Background:
Autism Spectrum Disorder (ASD) has steadily increased over the years. The CDC estimates that autism prevalence will increase to 1 in 59 children in the United States. This is a substantial increase from data in 2004 that showed autism prevalence was 1 in 166 children1. ASD is a relatively new disorder. Its pathogenesis has eluded scientists since its initial characterization in 1943 by physician Leo Kanner2. Since then, ASD has evolved into an umbrella term for a disorder that is characterized by a myriad of behaviors. Repetitive behaviors, impaired social interactions, and language and communications abnormalities are a few of the many different common symptoms of ASD. Although researchers are still unsure of an exact mechanism in which ASD undergoes, they have a few pieces figured out of the complex puzzle that is ASD.
Too Many Neurons, Too Many Connections:
One of the most common findings of different research efforts is that ASD patients suffer due to impaired neural connectivity. This impaired connectivity stems from the significantly increased number of neurons present in autistic patients. The increased number of neurons diminishes the process of shaping and fine-tuning of neural circuits in ASD patients3. The impaired connections in the brain also cause reduced lateralization of the brain which is needed for higher order brain functions. A specific study exhibited that the corpus callosum of ASD patients had increased white matter (from too many neurons), and that this increase in size of corpus callosum inhibited the lateralization of each hemisphere that is used for language production and comprehension3. Simply, there are too many connections between too many neurons which as you can imagine creates too many signals for an autistic patient to comprehend, hence the symptomatic behaviors. This may cause someone to the question: What is causing the increase in neurons and connections seen with ASD?
Precious Pruning:
During “normal” development, cells prune unneeded connections between neurons. Microglia are the cells responsible for this synaptic pruning in babies’ brains. In autism, however, this pruning is not present. Therefore, they have nearly twice as many neurons after development compared to someone without ASD. This leads us to the next question: Why is there no synaptic pruning in ASD? Autophagy is not occurring in ASD brains; therefore, they are not getting a decline in synapses. Autophagy is related to the mTOR pathway, which induces cell growth, differentiation and survival, and down-regulates apoptotic signals and inhibits autophagy. In autism, the mTOR pathway is overactive, inhibiting the process of autophagy. If there is no autophagy, then there is no synaptic pruning, and ultimately leads to an excess of neurons. Researchers have then studied genes and risk factors during development to cause the lack of pruning.
Genetics Role in Autism:
After extensive research, it is clear that many certain genes and environmental factors contribute to the development of autism. There is no “autism gene.” However, there are affected genes that fit into several clusters that may underlie ASD. Mutated NLGN3/4, SHANK3, NRX1 genes alter the synaptic function and lead to autistic disorders such as Asperger’s syndrome3. Other strong contributors to ASD are TSC1/2, PTEN, and NF1 which are associated with autophagy and the mTOR pathway. Finally, another cluster of genes that control gene transcription and translation are related to the pathogenesis of ASD. Mutations of these genes are hypothesized to cause a loss of normal constraints on synaptic activity-induced protein synthesis. This specific loss may be one of the several mechanisms leading to ASD.
Summary:
Autism’s complicated umbrella is covering many families across the world. Understanding ASD will be more important than ever as we see its prevalence increasing across the United States. Although it is a very complex disorder, pieces have been placed together by researchers. Many genes affect ASD. In my mind, it makes the most sense focusing on the specific cluster of genes including TSC1/2, PTEN, and NF1. Mutations in these genes, which are associated with the mTOR pathway, could cause over-activation of this pathway. If the mTOR pathway in ASD is overactive, it inhibits the process of autophagy. This causes a lack of synaptic pruning, which proceeds by microglial autophagy. If microglia are inhibited, a build-up of neurons and connections between these could occur. The increased connectivity and neurons cause the symptoms associated with ASD. These are not all of the pieces to this puzzling umbrella disorder, but it is a starting point to understanding ASD.
