A new paper published in Nature Neuroscience this week out of Mark Bear’s lab at MIT suggests that a previously identified synaptic deficit in fragile-X syndrome, a neurological disorder commonly associated with autism-related symptoms, may not be specific to fragile-X, but may actually be a more common deficit amongst autism-related disorders. In the study, Tian et al. used a mouse model to study the synaptic pathophysiology associated with a microdeletion of the chromosome 16p11.2 region, a disorder in which patients present with common autistic-like symptoms including language impairment, intellectual disability, and seizures. Interestingly, changes in this chromosomal region actually account for ~1% of autism spectrum disorders (ASD), which is a fairly high percentage for a disorder as heterogenous as autism.
From research over the past decade it has become clear that, though ASD is a heterogenous disorder, the underlying cellular and synaptic deficits may not be so heterogenous. It seems that deficits in synaptic function, formation, maintenance, and/or plasticity underly many genetic disorders commonly associated with autism. Previous work out the of Bear lab has investigated a specific form of plasticity, long-term depression (LTD), in fragile-X models, identifying deficits in this specific form of plasticity in fragile-X neurons. Specifically, the deficits are seen in a form of LTD mediated by a specific receptor, the metabotropic glutamate receptor (mGluR). These deficits have been well studied and targeting this pathway has actually been shown to correct both plasticity and behavioral deficits in mouse models of this disorder, providing a promising therapeutic target for treatment of fragile-X.
With the fragile-X mGluR plasticity deficits in mind, Tian et al. aimed to study this and other forms of plasticity in a mouse model of chromosome 16p11.2 microdeletion. Initial experiments suggested that all three types of plasticity were similar between the mutants and controls. Despite similar plasticity, the authors suspected something may still be awry. Under normal conditions, mGluR-mediated LTD requires protein synthesis, as disrupting this synthesis through drug inhibitors prevents the LTD. It has been previously shown, however, that LTD in a mouse model of fragile-X is unaffected by protein synthesis inhibition, a finding that has been attributed to a baseline elevation of proteins downstream of mGluR. By studying mGluR-mediated plasticity in the 16p11.2 mutants under conditions in which protein synthesis is inhibited, Tian et al. was able to show that LTD in these neurons was also unaffected by this treatment, identifying a specific synaptic deficit that is shared between both fragile-X and chromosome 16p11.2 micro deletion, two disorders with autistic-like features.
Perhaps most importantly, the authors were able to reverse behavioral deficits in the mutant mice using a negative modulator of mGluR5, CTEP, a treatment that has previously been used to rescue behavioral deficits in fragile-X mice. In this set of experiments, Tian et al. used behavior tests of fear conditioning and avoidance, tasks that depend on the hippocampus, a brain structure important for proper memory formation. In these behavioral tests, wild type animals exhibit behaviors such as freezing in response to a foot shock or avoidance of an environmental context that has previously been associated with an aversive stimulus. Such freezing behavior and avoidance are learned by the animals after repeated trials. In the mutant mice, however, learning was impaired in both behavioral tests, as these animals showed less freezing and displayed impairments in avoidance memory acquisition and extinction. Treatment with CTEP helped improve performance on these tasks in the mutant mice.
This paper provides evidence for a common deficit between two mouse models of disorders associated with autism-related symptoms and contributes to the body of literature suggesting that a general synaptic pathophysiology may underlie many of these disorders. Furthermore, deficits in a specific form of plasticity, such as the mGluR-mediated LTD studied here, provides a common signaling pathway that is disrupted in fragile-X and 16p11.2 microdeletion, a pathway that can be targeted to correct behavioral deficits associated with mouse models of these disorders. Importantly, identifying signaling pathways that are disrupted in these disorders provides a variety of therapeutic targets, as many proteins and molecules participate in these pathways at various levels of signaling. It will be interesting to see how treatments for these two disorders develop and which specific proteins, if any, may provide effective therapeutic targets.
Tian, D., Stoppel, L. J., Heynen, A. J., Lindemann, L., Jaeschke, G., Mills, A. A., & Bear, M. F. (2015). Contribution of mGluR5 to pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion. Nature Neuroscience, 18(2), 182–184.
