To function normally, the brain needs to maintain a precise level of synaptic protein synthesis—too much or too little can cause problems, according to research by HHMI investigator Mark F. Bear and his lab team. Their findings provide insight into two forms of autism with overlapping symptoms.
A decade ago, Bear and his colleagues at the Massachusetts Institute of Technology discovered that fragile X mental retardation protein (FMRP) counterbalances a neurotransmitter receptor called mGluR5. Normally, FMRP keeps mGluR5 from turning on protein synthesis at the synapse between neurons. But in fragile X syndrome, FMRP is missing so protein synthesis proceeds unchecked. This increase in protein synthesis in brain cells, Bear has shown, accounts for multiple symptoms in animal models of fragile X. Drugs that block mGluR5 are now in clinical trials to treat autism and intellectual disability in fragile X patients.
Bear wanted to see if the same drugs could be used to treat another disease—tuberous sclerosis complex—that causes autism and learning delays and is also linked to genes that regulate synaptic protein synthesis. The disease is caused by mutations in tuberous sclerosis complex protein 1 or 2 (Tsc1 or Tsc2). Inactivation of either of these proteins results in an increase in the activity of mTOR, a protein involved in RNA translation. Scientists hypothesized that a boost in mTOR levels might increase synaptic protein production via the same pathway as mGluR5.
Using a mouse model of tuberous sclerosis, Bear’s team looked at how mutations in Tsc2 affect protein synthesis at the synapse. To their surprise, synthesis decreased in neurons with the Tsc2 mutations—the opposite of what happens in fragile X. Interestingly, mice engineered to carry mutations in both the Tsc2 and Fmr1 genes generate just the right amount of synaptic protein. The team published its findings online November 23, 2011, in Nature.
A drug that blocks mTOR—called rapamycin—is already in clinical trials to treat tuberous sclerosis, and Bear’s new study offers an explanation of how the drug works to reverse some problems caused by the disease. Next, he hopes to more fully understand how the pathway controls synaptic protein synthesis.
