Artstract by Allegra Bentrim
Autism spectrum disorders are genetic disorders and are present in about one percent of children. Differences in social behaviour and communication often stereotype ASD, with high-functioning individuals on the spectrum being thought of as intelligent, if quirky. However, there are much more serious and debilitating forms of autism that individuals experience. Termed severe or nonverbal autism, children with these conditions are unable to sit and focus, to eat, and even unable to sleep through a night.
Researchers have been looking for a mechanistic explanation for how ASD develops and is expressed in individuals throughout the spectrum. One review article focusses on the dysregulation of activity-dependent signalling at synapses in the brain. Diving into the genetic molecular causes for development of ASD, there is one key player that stands out: ARC.
ARC is a protein that seems to play a role in the development of autism. These proteins are made immediately following activation of an excitatory neuron, transcribed from a class of genes characterized by their quick transcription: Immediate Early Genes. Essentially, if all works normally, the ARC protein gets synthesized following an excitatory synapse and does its job to prune synapses. Transcribed in the right amounts, the ARC protein helps the right amount of AMPA receptors to be present in the synapse which allows the synapse to grow stronger at a healthy rate over time. ARC proteins function to modify synapses in all sorts of pathways including memory, addiction, and depression. It modifies synapses by pulling AMPA receptors out of the post-synaptic density, which causes the synapse not to strengthen to the same degree as if ARC had not played a role. The ARC protein is important because if excitatory activity lead to unmediated increase of synapse strength, then this over-stimulation of neural connections would contribute to dysregulation of synaptic plasticity.
Under transcription of the Arc gene leads to over-activity of synapses because there is less ARC protein around to influence and balance the synapse. This is a part of what we think is happening in the development and proliferation of ASD. This ARC inactivity hypothesis posits that the activation of neurons in the presence of an unhealthy diminished production of ARC leads to over-excitation and over-activation of synapses. Too much stimulation of synapses leads to long term potentiation of signals and if these signals repeatedly trace neural pathways enough times, morphological changes happen in the neurons. This property of neurons is productive under healthy circumstances: this is how we form memories and how we learn. However, over-stimulation and too much morphology could be why high-functioning and severe ASD is developing.
Other genetic diseases seem linked to the ARC protein as well. Fragile X Syndrome is an example of the opposite effect as what we see in ASD. In Fragile X Syndrome, over production of the ARC protein is linked to increased depression of synapses. The over-abundance of the ARC protein causes more AMPA receptors to be pulled out of synapses, weakening neural connections. Similar to the ARC deficiency seen in ASD, in tuberous sclerosis there is a decrease in ARC protein abundance stemming from a decreased translation of ARC mRNA.
ARC plays a fundamental role in the pruning of excitatory synapses, the dysregulation and dysfunction of which can lead to neural disorders on either side of the ARC balance.
