Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2+/− and Fmr1−/y mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.
This is a preview of subscription content
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.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Newschaffer, C. J. et al. The epidemiology of autism spectrum disorders. Annu. Rev. Public Health 28, 235–258 (2007)
Krueger, D. D. & Bear, M. F. Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu. Rev. Med. 62, 411–429 (2011)
Kelleher, R. J., III & Bear, M. F. The autistic neuron: troubled translation? Cell 135, 401–406 (2008)
Ehninger, D. et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nature Med. 14, 843–848 (2008)
Meikle, L. et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci. 28, 5422–5432 (2008)
Onda, H. et al. Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol. Cell. Neurosci. 21, 561–574 (2002)
Ehninger, D., de Vries, P. J. & Silva, A. J. From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis. J. Intellect. Disabil. Res. 53, 838–851 (2009)
Carbonara, C. et al. 9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. Hum. Mol. Genet. 3, 1829–1832 (1994)
Green, A. J., Smith, M. & Yates, J. R. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nature Genet. 6, 193–196 (1994)
de Vries, P. J. & Howe, C. J. The tuberous sclerosis complex proteins–a GRIPP on cognition and neurodevelopment. Trends Mol. Med. 13, 319–326 (2007)
Goorden, S. M., van Woerden, G. M., van der Weerd, L., Cheadle, J. P. & Elgersma, Y. Cognitive deficits in Tsc1+/− mice in the absence of cerebral lesions and seizures. Ann. Neurol. 62, 648–655 (2007)
Cheadle, J. P., Reeve, M. P., Sampson, J. R. & Kwiatkowski, D. J. Molecular genetic advances in tuberous sclerosis. Hum. Genet. 107, 97–114 (2000)
Onda, H., Lueck, A., Marks, P. W., Warren, H. B. & Kwiatkowski, D. J. Tsc2+/− mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J. Clin. Invest. 104, 687–695 (1999)
Nie, D. et al. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nature Neurosci. 13, 163–172 (2010)
Young, D. M., Schenk, A. K., Yang, S. B., Jan, Y. N. & Jan, L. Y. Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism. Proc. Natl Acad. Sci. USA 107, 11074–11079 (2010)
Hoeffer, C. A. & Klann, E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67–75 (2010)
Sharma, A. et al. Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 30, 694–702 (2010)
Huber, K. M., Kayser, M. S. & Bear, M. F. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288, 1254–1257 (2000)
Huber, K. M., Roder, J. C. & Bear, M. F. Chemical induction of mGluR5- and protein synthesis–dependent long-term depression in hippocampal area CA1. J. Neurophysiol. 86, 321–325 (2001)
Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746–7750 (2002)
Bear, M. F., Huber, K. M. & Warren, S. T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004)
Gallagher, S. M., Daly, C. A., Bear, M. F. & Huber, K. M. Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor-dependent long-term depression in hippocampal area CA1. J. Neurosci. 24, 4859–4864 (2004)
Osterweil, E. K., Krueger, D. D., Reinhold, K. & Bear, M. F. 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)
Fitzjohn, S. M. et al. A characterisation of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro. J. Physiol. 537, 421–430 (2001)
Nosyreva, E. D. & Huber, K. M. Developmental switch in synaptic mechanisms of hippocampal metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 25, 2992–3001 (2005)
Mockett, B. G. et al. Calcium/calmodulin-dependent protein kinase II mediates group I metabotropic glutamate receptor-dependent protein synthesis and long-term depression in rat hippocampus. J. Neurosci. 31, 7380–7391 (2011)
Luscher, C. & Huber, K. M. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65, 445–459 (2010)
Snyder, E. M. et al. Internalization of ionotropic glutamate receptors in response to mGluR activation. Nature Neurosci. 4, 1079–1085 (2001)
Waung, M. W., Pfeiffer, B. E., Nosyreva, E. D., Ronesi, J. A. & Huber, K. M. Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 59, 84–97 (2008)
Park, S. 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)
Dolen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007)
Conn, P. J., Christopoulos, A. & Lindsley, C. W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nature Rev. Drug Discov. 8, 41–54 (2009)
Kinney, G. G. et al. A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J. Pharmacol. Exp. Ther. 313, 199–206 (2005)
Frankland, P. W., Cestari, V., Filipkowski, R. K., McDonald, R. J. & Silva, A. J. The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav. Neurosci. 112, 863–874 (1998)
Lu, Y. M. et al. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 17, 5196–5205 (1997)
Stiedl, O., Palve, M., Radulovic, J., Birkenfeld, K. & Spiess, J. Differential impairment of auditory and contextual fear conditioning by protein synthesis inhibition in C57BL/6N mice. Behav. Neurosci. 113, 496–506 (1999)
Bassell, G. J. & Warren, S. T. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60, 201–214 (2008)
Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011)
Dolen, G., Carpenter, R. L., Ocain, T. D. & Bear, M. F. Mechanism-based approaches to treating fragile X. Pharmacol. Ther. 127, 78–93 (2010)
Narayanan, U. et al. S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade. J. Biol. Chem. 283, 18478–18482 (2008)
Fombonne, E. Epidemiological surveys of autism and other pervasive developmental disorders: an update. J. Autism Dev. Disord. 33, 365–382 (2003)
Ramocki, M. B. & Zoghbi, H. Y. Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455, 912–918 (2008)
Krueger, D. D., Osterweil, E. K. & Bear, M. F. Activation of mGluR5 induces rapid and long-lasting protein kinase D phosphorylation in hippocampal neurons. J. Mol. Neurosci. 42, 1–8 (2010)
Bateup, H. S., Takasaki, K. T., Saulnier, J. L., Denefrio, C. L. & Sabatini, B. L. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J. Neurosci. 31, 8862–8869 (2011)
This work was partly supported by grants from the National Institute of Mental Health (T32 MH-082718 and T32-MH-074249), the National Institute of Child Health and Human Development (2R01HD046943), the Department of Defense (W81XWH-11-1-0252) and The Simons Foundation. We acknowledge A. Heynen for advice and comments, as well as K. Oram, E. Sklar and S. Meagher for technical and administrative assistance. Monoclonal Arc antibody was a gift from P. Worley.
M.F.B. has a financial interest in Seaside Therapeutics, Inc.
About this article
Cite this article
Auerbach, B., Osterweil, E. & Bear, M. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011). https://doi.org/10.1038/nature10658
Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling
Molecular Psychiatry (2022)
Nature Communications (2022)
Molecular Neurodegeneration (2021)
Cell & Bioscience (2021)
mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity
Nature Communications (2021)