It is believed that over 1.5 million people in the United States have Autism spectrum disorders (ASD). Individuals that have been diagnosed with ASD typically display symptoms of ritualistic or repetitive behaviors, have difficulty communicating with others, and often have unusual social interactions. As this disease continues to become more prevalent with no known explanation, researchers have begun to try and find a link that may combine the many different theories as to how ASDs develop.
The Puzzle Pieces (Theories):
Imagine the brain as a sophisticated computer complete with many delicate connections, wires, and an instruction manual so thick that it’s impossible to know all of its functions.
“Faulty Wiring”
It is believed that ASD may be the result of improper neuronal connection in the brain. If neurons are unable to connect to each other successfully, they will not be able to communicate properly. As seen in a computer, if the wiring is faulty, the device will not be able to carry out its desired function. This is exactly what occurs in the brains of individuals with ASD. This faulty wiring can happen in many ways:
(1). Too many neurons
If there are too many “wires” in the circuit, it will not function properly due to excess “noise”. This is exactly what happens in brains that have too many neurons. The abundance of neurons impairs the proper functioning of the circuit, or in the case of the brain, the synapse. In a “normal” brain, excess neurons are removed through synaptic pruning, and the remaining neurons strengthen their connections with one another to improve communication via synaptic plasticity. In a brain with too many neurons, such as in ASD, these connections are unable to properly form and remain weak.
Figure 1. The image on the left shows a brain unaffected by ASD, while the one on the right shows an increase in neurons found in an individual with ASD. This increase may be the result of the aforementioned failed synaptic pruning. (Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center) http://www.kurzweilai.net/children-with-autism-have-extra-synapses-in-brain
(2). Neurons in the wrong place
It is believed that during development a mutation in the reelin gene (RELN), responsible for the proper placement of neurons, may lead to neurons developing in the wrong place. If neurons are in the wrong place, they are unable to communicate properly and functioning is impaired; this is the case in ASD.
(3). Too many synapses
A mutation in the MeCP2 gene, a silencer of gene expression, leads to an inability of the brain to properly rid itself of excess synapses within the brain. In addition, an abundance of dendritic spines (the receivers of the message) resulting from defective pruning has also been shown to induce a hyperactivated mTOR pathway. The mTOR pathway inhibits autophagy. As autophagy is responsible for removing excess dendritic spines, synapses, and neurons, these structures remain in the brain and induce further faulty wiring, which inhibits proper communication.
“Defective ‘Current'”
(4). An imbalance of On/Off signals – Excitation and Inhibition
A balance between excitatory (glutamate) and inhibitory (GABA) neurotransmitters, the chemical messengers in the brain, is essential for proper communication. It is believed that this imbalance may be the result of gene mutations, a defective blood brain barrier (BBB), or neuroinflammation, which will be discussed later. When this balance is not maintained, the neurons (wires) may die. This is often the result of excess glutamate in the brain. Under these exitotoxic conditions, further neuroinflammation may occur inducing more cell death.
“Faulty Programming”
(5). Mirror neurons
Mirror neurons and the connections they form are responsible for one’s ability to learn from their environment through imitation. If an individual is unable to recognize, understand, and learn from the actions and emotions of those that they are in close contact with, it is impossible for them to understand how to act “normal” in social situations. Being that two of the main symptoms of ASD are problems with communication and difficulty behaving in social situations, it is believed that faulty mirror neurons may play a role in the development of ASD.
(6). Genes/Epigenetics
It is impossible for a computer to work properly if it is programmed incorrectly. This is exactly what occurs with mutated genes that may cause ASD. As there is no single gene responsible for ASD, through extensive research, scientists have been able to classify the defective genes into three main families:
- Genes responsible involved in synaptic transmission
- Ex: SHANK3, NXN1, NLGN3/4
- Genes related to abnormal cellular/synaptic growth
- Ex: Genes associated with autophagy/mTOR: TSC1/2, PTEN, NF1
- Genes that control gene transcription and translation
- Ex: FMR1 and MECP2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688327/
“Unexpected Error”
(7). Immunity and Neuroinflammation (The Main Piece?)
The immune system and glial cells (astrocytes and microglia) are responsible for the proper development of the nervous system, neurons and functional synapses. With this being said, if the immune system is disturbed in any way, the proper development of these structures is compromised. As glial cells are responsible for secreting pro-inflammatory cytokines when exposed to antigens, and as neuroinflammation is responsible for cell death, an exposure to an antigen during development may be the reason for ASDs.
Resources:
https://moodle.cord.edu/pluginfile.php/723245/mod_resource/content/0/pathophys%20of%20ASD%202017.pdf