R&D News: Tuberous sclerosis is caused by the opposite malfunction
Most cases of autism are not caused by a single genetic mutation. However, several disorders with autism-like symptoms, including the rare Fragile X syndrome, can be traced to a specific mutation.
Though the findings might seem counterintuitive, they fit into the theory that autism can be caused by a wide range of brain-synapse glitches, Mr Bear says.
Furthermore, the study suggests that any potential drugs developed to treat the cellular origins of autism would need to be carefully matched to the patient to ensure they do more good than harm. Drugs developed to treat Fragile X syndrome have shown encouraging results in human studies and are currently in Phase III clinical trials.
Mr Bear did not set out to study autism or Fragile X syndrome, but ended up discovering how Fragile X develops through his studies of a receptor found on the surface of neurons.
That receptor, known as mGluR5, plays an important role in transmitting signals between two neurons at a synapse (known as the presynaptic and postsynaptic neurons). When the presynaptic cell releases a neurotransmitter called glutamate, it binds to mGluR5 on the postsynaptic neuron, triggering synthesis of new synaptic proteins. Fragile X protein (FMRP) acts as a brake on this protein synthesis.
When FMRP is lost, there is too much protein synthesis, which leads to the symptoms seen in Fragile X syndrome: learning disabilities, autistic behavior and seizures. Bear and others have since shown that blocking mGluR5 in mice can reverse those symptoms.
After making the connection between Fragile X and mGluR5, Bear and his colleagues started to wonder if mGluR5 overactivity might also cause other single-gene syndromes that produce autism symptoms. They began their investigation with tuberous sclerosis (TSC).
The researchers, including co-authors Benjamin Auerbach and research scientist Emily Osterweil, felt confident in their hypothesis that they would see a similar synaptic defect in TSC as they had seen in Fragile X.
However, the team found the exact opposite of what they and the reviewers had expected. The two diseases â€œappear to be mirror images of each other,â€ Bear says. In mice with TSC, synapses have too little protein synthesis - so instead of improving when treated with a drug that inhibits mGluR5, the animals respond to a drug that stimulates it.
The findings show that not all cases of autism spectrum disorder will respond to the same kind of treatment, Bear says.
â€œThis study identified one functional axis, and it will be important to know where a patient lies on this axis to devise the therapy that will be effective,â€ he says. â€œIf you have a disorder of too little protein synthesis, you donâ€™t want to inhibit the neurotransmitter receptor that stimulates protein synthesis, and vice versa.â€
This should not be surprising, he says, pointing out that psychiatric-drug development has encountered the same difficulties, because disorders such as bipolar disorder and schizophrenia have such varied origins. In the case of autism, researchers hope that identifying the root causes of single-gene disorders can help them figure out how to treat other forms of autism that may have similar origins.
There are currently no good tests for which genetic markers a particular autistic patient may have, but if drugs that inhibit and/or stimulate mGluR5 are approved, scientists may be able to identify which autistic patients respond to which drugs, and then try to identify a biomarker in those patients that could be used for future diagnostic tests.
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