Picower Institute researchers demonstrate that different genetic causes of autism and intellectual disability can respond to the same treatment
Several inherited genetic disorders lead to intellectual disability and autism spectrum conditions. For many years these disorders were considered largely untreatable, but recent work in animal models has shown that some debilitating effects of specific gene mutations can be reversed. A central unanswered question, however, has been whether distinct genetic mutations disrupt common synaptic and cellular processes. If different mutations converge on the same physiological pathways, then therapies developed for one genetic form of autism or intellectual disability could potentially benefit others.
In a study published in Nature Neuroscience, a team led by Mark Bear, Picower Professor of Neuroscience at MIT’s Picower Institute for Learning and Memory, reports that two very different genetic causes of autism and intellectual disability both disturb protein synthesis at synapses. Importantly, a treatment originally developed to address one disorder produced measurable cognitive improvement in the other. The research was conducted by postdoctoral fellow Di Tian (lead author), graduate student Laura Stoppel, and research scientist Arnold Heynen, in collaboration with colleagues at Cold Spring Harbor Laboratory and scientists at Roche Pharmaceuticals.
Investigating fragile X syndrome and synaptic protein synthesis
Fragile X syndrome is a well-characterized, heritable cause of intellectual disability and autism that results when the FMR1 gene on the X chromosome is silenced during development. Although fragile X is relatively rare—occurring in roughly one in 4,000 people—studies using mouse models have revealed key molecular changes associated with the disorder. Prior research from Bear’s laboratory and others demonstrated that loss of FMR1 leads to excessive protein synthesis at synapses, the specialized junctions where neurons communicate.
Crucially, this excessive protein synthesis is driven by glutamate signaling acting through a specific receptor subtype, mGluR5. These findings inspired the “mGluR theory,” which proposes that exaggerated protein production downstream of mGluR5 activation contributes to many of the neurological and behavioral symptoms of fragile X. In mouse experiments, pharmacological inhibition of mGluR5 rebalanced synaptic protein synthesis and rescued multiple functional deficits.
Converging consequences from distinct genetic lesions
Another genetic cause of autism and intellectual disability is the 16p11.2 microdeletion, a chromosomal deletion that removes a cluster of genes on human chromosome 16. The 16p11.2 region includes genes implicated in the regulation of protein synthesis, prompting the hypothesis that this microdeletion might impair synaptic function in ways similar to fragile X. To test this, the team evaluated a mouse model of the 16p11.2 microdeletion developed by Alea Mills at Cold Spring Harbor Laboratory.
Using electrophysiological recordings, biochemical assays, and behavioral testing, the MIT researchers compared synaptic function in the 16p11.2 deletion mice to what had already been established in fragile X models. Their experiments revealed disrupted protein synthesis at hippocampal synapses, a brain region essential for learning and memory. Behaviorally, the 16p11.2 mice showed pronounced memory impairments that paralleled deficits observed in fragile X mice, indicating a common functional consequence despite different genetic origins.
Therapeutic restoration of cognitive function after development
Encouraged by the shared synaptic phenotype, the researchers treated the 16p11.2 mice with an mGluR5 inhibitor—the same pharmacological approach that had shown benefit in fragile X models. This compound, provided by a Roche team led by Lothar Lindemann, produced a substantial improvement in memory and cognitive performance in the 16p11.2 mice. Notably, the beneficial effects were observed after a one-month course of treatment initiated well after birth, demonstrating that some cognitive impairments previously attributed to irreversible early developmental disruption may instead result from ongoing aberrant synaptic signaling and therefore be amenable to later intervention.
These results carry important implications for autism and intellectual disability research and therapeutic development. More than 100 different gene mutations have now been linked to intellectual disability and autism, and the current findings suggest that genetically distinct disorders can share convergent synaptic mechanisms. Consequently, drug therapies designed to correct those shared mechanisms—such as excessive synaptic protein synthesis triggered by mGluR5—might have broader applicability across multiple genetic forms of autism and cognitive impairment.
This work received support from the Howard Hughes Medical Institute, the National Institute of Mental Health, the Simons Foundation, the Simons Center for the Social Brain at MIT, and the National Institute of Child Health and Human Development.
Contact: Press Office – Picower Institute for Learning and Memory, MIT
Source: Picower Institute for Learning and Memory/MIT press release
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Original Research: Abstract for “Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion” by Di Tian, Laura J. Stoppel, Arnold J. Heynen, Lothar Lindemann, Georg Jaeschke, Alea A. Mills, and Mark F. Bear, published in Nature Neuroscience. Published online January 12, 2014. doi:10.1038/nn.3911