Mutations causing syndromic autism define an axis of synaptic pathophysiology

Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nature (Impact Factor: 41.46). 11/2011; 480(7375):63-8. DOI: 10.1038/nature10658
Source: PubMed


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.

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Available from: Emily K Osterweil, Mar 19, 2014
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    • "Rheb overexpression increased the viability of the HEK293 cells in an MTS ([3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]; inner salt) assay (which measures mitochondrial activity), but it did not significantly alter the cell number (counted using a hemocytometer ) (Figure S2). In TSC2 depleted fibroblasts, which possess high Rheb–mTOR activity (Inoki et al., 2003; Zhang et al., 2003), we observe diminished protein synthesis (Figure 1E), consistent with previous report compared to TSC2 intact cells (Auerbach et al., 2011). TSC2 depleted fibroblasts also exhibited reduced polysome/monosome ratio (Figure 1F) and diminished cell numbers, compared to TSC2 intact cells (Figure S3). "

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    • "Whilst mGluR5 has been implicated in ASD pathogenesis, controversy exists as to whether mGluR5 signalling is increased or decreased in the brains of individuals with ASD, with evidence for the use of drugs to potentiate or inhibit this receptor having therapeutic potential (Carlson, 2012). With respect to potentiation of mGluR5 signalling being beneficial to symptoms associated with ASD, it has been demonstrated that a positive allosteric modulator (PAM) of mGluR5, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) corrected synaptic and biochemical defects in the hippocampus of tuberous sclerosis 2 (Tsc2 +/À ) mutant mice, as well as restoring cognitive deficits present in these mice (Auerbach et al., 2011). MGluR5 also has a strong interaction with N-methyl-D-aspartate (NMDA) receptors causing enhancement of NMDAR signalling (Benquet et al., 2002). "
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    ABSTRACT: Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, while activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p = 0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p = 0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 06/2015; 49. DOI:10.1016/j.bbi.2015.05.009 · 5.89 Impact Factor
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    • "While investigating the relationships between Tsc2+/À and Fmr1À/y mouse phenotypes , Bear and colleagues made the surprising finding that Tsc2+/À mice had reduced protein synthesis in the hippocampus . Fmr1À/y;Tsc2+/À double mutants demonstrated normalization in hippocampal mGluR-LTD, protein synthesis rates, and cognitive behaviors, suggesting that FMRP and TSC1/2 balance one another (Auerbach et al., 2011). Whether this interaction occurs in other regions of the brain is not clear, and the biochemical events that might mediate such a relationship have not yet been determined. "
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    ABSTRACT: The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.
    Neuron 10/2014; 84(2):275-291. DOI:10.1016/j.neuron.2014.09.034 · 15.05 Impact Factor
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