This blog was written by Dr. Boaz Barak, an ASF fellow and an author on a recent publication in Neuron that used animal models to show that different mutations of the same gene can lead to different psychiatric disorders. The study was led by Dr. Yang Zhou in Prof. Guoping Feng’s lab at MIT. In this case, one mutation has been associated with schizophrenia and the other with autism. Dr. Barak explains their findings below.
Autism is one of the most heritable neuropsychiatric disorders. Mutations in genes associated with autism will eventually lead to the expression of malfunctioning proteins. One such gene that is known to be mutated in Phelan-McDermid syndrome is Shank3, encoding the postsynaptic protein SHANK3. People with Phelan-McDermid Syndrome, or PMS, often show symptoms of autism.
To study the role of genetic mutations in autism etiology, our lab engineered mouse models that express the mutated gene in their brains, allowing the researchers to study the behavioral, physiological and biochemical consequences of these gene mutations.
We induced two different mutations but in the same gene, Shank3, based on human mutations found in patients. By doing so, we showed evidences how different mutations in the same gene can lead to two different disorders, autism and schizophrenia.
Interestingly, we found that mice with the autism-related mutation (InsG3680), demonstrate impairments earlier in life than those with the schizophrenia-related mutation (R1117X), coinciding with the early onset of autism spectrum disorders symptoms. Specifically, starting from very early age, impaired electrical activity of neurons was measured in the striatum, a brain region important for integration and coordination of multiple neurological processes necessary for normal behavior. Along with the abnormal neuronal activity of cells, we found impaired social behavior in the mice with the mutation, together with extensive repetitive behavior. Looking for biological findings that might explain these abnormalities, we found molecular changes in the composition of proteins in the synapse and the transcripts (mRNA) responsible for the expression of those synaptic proteins.
Overall this study shed new light on the pathophysiology of autism and schizophrenia, and enables the research community to study the consequences of two different human-based mutations in novel mouse models.
Why is this important for people with autism? Hopefully, the data published will help in developing drugs targeted to fix the physiological and the behavioral abnormalities of the Shank3 mutation. Improved understanding of such syndromic cases will lead to better basic understanding of also other types of neurodevelopmental disorders, and ultimately, the discussed mouse models will assist the research community in validating potential drugs before testing them on people with autism.