Mutations in the gene that encodes SynGAP1, a protein, is estimated to cause disabilities in approximately one million people worldwide. The authors explained that this single gene mutation is known to cause intellectual disability and raises the risk of developing an ASD (autism spectrum disorder).
The gene mutation severely disrupts how the developing brain circuits organize themselves during the early years of a human's life. The researchers said their study helps explain how genetic mutations can be responsible for profound behavioral and cognitive problems.
Genetic mutations that cause intellectual disability and autism spectrum disorders typically affect synapses. Synapses are junctions where two nerve cells communicate with each other within the brain's sophisticated electro-chemical signaling system.
The scientists say that a considerable proportion of children with severe behavioral and intellectual impairments are thought to carry single mutations in key neurodevelopmental genes. Nobody knew, before this study, exactly how pathogenic genetic mutations and synapse functions were linked to impaired intellectual development.
Team leader, Prof. Gavin Rumbaugh, said:
"In this study, we did something no one else had done before. Using an animal model, we looked at a mutation known to cause intellectual disability and showed for the first time a causative link between abnormal synapse maturation during brain development and life-long cognitive disruptions commonly seen in adults with a neurodevelopmental disorder.
There are a few genes that can't be altered without affecting normal cognitive abilities. SynGAP1 is one of the most important genes in cognition - so far, every time a mutation that disrupts the function of SynGAP1 has been found, that individual's brain simply could not develop correctly. It regulates the development of synaptic function like no other gene I've seen."
In animal experiments, the scientists found that when one copy of SynGAP1 was missing, certain synapses develop too early shortly after birth. This makes the cells "fire" much more often - scientifically, they said that "this dramatically enhances excitability". The brain cells fired more often than normal in the developing hippocampus, a region in the brain which is critical for memory.
During a child's early developmental period, the balance between inhibition and excitability is critical - this is when neural connections that ultimately give rise to normal behavioral and cognitive functions are being formed.
"You might think this accelerated development of brain circuits would make you smarter. But the increased excitability actually disorganizes brain development. We think that early maturation of these excitatory synapses disrupts the timing of later developmental milestones. It rains down chaos on this complex process, preventing normal intellectual and behavioral development."
Mutation repairs must be done at just the right timeIf these mutations are induced after the critical development period is complete, the impact on normal synapse function is negligible, the authors found. If these pathogenic mutations are repaired during adulthood, behavior and cognition do not improve.
Rumbaugh said "A key finding is we were able to remove the mutation and restore SynGAP protein levels in adult mice with obvious cognitive and behavioral problems, but this intervention did not benefit the animals."
For effective interventions, they must be done early onTheir findings suggest that early intervention is crucial in neurodevelopmental disorders, especially where cognitive problems are concerned.
Rumbaugh and team are trying to find out when exactly mutation repairs should be carried out, for maximum benefit.
The authors believe that if these critical moments for treatment can be identified, together with the fast-approaching ability to identify these pathogenic mutations while the baby is still in the womb, we may have a possible path towards eradicating this kind of intellectual disability, and severely reducing the risk of autism.
Rumbaugh said "We believe a cure is possible. It is likely that there are many other single mutations out there that cause distinct forms of these spectrum disorders. Our strategy could be applied to these disorders as well."
Researchers from Yale School of Medicine reported in the Journal of Autism and Developmental Disorders that early intervention helps children with an ASD. Early intervention results in better brain functions, communications skills and behaviors.