Cobbers on the Brain

Introduction to autism:

Autism spectrum disorder is a developmental disease that results in impaired functioning in social communication and abnormal behaviors. People with autism generally use less eye contact, fail to know when or when not to use non-verbal gestures, and fail to recognize the emotions of others. Abnormal behaviors seen in autism include but are not limited to repetitive ritualistic behaviors, extreme interests in specific topics, and a need for unvarying routine. While it is difficult to draw the line between a normal and abnormal brain, research has suggested evidence that with autism spectrum disorder there are differences in neurochemical pathways that limit normal functioning of people with the disease.

Environmental causes:

The complex interaction among neural processes associated with autism begins early in development. During pregnancy, even slight changes in the environment can result in tremendous change in the development of the child. A pregnant mother could become infected with a minor pathogen and pass the infection on to the child through the placenta. This transfer may induce a change in the child’s immune response resulting in excess inflammation. Unfortunately, there is only so much preventative action mothers can take during pregnancy. Proper nutrition and avoidance of harmful chemicals and pathogens is all a mother can do to diminish problems with development. It is important for mothers to know that everything they do could in some way affect the baby, but it is also important to know that it is impossible to reduce all environmental risks down to nothing. Along with countless environmental factors associated with ASD, numerous genes have also been identified.

Genetic influences:

Thousands of genes have been linked to ASD creating a nightmare for scientists trying to fully understand why this disease occurs. One of the most common genetic abnormalities seen in ASD is a mutation in the MECP2 gene. This gene codes for a protein used in regulating the transcription of other genes. It helps to regulate synapse formation in the brain and makes sure that only necessary connections are made in the brain. People who have an alteration in this gene will have abnormal connections of neurons causing miscommunication among brain domains. Related to this gene is the process seen with the mTOR pathway. In this pathway, unused connections of the brain are removed allowing for normal communication between neurons. This pruning process is essential in normal brain functioning and it thought to be severely impaired in autism resulting in an unusually high density of neurons.

The role of the immune system:

The immune system plays a large role in both in peripheral body tissue and the nervous system. It is used to eliminate intruding pathogens and rid the body of any harmful substances. To do this, a close interaction of T and B cells is orchestrated. T-cells are a type of white blood cells used in initiating an immune response. They release chemicals that cause inflammation and notify the rest of the body where the infection is. These cells are also used in the destruction of harmful pathogens and infected cells. B-cells release antibodies that attach to invading substances and mark them for destruction by T-cells. It is thought that an abnormality of this general process in the brain leads to symptoms associated with autism. Careful regulation of these cells allows normal brains to eliminate harmful substances while preserving delicate brain tissue. In autistic brains, however, regulation of these immune cells is hindered causing excess inflammation. It is this point where many aspects of autism are thought to arise. The extra chemicals in the brain causes excess inflammation without enough regulation. From here, abnormalities in other brain processes are initiated leading to permanent damage during development.

Conclusion:

The pathophysiology of autism is extremely complex and difficult to map out. There are many different aspect of the disease that affect different pathways in neurochemistry. While we do know many of these parts and how they interact with each other, the exact order of events remains unknown. Perhaps genetic predispositions lead to higher probability of in utero infection leading to a malfunctioning immune response in the brain etc. Or perhaps the pathophysiology is much less linear and requires interaction between different processes all at once. Nevertheless, a complete understanding of ASD may never be reached but further research on the disease could provide helpful insight for prevention and treatment of ASD.

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.

1. https://www.autismspeaks.org/science-news/cdc-increases-estimate-autisms-prevalence-15-percent-1-59-children
2. https://www.spectrumnews.org/opinion/viewpoint/leo-kanners-1943-paper-on-autism/
3. https://moodle.cord.edu/pluginfile.php/723245/mod_resource/content/0/pathophys%20of%20ASD%202017.pdf

Autism is a relatively newly recognized disorder that is quickly affecting more and more children as time progresses, affecting 1 in 68 today compared to just 1 in 150 in 2000. While much progress has been made in recent decades with the understanding of the mechanisms of autism, its cause is still widely misunderstood. There is no solid proof of the exact cause of autism, but it seems that individuals with susceptible genes are triggered by environmental toxins and deficiencies, leading to defects in neural signaling. Because environmental factors can trigger gene expression for autism, the preventions and treatments of autism are intriguing areas of study.

What is Autism?

Autism is a spectrum disorder, which means it has varying degrees of severity. All classifications of the autism spectrum involve difficulty socializing and communicating with others, and most cases involve repetitive behavior.

What Goes Wrong in the Brain?

• Increased number of neurons leading to oversized and overactive temporal and frontal lobes
• Ineffective elimination of unnecessary synapses
• Imbalance of excitatory and inhibitory neurotransmitters
• Heightened levels of immune cells in the brain
• Defective blood-brain barrier

How Do Toxicities Lead to Autism?

There are over 77,000 man-made toxins in our environment that were not meant to be taken in by humans. Toxins, whether they are pesticides, heavy metals, or plastics, must be removed from our bodies through innate mechanisms, or the biochemical processes in our bodies will go haywire. When an individual has a toxic overload, their body is depleting all of its amino acids in attempt to detoxify. Unfortunately, these depleted amino acids are necessary for normal brain function, and this inability to efficiently detoxify the body can lead to autism.

Most people understand that pesticides and fossil fuels are harmful to our health, but one overlooked toxicity is heavy metals. A lot of metals are essential to our body’s function, such as iron, but when any of them are too concentrated, problems arise. Specifically, high concentrations of copper in the body are very common in autistic individuals. Copper is an antagonist to zinc, which means they work together to make sure concentrations of each stay in check. When copper levels are too high, zinc is depleted. Low zinc levels have been correlated to autism because it leads to a dysfunctional immune system.

Does Gut Dysfunction Affect Immunity?

The answer to this question is yes. Scientists are now saying that at least 80% of our immune systems reside in our gut, and at least 90% of autoimmune diseases correlate with gut dysfunction. So fixing our guts will fix all of our health problems? Well, actually in most cases, yes. A compromised immune system is pointed to as one of the main factors in developing autism, and we just learned that 80% of our immunity lies within our gut. But first, lets learn how our guts became compromised in the first place.

“Leaky Gut” has been coined as the term describing increased intestinal permeability. It means that the large intestine is letting things through its walls that shouldn’t be leaking through. Bacterial cells can leak through the weak gut lining into the bloodstream, eventually into the brain where they can wreak havoc on neurons. Leaky gut can be caused by a variety of factors, including an imbalanced microbiome, poor diet, stress, and toxicities. Remarkably, repairing “leaky gut” in autistic individuals has been shown to dramatically decrease symptoms.

Can Autism Be Prevented or Cured?

It has been proven that a compromised immune system is correlated with the development of autism. Therefore, keeping an eye on a child’s immune function as it develops could be key in preventing autism. Three factors that have a negative effect on immune function are inflammation, nutrient deficiencies, and toxic overload. They can be addressed in a variety of ways:

• One of the most prominent causes of inflammation is leaky gut
  • To fix leaky gut, removing food allergens is a great place to start
  • Additionally, restore healthy gut bacteria with probiotics, and stay away from antibiotics
• Nutrient deficiencies can be tested for and supplemented until levels are healthy again
• Once inflammation and deficiencies are taken care of, the body has a much easier time detoxifying and reducing free radicals

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What is autism? This is a very difficult question for people to answer for a variety of reasons. The biggest reason is because a wide spectrum of symptoms is experienced by individuals. This is because Autism Spectrum Disorders (ASD) are not caused by a specific gene mutation, but rather by a vast variety of environmental and genetic factors that all play a part in how the disease is presented in individual cases. Three of these factors will be discussed: Neural Connectivity, Mirror Neurons, and Excitation-Inhibition Imbalance. After discussing these factors, hopefully we will have a better understanding of what may lie as the root of the problem for ASD.

Neural Connectivity

In individuals’ brains with ASD, there is a significantly increased number of neurons. This is because there is a problem with ‘pruning’. In healthy brains, non-functional neurons are pruned away to give more room for working neurons to work and actually increase their power. This pruning process is done a lot with the mTOR pathway. This pathway enables apoptosis (cell death) and autophagy (cell absorption) to take place and effectively prune out the areas that are overgrown/unneeded. When the pruning does not take place, it leaves a crowded circuit causing lots of extra ‘noise’ causing the brain to function less efficiently. This is analogous to plants. Unhealthy branches are pruned off to give room for healthy ones to grow further and make the whole plant healthier.

Mirror Neurons

Do you ever wonder why you yawn when you see somebody else yawn? This is because of mirror neurons. Mirror neurons form connections that enable an individual to learn from its environment by imitation. In individuals’ brains with ASD, these mirror neurons are much less concentrated and possibly broken. This could possibly be the cause of those with ASD to have a lack of empathy for those around them. This could also cause lack of understanding of other individual’s movements and lead to the poor development of communication skills exhibited by many of those who suffer from ASD.

E/I Imbalance

There is a delicate balance in the brain called excitation and inhibition. Glutamate neurotransmitters are excitatory and GABA neurotransmitters are inhibitory. When working effectively, this balance gives the proper action potential to cells enabling them to fire or to rest. However, when this balance is not maintained only glutamate neurotransmitters can be activated. This causes excessive excitation in the cell. The glutamate then becomes excitotoxic and can kill cells, causing further damage to neurons and neural connections in the brain.

Closing 

Though we have just scratched the surface of the possible causes of ASD, this does help to give us an insight into what is happening in the brains of those around us that live with ASD. It’s important for us to try to understand these things as ASD is becoming more and more prevalent as 1 in 68 children today are diagnosed as being on the spectrum in some way, shape, or form, so we likely know someone living with ASD or we will know someone living with it in the future. As we know there is no real cure for ASD right now, but the first step to curing something is to understand what is going on and to identify the problem. Hopefully sometime soon we can start to put all of the pieces in place and figure out what is going on.

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With a rising frequency of affected individuals and increasing visibility in society, diving into the current knowledge of how autism affects the brain is important to inform us on how individuals with ASD’s (Autism Spectrum Disorders) experience the world from a different perspective. The following topics are of interest when considering autism’s cause and how the symptoms play out for individuals at any point on the spectrum. One of the most impactful and studied components of autism is the neuronal function/dysfunction that occurs in individuals with ASD’s.

Neural Connectivity and development:

In brains with autism, dysfunctional neural connectivity plays a large role in the manifestation of common symptoms seen in individuals with ASDs. Neurons are vital in passing chemical information from areas of the body to different areas of the brain. In brains of individuals with autism, these conversations between neurons are affected by an increased number of neurons and a lack of good communication between individual neurons. This concept can be understood by thinking about a 10-way phone conversation. With all ten individuals talking at once, it is impossible to pick out important bits of information and communicate the correct message to all the individuals! This is similar to the type of dysfunction seen in the neurons of brains with autism.

Another common developmental abnormality in brains with ASDs is the improper migration of neurons. This migration occurs before being born, and helps to place neurons where they need to be to function properly and align with each other. This has been connected to genetic mutations in the Reelin (RELN) gene that plays a huge role in the proper migration of neurons.

Genetic Mutations Contributing to Synaptic Malformation 

In nervous system, synapses are the gaps located between neurons which neurotransmitters and other molecules travel across to transmit signals to the next neuron in line. This process is vital to the proper communication between neurons, and outcomes in the cells. In individuals with ASDs, a common trait seen is malformed synapses between neurons. These malformations cause signaling, which is already at an increased level, to be inaccurate at transferring chemical information.

There are a few genetic mutations studied that play a role in the malformation of synapses in brains with ASD’s. This class of mutations has to do with the formation of Neurexin and Neuroligin, trans-membrane proteins tasked with physically docking the pre-synaptic (sending) neuron with the post-synaptic (receiving) neuron. Mutations causing deletions or mutated versions of these proteins negatively affect the ability of signals to reach the receiving neuron correctly.

These abnormalities play one piece in the puzzle of ASD’s, but is an important one to understand symptoms manifested in individuals with autism. Individuals with autism have symptoms related to complex malfunctions in the nervous system, immune system, and environmental stimuli that combine to create the experience of life with an autism spectrum disorder.