of the Williams–Beuren locus. N. Engl. J. Med. 353, 1694–1701 (2005).
Torniero, C. et al. Cortical dysplasia of the left temporal lobe might explain severe expressive-language delay in patients with duplication of the Williams–Beuren locus. Eur. J. Hum. Genet. 15, 62–67 (2007).
Ewart, A. K. et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nature Genet. 5, 11–16 (1993).
Tassabehji, M. Williams–Beuren syndrome: a challenge for genotype–phenotype correlations. Hum. Mol. Genet. 12 (special no. 2), R229–R237 (2003).
Zhao, C. et al. Hippocampal and visuospatial learning defects in mice with a deletion of frizzled 9, a gene in the Williams syndrome deletion interval. Development 132, 2917–2927 (2005).
Hoogenraad, C. C. et al. Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nature Genet. 32, 116–127 (2002).
Meng, Y. et al. Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35, 121–133 (2002).
Heredia, L. et al. Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid β-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer's disease. J. Neurosci. 26, 6533–6542 (2006).
Lim, M. K. et al. Parkin interacts with LIM kinase 1 and reduces its cofilin-phosphorylation activity via ubiquitination. Exp. Cell Res. 313, 2858–2874 (2007).
In memory of our mentor, Ralph D. Feigin. We are grateful to C. Rosenmund for careful reading of the manuscript, discussions and helping us to articulate our hypothesis. We are indebted to the Howard Hughes Medical Institute, the National Institute of Neurological Disorders and Stroke (grant number 1R01 NS057819-01 to H.Y.Z., and grant numbers T32 NS43124 and 1K08 NS062711-01 to M.B.R.) and the Simons Foundation for supporting our research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors declare no competing financial interests.
Reprints and permissions information is available at http://www.nature.com/reprints.
Correspondence should be addressed to the authors (firstname.lastname@example.org; email@example.com).
About this article
Frontiers in Neuroendocrinology (2019)
Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2
Cerebral Cortex (2019)
Cerebral Cortex (2019)
International Journal of Developmental Neuroscience (2019)
Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models