Brain synapses are the connections between neurons that enable them to communicate with each other.
In a new study published in Nature, Bear and his team have just discovered that tuberous sclerosis is caused by the opposite malfunction, i.e. too little synthesis of those synaptic proteins. Tuberous sclerosis is another rare disorder characterized by autism and mental retardation.
Mark Bear, Picower Professor of Neuroscience and a member of MIT's Picower Institute for Learning and Memory, says that although the findings may appear counterintuitive, they nevertheless apply to the theory that autism can be caused by a wide spectrum of brain-synapse glitches.
"The general concept is that appropriate brain function occurs within a very narrow physiological range that is tightly maintained. If you exceed that range in either direction, you have an impairment that can manifest as this constellation of symptoms, which very frequently go together - autism spectrum disorder, intellectual disability and epilepsy."
The study findings also indicate that any potential drugs designed to treat the cellular origins of autism would need to be accurately matched to each patient to ensure that they benefit the patient and not harm them.
Ongoing Phase III clinical trials are showing encouraging results for drugs developed to treat Fragile X syndrome.
Making connectionsThrough his studies of a receptor found on the surface of neurons, Professor Bear unintentionally ended up discovering how Fragile X develops.
The mGluR5 receptor plays an important part in transmitting signals between two neurons at a synapse, known as the presynaptic and postsynaptic neurons. The synthesis of new synaptic proteins is triggered when a presynaptic cell releases a neurotransmitter named glutamate, which binds to mGluR5 on the postsynaptic neuron. The Fragile X protein (FMRP) acts like a restraint on this protein synthesis.
"The appropriate level of protein synthesis is generated by a balance between stimulation by mGluR5 and repression by FMRP."
The loss of FMRP means too much protein synthesis, which results in learning disabilities, autism-like behavior and seizures symptoms observed in Fragile X syndrome. Bear and other scientists have since demonstrated that these symptoms can be reversed by blocking mGluR5 in mice.
Bear and team became intrigued after they made the connection between Fragile X and mGluR5, and decided to investigate whether mGluR5 overactivity might also cause other single-gene syndromes that produce ASD symptoms, which led to their investigation with tuberous sclerosis (TSC).
The team, including co-authors Benjamin Auerbach, a graduate student in brain and cognitive sciences, and research scientist Emily Osterweil, were sure that their hypothesis would reveal a similar synaptic defect in TSC as they had observed in Fragile X.
Bear recalls when they submitted their funding application for the study that
". . . . our reviewers thought we were being too conservative, because it seemed to them that the answer was so obvious, it was hardly worth doing the experiment."
To everyone's surprise, the team discovered the exact opposite of what they and the reviewers had expected. Bear says that the two disorders "appear to be mirror images of each other." A study of mice with TSC demonstrated that synapses have too little synthesis, which meant that rather than improving when treated with a drug that inhibits mGluR5, the animals responded to a drug that stimulates it.
Tailor-made treatmentsAccording to Bear's discovery, not all cases of autism spectrum disorder will respond to the same kind of treatment. He says:
"This 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. "If you have a disorder of too little protein synthesis, you don't want to inhibit the neurotransmitter receptor that stimulates protein synthesis, and vice versa."
He comments that this should hardly be surprising, seeing that disorders like bipolar disorder and schizophrenia have such different origins. He refers to psychiatric-drug development, which has come across the same problems.
The researchers anticipate that in the case of autism, identifying the root causes of single-gene disorders can help them to find a solution of how other forms of autism with similar origins can be treated.
"We have a huge advantage of really getting down to what actually is wrong in the brain in these diseases. Of course what we'd like to do is be able to go from these rare known causes of autism, which may account for at most 10 percent of cases of autism, into idiopathic autism - autism of unknown cause - and try to have some hope of selecting the right therapy for those individuals."
To date, there are no suitably efficient tests that can establish which genetic markers a particular autistic patient may have, however, scientists could potentially identify which ASD patients respond to which drugs, and subsequently try to identify a biomarker in those patients, which could be used for future diagnostic tests if drugs that inhibit and/or stimulate mGluR5 are approved.
Bear and team currently study other single-gene disorders, such as Angelman syndrome and Rett syndrome, to establish whether they also affect mGluR5 activity, in addition to exploring the steps in the mGluR5/protein-synthesis pathway in more detail.
Adapted from a piece written by Anne Trafton, MIT News Office