ARC: A Keystone Player in the Over-ARCing Storyline of the Development of ASD

Posted on November 12, 2019 by / 0 Comment

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.

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Autism: A Spectrum of Disorders

Posted on November 12, 2019 by / 0 Comment

Autism Spectrum Disorders (ASD) have become a large topic of discussion in the public eye for many years. While previously it had been treated and diagnosed as many distinct conditions, the medical community eventually recategorized it as a range of disorders on the same spectrum. If you’re interested in the rich history of diagnosing and characterizing ASD, check out this article. It is particularly difficult to characterize and discuss because it is a complicated array of diseases that have a large variety of symptoms, signs, and related diagnoses. It is also very difficult to properly analyze because there is widespread misinformation about ASD, in particular regarding vaccines. Due to this, it is very important for scientists to share information, especially novel research about ASD to combat misconceptions and ignorance about the topic.

What is ASD?

According to the Center for Disease Control (CDC) and the DSM5, or the diagnostic manual that psychiatrists use in practice, ASD is characterized by three main persistent deficits. First, is deficits in social- emotional reciprocity. People with ASD may struggle to share emotions, participate in normal back-and-forth conversation, or may have poor approach to social situations. Second, ASD is characterized by difficulties with nonverbal communication skills. Those affected may struggle making eye contact, lack of facial expressions and gestures, and an inability to interpret facial expressions and gestures from other parties. Finally, those with ASD will most likely struggle with interpersonal relationships. Adjusting to social context may be challenging or there may be a disinterest in peers overall. ASD includes a wide range of disorders, and the severity varies by a large number of characterizations as well. Additionally, characterization of a variety of related issues can coincide with a diagnosis of ASD, including identification of a intellectual or speech impairment, a behavioral disorder, or an underlying genetic cause, like Rett Syndrome.

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Autism: Losing the Trees in the Forest

Posted on November 12, 2019 by / 0 Comment

Autism is a very broad topic, mostly because the disorder manifests itself differently in every single person who has it. There are people with autism spectrum disorder who have difficulty completing daily tasks. There are also people with the disorder where it is completely invisible. Focusing on the broad, overview of autism masks the more complicated mechanism of the disorder. It is in these mechanisms that treatments for autism and its symptoms lie.

Some Context

Most neurological disorders can be classified into two categories: too much excitation of the neurons (neurons firing too much) or too much inhibition (neurons not firing enough). For example, excessive excitation in the amygdala is linked to anxiety disorders. Autism arguably fits into both categories, as it is linked to mutations that mess with the balance of inhibitory and excitatory neurons.

Image result for parts of a synapse"

[i]

How a Cell becomes a Neuron

Our experiences is what drives neuronal development. Excitatory synapses form on the dendritic spines (the spikey parts of the neuron). This makes since as glutamate (an excitatory neurotransmitter) binds to NMDA and AMPA receptors, which promote the development of dendritic spines. Additionally, these receptors help strength the synapse so it fires more quickly.

In our DNA[ii]

Dna, String, Biology, 3D, Biotechnology, Chemistry

We tend to think of DNA as something that is static, like something that is kept up in a safe and rarely pulled out. In reality, DNA is dynamic, playing a vital role in cell functioning and differentiation. How DNA interacts with the rest of the cell is determined by our experiences. For example, glutamate and the NMDA receptors trigger an increase in calcium inside the cell. This activates multiple pathways (outlined in the figure below). These pathways then activate transcription factors, which influence which genes get turned into mRNA. mRNA then helps make the proteins, which perform a specific function.

Autism is a genetic disorder. In the context of transcription, this means that mutated genes get transcribed, altering synaptic growth and development as a result of experience. Well, there are many different genetic mutations that lead to autism, there are two main proteins that are affected: neuroligins and neurexins and SHANK proteins.

Neuroligins and Neurexins

Neuroligins and neurexins are examples of adhesion proteins. They are involved in neuronal differentiation. Neuroligins are post-synaptic proteins, serving as receptors for neurexins. Certain neuroligins are excitatory whilst some are inhibitory. Neurexins help bind other postsynaptic proteins together.

Mice with a mutation on the neuroligin-3 gene show altered social behavior similar to that of autism and increased inhibitory transmission. However, the mice show no problems with excitatory transmission, creating an imbalance between these two types of neurons. Similarly, mice with an overexpression of the Nlgn1 gene (which codes for these proteins) increases excitatory synapses. Overexpression of the normal gene leads to a decrease in excitatory synapses, along with weaken of those present. When the gene is completely removed, problems with NMDA receptor mediated currents arise.

Overall, neuroligins and neurexins affect multiple pathways. All these problems may explain the broadness and diversity among autism.

SHANK

SHANK is a scaffolding protein. (For an explanation of scaffolding proteins, click here). These proteins help in the differentiation and function of synapses. Autism is linked to mutations in three different variants of the SHANK protein, creatively named SHANK1, SHANK2, and SHANK3. Mice without these proteins show varying symptoms. For example, mice without SHANK2 show problems with motor behavior and vocalization whereas those without SHANK3 show more problems with social interaction. All this might explain the diversity of symptoms of autism.[iv]

Comorbidity with Other Disorders

Autism may not be an isolated disorder. In some cases it can be, but it can also be a symptom of larger more complex disorders. Like autism these disorders come from genetic mutations and imbalance in excitatory and inhibitory neurons.

Fragile X syndrome: This disorder is caused by a mutation on the FMRI gene, located on the X chromosome. The mutation leads to a decreased amount of the FMRP protein. This protein plays a vital role in synaptic plasticity, basically ensuring that the synapses stay strong. Without the protein, dendritic spine growth becomes excessive, leading to too many immature spines. This causes behavioral issues and developmental delays.

Tuberous sclerosis complex: This disorder manifests as benign tumors on various organs and often coexists with autism. It is caused by a mutation on two genes that make two proteins: TSC1 and TSC2, both proteins work very closely with brain derived neurotropic factor (BDNF). The exact schematic is described in the figure below. Basically, when the TSC proteins are activated, the activity of GTPase activating protein (GAP) is reduced. This activates the protein Rheb, which in turn activates the protein mTOR. Without the activation of TSC, this pathway is disrupted and abnormal protein synthesis. It is still unclear exactly how this disorder is connected to autism.

Timothy syndrome: This disorder causes complications in many areas of the body. Symptoms include: heart problems, deformities in fingers and toes, problems in the central and peripheral nervous system. It is caused by a mutation in the CACNA1c gene, leading to an increase in calcium ions in the synapse. This leads to activation of a variety of calcium dependent pathways, which are heavily involved in synaptic plasticity and cell growth.

Angelman Syndrome: Typically diagnosed early in life, Angelman syndrome is linked to seizures, lack of coordination, a microcephaly and other symptoms. Unlike other disorders, Angelman syndrome is caused by a deletion of a single allele, chromosomal region 15q11-q13 to be exact. This leads to a loss of UBE3A, a gene that is essential for neuronal growth.

Rett Syndrome: Caused by mutations in the MECP2 gene, Rett syndrome causes motor system disabilities and seizures in addition to autism. Normally, MECP2 is involved in ensuring that DNA is folded into chromatins properly. In Rett syndrome, this is not the case. Additionally, the gene may play a role in regulating the balance between inhibitory and excitatory synapses.

The Forest

Autism is a complicated disorder, with so many varying symptoms and causes. But, this is where hope lies. If improved treatments for autism are going to be developed, this is where they will be. Examining these details can improve the quality of live for people with autism. At the very least, it can help those without empathize with those who have autism.

[i] https://ibguides.com/biology/notes/nerves-and-hormones/

[ii]Image courtesy of pixabay

[iv] Activity-dependent neuronal signaling and autism spectrum disorder

Artstract by Mitzi Probst

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Linking the Ends of the Spectrum – A Cellular Basis of Autism Spectrum Disorder

Posted on November 12, 2019 by / 0 Comment

When we hear the word “autism,” there are likely several things that come to mind. For many, it’s likely the image of the stereotypical “gifted” child – a child who often talks obsessively about unusual subjects, speaks in a specific tone, has trouble with social interactions or cues, and struggles to make friends. Maybe it’s the vaccination debate – if you’ve been around long enough, you’ve likely heard the social argument that “vaccination causes autism.” Or perhaps you’ve heard the term “autistic” thrown around as a derogatory slang term. Then again, some of us don’t even know what “autism” exactly is. Whatever it may be, the ever expanding subject of autism has made its way into modern day media through news, entertainment, stories, and even TV shows such as Netflix series Atypical, shaping the way that we define or view autistic individuals. Despite the stereotypes or television tropes you might have become familiar with, autism disorder is, quite literally, a spectrum – a complicated disorder that presents uniquely for each person, and one we are still far from understanding. Fortunately, advancements in research have allowed us to peer into the minds of these brilliant, fascinating individuals, and like most disorders, an understanding starts with studying things down at the cellular level. In this way, autism disorder is no different from the rest.

What is Autism?

The begging question still stands – what exactly is Autism Spectrum Disorder? Autism spectrum disorder, or ASD, as defined by the CDC, is “a developmental disability that can cause significant social, communication, and behavioral challenges.” This definition seems, frankly, quite vague. Typical symptoms include:

Intellectual and verbal impairments, especially during development, failure to hit developmental milestones
Repetitive actions and motions
Problems with coordination and motor development
Trouble interacting with, but having interest in others
Prefer to be alone and avoid physical contact
Trouble reacting to social cues
Avoiding eye contact
Does not understand sarcasm
Lose skills they once had over time
Hyperactivity
ADHD
Unusual reactions, temper tantrums
Aggression and self injury
Digestive or gastrointestinal disorders
Potential seizures

For a full list of symptoms, be sure to visit the CDC’s ASD symptom page here.

But what’s the deal with the word “spectrum?” Because the severity of autism manifest themselves to varying degrees, the disorder is characterized by a spectrum. The stereotypical “gifted” child often depicted in media is an example of High Functioning Autism, characterized by someone who can function normally. For example, someone with Asperger’s Syndrome has a mild form of autism. They likely have deficits in social interaction and may either excel in school, or be stressed out by the social situation, but otherwise they can perform day-to-day functions. On the other end of the spectrum, there is Severe Autism. In this form of the disorder, those afflicted might struggle to perform day-to-day tasks such as getting dressed, eating, and even walking and sitting. The graphic below summarizes three notable markers on the autism spectrum.

Symptoms often manifest when a child is 2-3 years of age, and the disorder is often diagnosed around this time as well, though diagnosis is more common in males than females. Above all, what can explain the curiously diverse range of symptoms seen in a single disorder? Keep reading to find out!

[Autism spectrum disorder] is a developmental disability that can cause significant social, communication, and behavioral challenges

Where Does the Spectrum Arise – Why does ASD Happen?

We often think of autism as being characterized by hyperconnectivity and too much brain activity. But is it true?

As we learned, autism can present as various combinations of symptoms across the spectrum. Behind it all, though, what happens in the body that leads to such a vast array of symptoms? What dictates whether or not a child will be born “gifted?” Like many pathologies and disorders in modern medicine, it all traces back to the brain – that big, pink, wrinkly organ that dictates our every move, behavior, judgment, and thought. Down to the core, autism is largely a genetic disorder, meaning that the changes in the brain that predispose someone to autism are already there, even before birth (though that’s not to say that behavior of autistic children can’t be shaped by their social environment as well). Other factors, such as exposure to toxins and parental age can increase a child’s likelihood of developing autism as well. Despite some misconceptions, autism is not a result of poor parenting, and it is a legitimate brain disorder – thus the term “autistic” should not be used as a negative label or slang term.

Fortunately, recent research has shed some light on the microscopic processes that lie behind the broad spectrum. Normally, when learning, neurons in the brain fire and result in one of two processes: long term potentiation (which results from high intensity firing and memory formation, such as reciting a word over and over to remember it) or long term depression (which results from low intensity firing and weakening of memory formation). To learn more about LTP , LTD, and synapses, be sure to visit my previous blog post, or the previous links. Both processes must be regulated to ensure a child’s brain develops properly, with just the right amount of neural connections, or synapses, in a process called pruning.

Similar to pruning a tree, neuronal pruning is an important regulatory process during development. Maintaining a balance between growing and removing synapses allows for just the right level of function.

The best way to explore the spectrum is to find which genes are affected to begin with. Notably, these include:

UBE3A: This gene is mutated or deleted in ASD. UBE3A normally codes for an enzyme that breaks down substances in cells. One of these substances is another protein, named ARC. The job of ARC is to reduce neuron excitation by pruning and weakening a synapse by removing AMPA receptors. When there’s too much ARC, too many of these receptors are removed, promoting LTD and decreasing synaptic strength.
SHANK: This creatively named protein refers to a protein found in synapses. It is quite literally a scaffold that supports the placement of receptors. It’s safe to say that mutations in genes that code for SHANK proteins could result in defective scaffolds and poor or irregular placement of receptors in a synapse. This could lead to deficits in learning, memory, and development.

Depending on the severity of the mutation and the degree of biochemical damage done downstream, autism symptoms can manifest at various points along the spectrum. Because autism is so complicated, another easier way to understand the spectrum is by studying other disorders that share common mutations with the disorder:

Angelman Syndrome: This genetic disorder often has a comorbidity of ASD and shares many common symptoms. Similar to ASD, it is marked by the loss of a gene called UBE3A.
Tuberous Sclerosis: Also a genetic disorder, this syndrome is marked by mutations in genes called TSC1 and TSC2. Normally, these genes are tumor suppressors. Mutations in these genes might lead to the development of benign tumors, or too much growth or hyperconnectivity as seen in ASD.
Fragile X: Yet another genetic disorder (see a trend here?). The gene at focus here is called FMR1, found on the X chromosome (as noted by the name, Fragile X). Mutation to this gene prevents the production of a protein called FMRP, which is important in proper brain development.

By connecting what we know about autism and similar disorders, we can get a small glimpse into the microscopic world that creates the spectrum and each unique case of autism. At the end of the day, some might find themselves asking, should we cure autism, if the advances of modern day technology and genetics allow us to? Throughout history, autism has been viewed as a gift, a blessing, and for some, a curse. For some, if a cure allows their child to eat, talk, sit, and even walk on their own, then a cure might be the blessing they need to improve their child’s quality of life. But then again, history has seen dozens of gifted individuals who have been, or are suspected to have been, on the spectrum. Among these are Hollywood director Tim Burton, actor Dan Aykroyd, and Scottish artist Susan Boyle. Records even suggest that the genius himself – Albert Einstein – might have shown symptoms characeristic of the spectrum! It’s no doubt that the contributions these people brought to the world have been gifts. But whether you view autism as a blessing or a curse, it all goes to affirm one true statement – at the end of the day, we are all, simply, unique.

For more information about autism, be sure to visit this page, by the Autism Speaks program.

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Do we want a cure for Autism?

Posted on November 12, 2019 by / 0 Comment

What is autism?

Autism is a developmental disorder associated with dysfunction in social interaction and communication. Those diagnosed with Autism Spectrum Disorder (ASD) often engage in repetitive behaviors and/or interests. It’s important the diagnosis is labeled as a spectrum because there is a wide variety of symptomology that can fall on the scale. Some diagnosed are completely non-verbal and need daily care for the entirety of their lives while others go on to be esteemed professors in their field of interest.

What is different in an autistic brain?

There is not just one thing that is different in autism, making it a difficult disorder to pin down. Essentially, there are a number of variables that can influence the development of ASD including genetics environmental factors. Genetically, mutations in a variety of different proteins and genes are seen like SHANK, UBE3A, TSC1-TSC2, and others. Environmentally, increased age of the parents, pregnancy complications and exposure to some teratogens can increase the probability of ASD.

Let’s look at two examples of issues with proteins to see where some of the problems may be occurring:

The protein UBE3A degrades a protein called ARC. The main job of ARC is to reduce the amount of excitatory information by pruning at the synapse. When there are mutations of UBE31, ARC cannot do its job of reducing AMPA channel recruitments and pruning at a normal level and is often overexpressed.

Similarly, problems with genes encoding SHANK proteins are seen in individuals with ASD. Changes and communication need to be made regularly at the synapse and when the genes that help with the changes and communications mutate and don’t encode correctly, we see some of the behavioral issues known to be present in ASD like repetitive routines and anxiety-like phenotypes. One study on Shank2 suggested that mutations in the gene encoding process are alleviated by a partial agonist of NMDA receptor function suggesting that problems with NMDA receptors may be an important indicator of ASD.

What treatments are available

SHANK3 is one of the genes that encode the SHANK family of proteins. Some have found that restoration of SHANK3 levels in adulthood may be helpful in alleviating some of the impairments created by its mutations. This may seem like a step in the right direction but not everybody feels the same way. The video below talks a little more about the SHANK3 gene and how it works.

Some individuals in the autistic community take issue with the word “cure” as they don’t feel there is anything to be cured. For some, the diagnosis is an important aspect of their personality and not a detriment but an asset to their lives. It can be argued that trying to “cure” autism is simply trying to make sure everyone fits into the neuro-typical mold and eliminates variance in society. While there are those whose lives are severely impacted by ASD and are in immense pain and discomfort, we must be wary of labeling things a “treatment” versus a “cure” as those terms can mean different things to different people. If we “cured” autism, we may not have had Hans Christian Andersen’s famous children’s stories or Bobby Fischer’s incredible chess talent. Yet, we must not point to celebrity success as the only reason ASD should not be eliminated as each individual contributes uniquely to society.

Sources:

https://www.researchgate.net/publication/313495385_SHANK_proteins_roles_at_the_synapse_and_in_autism_spectrum_disorder

www.autismspeaks.org

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A Piece of the Puzzle: How Autism fits into the World

Posted on November 11, 2019 by / 0 Comment

Autism spectrum disorder (ASD) is a debilitating development disorder. Frequent signs include impairments in social interactions and communication, and restricted, repetitive and stereotyped behaviors or interests. Autism is typically diagnosed in ages 2-3 but can sometimes be diagnosed later in life, especially in females. ASD is primarily a genetic disorder but can also be due to mutations. Some of these are:

Fragile X syndrome – Caused by a mutation in the FMR1 gene which is found on the X chromosome. People have a longer FMR1 in FXS and it cannot produce FMRP which is crucial to brain development. Because of its location on the X chromosome, it is more likely that males are diagnosed with FXS.

Tuberous sclerosis complex – Caused by a mutation in TSC1 or TSC2 which encode a tumor suppressor. Because of this, people with this typically have benign tumors in multiple organs.

Angelman syndrome – A genetic development disorder due to the loss of the gene UBE3A. It is similar to ASD but typically has more severe signs such as seizures, ataxia (lack of coordination), strange fascination in water and more.

Timothy syndrome – Mutation in the CACN1C gene and is also known for its complication in heart problems, digits and malfunction of central and peripheral nervous systems.

Rett syndrome – A gene called MECP2 is supposed to help normalize the function of nerve cells. In ASD, this gene in under expressed and doesn’t work properly.

Due to the increasing diagnoses of ASD, it is important to underst See the source image and what is happening deep down. Autism is something that one is born with, but is not diagnosed until certain developmental bench marks are missed. Autism is diagnosed and then a spectrum is used to help define the severity. Some who are high functioning are considered to have Asperger’s. Autism is a complex disease and affects each person differently. However, even though they have a disease, they are still people living their life.

Researchers are continuously searching for ways to help better the lives of those with autism, especially those who are non verbal and cannot express their pain or emotions. Probiotics and changing children’s diets have been found to help behavior and those with autism also suffer from some sort of digestive problem.

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Missing Puzzle Pieces: Mechanisms of Autism Spectrum Disorder

Posted on November 8, 2019 by / 0 Comment

Autism spectrum disorder (ASD) manifests itself in early childhood during development. Behaviorally, ASD is commonly marked by challenges with social interaction, motor impairment, and unusual, repetitive behaviors. ASD has been found to be associated with the development of excitatory and inhibitory synapses. The excitatory synapses mature, and the inhibitory synapses develop during the earlier stages of childhood, around the time children are usually diagnosed. Due to this, ASD is correlated with synaptogenesis. Specifically, the synaptic adhesion molecules, neuroligin and neurexin, have often been linked to ASD. When a synapse forms, cell adhesion molecules (CAM) recruit neurexin and neuroligin which then link the two neurons through a heterophilic dimer. Neurexin and neuroligin then lead to the recruitment of receptors and ion channels that establish communication at the synapse. Many mutations of the genes that encode these proteins result in behaviors similar to that of autism in animal models. Neurexin and neuroligin are associated with neuro transmission and synaptic plasticity and may have a role in ASD. The SHANK scaffold proteins function in synapse morphology and function and have also been correlated to ASD behavior. However, the underlying causes of ASD still remain elusive.

But there is evidence that specific genes are linked to activity-dependent neuronal signaling that may be involved in autism. Many of these specific genes have mutations that cause other developmental disorders such as fragile X syndrome, tuberous sclerosis complex, Angelman syndrome, Timothy syndrome, and Rett syndrome. The mechanisms of these disorders may provide insight into the root of ASD.

Fragile X Syndrome: The mutation of FMR1 leads to decreased expression of the transcription repressor FMRP. The expression of ARC protein increases which acts in removing AMPA receptors causing long term depression.
Tuberous Sclerosis Complex: TSC1 and TSC2 inhibit the activity of mTOR which typically leads to the expression of proteins, thereby inhibiting protein synthesis. A mutation in TSC1 or TSC2 can impair their function. Similarly, binding of brain derived neurotrophic factor (BDNF) or a mutation in the AKT repressor, PTEN, both of which inhibit the activity of TSC1 and TSC2. This leads to excessive protein synthesis.
Angelman Syndrome: UBE3A is a ubiquitin ligase, meaning it marks proteins for degradation by the proteasome. In Angelman syndrome, UBE3A function is impaired. ARC protein is one of the proteins marked by UBE3A and because of the loss in functionality, ARC is present at high levels and decreases the AMPA receptors.
Timothy Syndrome: A certain Ca²⁺ channel is mutated, impairing channel inactivation which elevates the Ca²⁺ concentration in the cell. This could inhibit activity-dependent gene transcription.
Rett Syndrome: A mutation in MECP2, a transcription repressor, causing an imbalance between inhibition and excitation.

All these mechanisms affect activity-dependent signaling, specifically in synaptogenesis and synaptic plasticity, both of which are implicated in ASD. Therefore, these mechanisms may be a starting point for further research into the underlying mechanisms of ASD. This could include researching genes that are associated with ASD that are involved in activity-dependent signaling. Such research could ultimately provide treatment for severe cognitive impairments that are expressed in some individuals on the spectrum.

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Caffeine & Cocaine: Is There a Difference Between Addictions?

Posted on November 5, 2019 by / 0 Comment

Many of us out there are coffee drinkers. I myself have at least one cup every morning. I will admit, yes, I am slightly addicted to my morning coffee. But am it’s not really the coffee I am addicted to. It’s the caffeine in the coffee that wakes me up every morning.

According to the American Psychiatric Association, addiction is a disease that is caused by compulsive substance use despite harmful consequences. People who have an addiction or multiple addictions, are no longer able to control their will to use the substance or not to. The most common substance people become addicted to are drugs including alcohol, cocaine, methamphetamine, and opioids, among several others.

People use drugs to feel good, feel better, to do better, or just out of sheer curiosity. Some people just want to feel good or to experience the high that accompanies several drugs. Others, such as those with anxiety or depression, use drugs because it makes them feel better. Some use because they believe it helps them perform better at certain tasks. But no matter the reason people use drugs, the same pathways are activated in the brain.

The pathway that gets activated when a person uses a drug is the mesolimbic dopamine pathway. This is also known as the reward pathway. This pathway involves the release of dopamine. Rewards such as food, sex, or some sort of drug increase the concentration of dopamine in the brain.

When someone drinks a cup of coffee, this same mesolimbic pathway releases dopamine. This causes the person to feel good. Because of this, the person associates drinking coffee with feeling good. The more coffee the person drinks, the more caffeine they consume. Caffeine is a stimulant that causes chemical changes in the brain. Consuming caffeine on a daily basis can build up a tolerance to the caffeine, requiring more and more to feel the same effects as before. When someone like this does consume caffeine one day, they may experience a headache or shakiness, because the body is not used to not having caffeine in it.

So, what about drugs such as cocaine? Cocaine is a powerful stimulant, just like caffeine. It acts as a mood modulator and anti-depressant. So far this sounds pretty good. But the effects of cocaine only last for about 30 minutes. After that, to feel the same effects, more of the drug would have to be consumed. When cocaine is consumed, it binds to dopamine transporters on the cell’s membrane. Here, it blocks the cell from from being able to reuptake the dopamine molecules that are present from being released from the mesolimbic pathway. This further increases the concentration of dopamine and its probability of binding to its receptors. So, similarly to caffeine, a person has to take more and more to feel the same effects as the first time.

In the end, caffeine addictions and cocaine addictions arise from the same cause: dopamine. They both call for the need to use more and more. They both can lead to withdrawal symptoms when not consumed. The difference between the two is that one is more socially acceptable than the other. More people consume caffeine every day than cocaine. So how come one is seen as a problem and the other is not?

https://www.psychiatry.org/patients-families/addiction/what-is-addiction

https://neuroscience.mssm.edu/nestler/brainRewardpathways.html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920543/

https://www.addictioncenter.com/stimulants/caffeine/

https://moodle.cord.edu/pluginfile.php/818256/mod_resource/content/0/Overview%20of%20addiction%202019.pdf

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Who decides who made the choice?

Posted on November 5, 2019 by / 0 Comment

It’s their fault. They made that choice. Why should I help them. All they will do is spend the money on drugs. These are all things many of us have heard in person, on the radio, on tv or even a song. Addiction is a scary and complex thing. It’s hard on the addict, friends, and family. However, we often hear “it’s their fault. They made the choice” but did they really make the choice or was there something deep down out of their control?

Humans are pleasure seeking creatures which is triggered by neurotransmitters such as glutamate, dopamine, oxytocin and norepinephrine. Through these neurotransmitters, the reward-pleasure pathway incentivizing behavior. But these can also be triggered through the use of drugs such as opioids, cocaine and amphetamines. Therefore, the use of drugs is associated with a synthetic high with effects of euphoria, increased libido, enhanced sexual pleasure and more.
Cocaine and amphetamines increase the amount of dopamine in a neuron binding to receptors called D1. A cascade of events occurs, but the most important is the increase in two transcription factors, CREB and FOS-B. This increase in transcription factor causes more proteins to be produced than normal and affects the neural connections within the brain. Now, understanding slightly better what happens deep in the brain. So, is addiction within a person’s control?

It depends. Yes, there is the choice to take a drug but after that initial taste. However, many can’t stop because their brain is telling them they cannot function without it. Caffeine is an addiction on a smaller scale. When you have caffeine every morning and afternoon and then decide to quit cold turkey. You experience headaches, drowsiness, changes in mood and more. This is because you rapidly took something away your brain depended on. This, but on a more extreme is what happens to addicts.

A recent study published explained one possible treatment of addiction is through giving oxytocin. This is a neuro stimulus that many of us receive through our mothers. It provides a sense of well-being and connectedness. But, if someone was deprived and doesn’t produce enough oxytocin. Is it their fault that they unintentionally crave this sense of well-being/connectedness and the only similar feeling is through drugs? It is not only nurturing that impacts addicts but also nature. Some people are more predisposed than others genetically. There are many other factors that should be considered before directly blaming and shaming the addict. This way of thought will help eliminate the negative connotation of addiction and possibly help develop a better way of preventing and helping drug addicts.

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Shedding a Light on Addiction

Posted on November 5, 2019 by / 0 Comment

[i]

Drugs have been a controversial part of American culture practically since its infancy. For centuries, scholars have argued about the role of alcohol all while Americans celebrate its use. Most people remember some sort of anti-drug education in their schools, whether it be the DARE program or public service announcements (PSAs). All of this anti-drug propaganda seems to have sparked a bit of a controversy, mainly surrounding whether or not these drugs are that harmful in the first place. While this is certainly a compelling debate, the answer cannot be reached without looking at the science behind these drugs.

In the article, A Schematic Overview of Addiction: Molecular Effects of Cocaine, Methamphetamine and Morphine on Limbic Neurons, researchers summarize the neurological effects of three major drugs: cocaine, methamphetamine, and opioids like morphine and heroine[ii].

Cocaine

Cocaine is a stimulant, much like the common drug caffeine. Like other stimulants, cocaine pushes the body into action, making us feel elevated, excited, focused, and eager to do things. Cocaine mainly interacts with dopamine, a chemical involved in the reward pathway. Dopamine is also responsible for the pleasurable feeling that comes from using drugs. In the normal brain, dopamine is released from the neuron and then binds to receptor on the next neuron. After it has done its job, dopamine gets picked by a transport protein. (The figure below outlines the basics of neurotransmitter reuptake). Cocaine prevents this last part from happening. Thus, dopamine’s affect is increased, leading to increased pleasure and reward.

[iii]

Methamphetamine

Methamphetamine, or meth as it is more commonly known, is also a stimulant. However, there are few major differences between it and cocaine. For one thing, methamphetamine lasts a lot longer, mainly because it has a stronger effect on dopamine and other chemicals. Like cocaine, methamphetamine can block the transport proteins that take up dopamine, but it can trigger the release dopamine as well. Additionally, methamphetamine triggers the release of norepinephrine, another neurotransmitter involved in the reward pathway.

[iv]

Heroin

Unlike methamphetamine and cocaine, heroin and other opioids are sedatives or depressants (like alcohol). These drugs generally produce a more relaxed feeling, rather than one of excitement and “let’s get things done”. Opioids still produce a strong sense of euphoria.

Your brain naturally has a set of opioid receptors. Normally, neurotransmitters like endorphin bind to these receptors. However, drugs like heroin can mimic these neurotransmitters and produce a similar response. These receptors are linked to special proteins called the g protein. When heroin or other opioids binds to the receptor, the alpha sub-unit of the g protein breaks away. This process is aided by GTP. Opioids increase the activity of GTP.

Additionally, these g proteins are linked to various calcium and potassium channels within the neuron. (For a brief summary on the g protein, click here). When activated, the g protein helps close these channels. This makes the inside of the neuron more negative in terms of charge, preventing it from firing. This is what causes the sedative effect of opioids. (Note: this occurs because opioids interact with a specific type of g protein. A list of the different types of g proteins can be found here).

Why does this matter in the debate?

Whether a depressant like heroin or a stimulant like cocaine, all drugs trigger the release of dopamine. While dopamine is capable of exciting a neuron, in this case it mostly inhibits the inhibitory neurons. Think of this like a double negative. Inhibition of inhibition leads to excitation. A side effect of this excitation is the release of glutamate and the subsequent recruitment of AMPA receptors. This helps our brain remember where the pleasurable stimulus came from and makes us more likely to seek it again. This is what leads to addiction.

Addiction, in a certain light, is more or less a mechanism of how substances take over the brain, controlling wants and cravings for the substance. Addiction can be a terrible thing. It is also incredibly complex and difficult to treat, which is why some advocates for legalization/decriminalization of drugs have simply given up and said “let them do it.” If drugs like methamphetamine, cocaine, and heroin are going to be legalized, then they need to be deemed safe to use. The safety of this drugs is something the researchers acknowledge is not really well known[v]. There is some information. Both cocaine and methamphetamine can lead to heart problems, and potentially lead to a state of psychosis similar to schizophrenia. A lot of the dangers of using these drugs comes from impurities. Dealers often mix drugs like heroin with other illicit drugs or substances to either cut cost or alter the affect. These substances often have terrible side effects and can exacerbate the side effects of the original drug. Legalizing drugs is theorized to cut down on these impurities and the dangers associated with them. Now, how much of the danger of using illegal drugs comes from impurities and how much comes from the drugs themselves is unknown at this time.

Knowing the science on addiction really showcases it as the complex issue that it is. There are multiple chemical pathways of addiction. It affects nearly every area of the brain, and in different ways. Looking at the science behind these drugs and addiction in general shifts the debate from vilifying drugs and those who are addicted to them to discussing how to properly solve the problem of addiction.

[i] Artstract by Mitzi Probst.

[ii] https://moodle.cord.edu/pluginfile.php/818256/mod_resource/content/0/Overview%20of%20addiction%202019.pdf

[iii] https://www.ck12.org/biology/drugs-and-the-nervous-system/lesson/Drugs-and-the-Nervous-System-Advanced-BIO-ADV/

[iv] https://www.christian.org.uk/news/surge-free-needles-belfast-heroin-addicts/

[v] https://moodle.cord.edu/pluginfile.php/818256/mod_resource/content/0/Overview%20of%20addiction%202019.pdf