This document summarizes research on genes related to autism spectrum disorder (ASD). It discusses five genes - mTOR, CNTNAP2, NRXN1, NLGN3, and MET - that are associated with ASD. These genes are involved in brain cell functioning and pathways, especially related to neurons and synapses. The document provides background on brain cells, how synapses work, how neurons connect, and how neuronal pathways can affect those with ASD. It discusses in more detail the neurexin and neuroligin families, which help form bridges between neurons, and are important for ASD research.
1. Melissa Maack
Honors Project Biology 100
Natalie Schmidt
Genetics Related to Autism
ABSTRACT:
Autism or autistic spectrum disorder (ASD) as defined by the medical dictionary is “a complex
developmental disorder distinguished by difficulties with social interaction, verbal and nonverbal
communication, and behavioral problems, including repetitive behaviors and narrow focus of
interest. Sensory problems, restricted interests and activity, language problems” (Miller-Keane
2003). Autism is a heterogeneous disease: over 3000 genes associated with its development.
The disease is not caused by any one single gene, it is caused by the interaction of several
genes working improperly. For this literature review, I have chosen to present five of these
genes: mTOR, CNTNAP2, NRXN1, NLGN3, and MET. After ascertaining the genes to be
studied, the questions asked in this paper were the following: What do they do? How are they
related to nerve cell functioning and pathways?
INTRODUCTION:
.
Autism is a mental condition usually present from childhood, and it is a lifelong disease. There is
little known about it, other than it is a genetic condition. This is a heterogeneous disease. It has
many diverse characteristics. In order to find a solution, one must be able to identify its causes.
It is believed to be a genetic disorder. The purpose of this literature review is to review the
smallest component, the genes. This is a start; a base for further research opportunities.
Materials and Methods:
For the purposes of this literature review, the sources used were: the studies done on genes
from many peer reviewed sources, the autismkb genetic list, Mosby’s dictionary, medical
dictionaries etc. The researchers for the autismkb list used previous studies done on the genes.
Using those studies in conjunction with the algorithm they devised they were able to narrow to
171 genes from a list of 3075 genes. They relied on Genome Wide Association Studies
(GWAS), Genome Wide CNV studies, linkage analysis, low scale genetic association studies,
expression profiling, and other low scale gene studies, and using an algorithm, the study gave
each gene an assigned confidence weight. Confidence weight is the percentage of likelihood to
find that gene in the disease. Ninety-nine were syndromic genes, which is a specific list of
2. genes that are considered to be a part of the disease and are characteristic of this disease.
3022 were non-syndromic genes, which are not suspected or not as likely to be a part of the
disease. 4964 were copy number variations genes (CNVs) or duplications of genes that are not
functional to the body, and 158 linkage region studies (Xu, et al. 2012). Genetic linkage is
independent genes that are close together, and located on the same chromosome (Mosby’s
2013). Linkage region or analysis studies focus on this link. According to their list of parameters,
they used reviewed papers from 2004 to 2010, and the genes listed must have been in at least
two review papers. Using the methods shown below for data collection and the function listed
below they were able to give each gene an assigned confidence weight. Only the best gene
rankings were chosen. The lowest score given by the algorithm was 16% to SHANK2 (Xu, et al.
2012). Below is the process used for their study.
(Figure 1: Flow Chart of Data Collection Xu, L.M., et al. 2012 )
Scorei=0 if no positive evidence.
For N datasets, there are possible K (e.g. N+1) different weights, thus, it forms a KN weight
matrix pool (Xu, et al. 2012).
3. (Figure 8: Distribution of the combined score upon cutoff Xu, et al. 2012)
For the purposes of this literature review the autismkb list was primarily used, and further
narrowed by using the following parameters:
First: Research on the gene in question. For the purposes of this paper the number of autism
related publications needed to have been at least ten studies and publications per gene.
Correlation needs a lot of data in order to be declared possible causation.
Second: In the genes studied, there must have been more positive correlations than negative
correlations with autism overall. A basic math formula was used, which was the number of
positive test results over the number of overall test results, giving a percentage of likelihood. For
the purposes of reducing the number of genes researched in this paper, the percentage of 70
and above was chosen. For example, in the CNTNAP2 gene, ten studies were done, and nine
of those studies were shown to have correlation with symptoms of autism. Using this method,
CNTNAP2 scored ninety percent.
Third: Only genes that scored a confidence rating of 20 or above using the algorithm the
autismkb devised were used. A confidence rating or interval in statistics is the percentage of
likelihood that what is being tested is more or less likely to be present in the entire population. In
4. this case, the confidence rating is the likelihood of the genes to present themselves in the
autistic community according to the data in the studies.
RESULTS:
Brain Cells:
The genes associated with autism have components in the brain as well as other organs. It is
thought that the connections between brain cells may be part of the cause.
The brain is a collection of two categories of cells, the glials and the neurons. This collection of
cells overlaps and allows for sending and receiving of messages in a cascade-like motion
(Südhof, 2008). The glia or neuroglia: cells that act as insulators for electrical impulses between
neurons. There are actually three types of glial cells each type pertaining to its own areas in the
central nervous system. The particular glial cells that act as insulation are called
oligodendrocytes, Schwann cells or myelin sheath cells. These cells provide structure and
support as well as insulation (Purves, et al., 2001). The neurons: These are the functional parts
of the brain, they are cells that conduct electrical impulses from one cell to another (Medical
Dictionary 2006).
Neurons can be classified by direction of the impulses. Unipolar neurons: which has one axon
and one dendrite. Bipolar neurons: while fewer in number than other neurons, have one axon
and one dendrite. Multipolar neurons: have one axon and several dendrites. The other
classification is where those impulses are sent to: Sensory neurons send impulses to the spinal
cord and brain, motor neurons send impulses from the brain and spinal cord to the muscles.
Interneurons send impulses specifically to other neurons (Mosby’s 2013). Several of the genes
involved in autism are interneurons.
How a synapse works:
As ASD is associated with the nerve cells and synapses, it is important to know how a synapse
works. An impulse is sent along a nerve cell, which is protected by the glial cells to the end of its
terminal. The synapses that send the amino acid glutamate are called excitatory synapses,
those that send GABA are called inhibitory synapses. The presynaptic and postsynaptic
membranes must always be perfectly aligned and the cleft must be less than 20 nanometers
across. The presynaptic cell adhesion molecules called Neurexins and the postsynaptic cell
adhesion molecules called Neuroligin are believed to be the bridge between the pre synapse
and post synapse (Südhof, 2008). Within the presynaptic cell, a vesical carrying the glutamate
or GABA goes to the membrane of the cell, then starts to build a bridge between neurons. The
post synapse sends its own bridge portion to complete the transfer. This bridge brings the
neurotransmitter (brain hormone/chemicals) into its membrane at the post synapse. Depending
on the neurotransmitter that the pre synapse sent, depends on the action potential or short term
change in the electrical potential on the membrane of the cells. If it is the amino acid glutamate
it will span the synaptic cleft and to the post synaptic membrane in an effort to open the
5. positively charged calcium ion channels. This will enable the pulse to connect to the post
synapse for transfer. The synapses that release glutamate are called excitatory synapses, those
that release GABA or the inhibitory neurotransmitter, are called inhibitory synapses, which
prevent the ion gate channels from opening. Either of these neurotransmitters change the action
potential of a nerve cell. It either increases its likelihood to travel, or decreases it (Südhof,
2008).
How do the neurons connect?:
Autism research is showing that there is a convergence along the neuronal glutameragic
pathways specifically targeting the post synapses. Glutamate is an amino acid that enables the
post synapse to open its ligand gate channels. When these channels open, it allows ions (e.g.
calcium, potassium, sodium, etc.) to enter the post synapse and increases the cell's action
potential to pass along nerve impulses.
Once a neuron is created, it travels, and once it reaches its destination, it changes shape
(Shenfeng, et al. 2014). This makes it different than other nerve cells; the cell differentiates so
that it can perform specific tasks. Once the cell forms its shape, it has two sides, one that
gathers information: the dendrites, which look like long branches of a tree, and the output (the
axon). The axon sends out a signal to the dendrites that are forming so that they can reach out
to the axon. Once activated, the dendrites grow in response to this signal. Once the dendrites
have reached out to their destination, synaptic connections form (Yun Peng, 2013). These
connections are called the presynaptic neurons, which is a neuron from the axon terminal of one
cell body that sends an impulse across the synaptic cleft to one or more dendrites of the post
synaptic neuron by the release of a neurotransmitter (Medical dictionary 2006). This impulse is
sent to the postsynaptic neuron, via the dendrites by the release of a neurotransmitter from the
axon terminal of the presynaptic cell. (Medical dictionary 2006). Basically, this means that the
dendrites direct the impulse from the presynaptic neuron to the cell body from the cleft. The cleft
is the space between neurons. It measures roughly 10-20 nanometers across from the axon
terminal to the postsynaptic surface (Medical Dictionary 2006).
There are two types of synapses: the excitatory and the inhibitory synapses. Both of these refer
to the synaptic action potential of a cell. Action potential is the likelihood of impulse transmission
conducted from the axon terminal of the pre synapse along the cleft, to the post synapse.
“Action potential is the electrical signal conducted along axons by which information is conveyed
from one place to another in the nervous system” (Purves, et al., 2001). The likelihood of this
impulse is either increased or decreased depending on the neurotransmitter output from the
axon terminal of the presynaptic neuron. Glutamate, an amino acid increases likelihood
(excitatory), conversely GABA decreases likelihood (inhibitory) (Purves D, et al. 2001).
6. How do Neuronal Pathways affect those with ASD?:
Several of the genes that this paper examines are genes that affect neuronal pathways, and
several seem to converge on the glutamate (excitatory) synapses. “Multiple ASD susceptibility
genes converge on cellular pathways that intersect at the postsynaptic site of glutamatergic
synapses” (Guomei Tang, et al. 2014). Glutamatergic simply means having to do with glutamate
(Medical Dictionary 2006). Glutamate is the most common excitatory neurotransmitter. It is
actually more prevalent than serotonin and dopamine combined. It has a role in memory,
sensory nerves, and in impulse transmission as this particular neurotransmitter opens the ligand
gate channels in the post synapse (Fitzgerald, et al. 2012).
ASD is characterized by issues with social interactions, communication, and repetitive behaviors
(Guomei Tang, et al. 2014). Autism is considered to be a neurodevelopment disorder, which by
using etymology, is a disorder that deals with the growth and development of the brain. This can
lead to anxiety and issues with social interactions. It can also lead to issues with neuron
excitability, and complex information processing (Pat Levitt, et al. 2004). Several studies are
showing that if the interneuron is changed in any way, it could be part of the pathology process
that causes ASD (Pat Levitt, et al. 2004). The Diagnostic and Statistical Manual of Mental
Disorders (DSM) 5 tells us that issues with the following are common while not expressed in all
individuals, is seen frequently in varying degrees of severity. This list is not exhaustive however,
and doesn’t include all symptoms (American Psychiatric Association 2013).
• Social interactions include:
1. social-emotional reciprocity
2. Give and take in a conversation
3. Improper rephrasing to help the audience understand the speaker.
4. Greeting, the sharing information, appropriate to the social context of the
situation.
5. An individual with ASD may fail to attempt communication at all or respond
in a way that is unexpected.
• Communication:
1. Proper eye contact
2. Body language
3. Use of gestures
4. Some of these communications issues are changing the context per situation
or to the needs of the other participant(s). One example would be the
different manners of speech used with an adult versus the way one would
speak to a child.
5. The volume of the voice
6. Use of overly formal language
7. 7. Misunderstanding of idioms, and taking jokes or phrases literally are
common with ASD.
Repetitive behaviors:
1. Flapping of the hands,
2. Constant fidgeting, bouncing of the legs and so on.
3. The repetitive use of objects; playing with an object over and over, flipping
it, toying with it.
4. Repeating noises and phrases that they hear called echolalia, sometimes
when in high state of emotion repetition of self as well.
5. Repetition also refers to routines and insistence upon them.
6. Severity is determined by the repetitive behaviors category
(Symptoms of ASD American Psychiatric Association 2013)
Neurexin and neuroligin families:
These families are important in autism due to their functions. They are responsible for creation
of bridges across the synaptic clefts to aid in transmission of impulses. The neurexin family is
located on the presynaptic membrane. The neuroligin family is located on the post synaptic
membrane. Their function is cell adhesion in the receptor sites; providing a bridge between the
presynaptic and postsynaptic membranes. The neurexin and neuroligin families build a bridge
across the synaptic cleft. This is one of the primary functions for the neurexin and the neuroligin
families. Other functions of these families include: cell growth, differentiation (cell change to
carry out a specific function), proliferation (increase in cells), apoptosis (cell death), their
repeats, and cell migration as well (NCBI. 2015, UCSC. 2015). When a pulse is sent through the
cell and to the presynaptic membrane, it changes the electrical ability to increase or decrease
probability to send a message across (action potential). This action potential releases one of
two neurotransmitters or brain hormones/chemicals GABA which decreases action potential of
the neuroligin, or glutamate which increases the likelihood of action potential to the next cell
(Medical Dictionary 2006). This particular gene has also been thought to have a major
developmental role in the mitigation (reduction) and development of neurons, and is shown to
be expressed in the brain region where the excitatory and inhibitory interneurons come from.
This has led to speculation that this would also lead to the development of circuits in the brain
(neuronal pathways) (Olga Peñagarikano and Daniel H. Geschwind 2012). It is also required for
dendritic spinal development, and are responsible for synaptic connectivity (Olga Varea, et al.
2015). This pathway suggested to be an underlying factor in ASD pathogenesis involves the
trans-synaptic interactions between neurexins and neuroligins (Südhof, 2008). This disease
may affect how impulses are passed from the presynaptic membrane to form a bridge to the
post synaptic membrane. The space between them is nanometers across, and if they are not
perfectly in sync with each other, and/or if they are not extending the bridge pieces correctly,
8. messages are lost. This is called the trans synaptic interaction hypothesis. This hypothesis was
confirmed by the discovery of mutations in the neurexin and neuroligin family bridges. This
mutation can alter homeostasis and/or impair the development of synapses (Jindan Yu, et al.
2011).
Chromosome Overview:
The human body has 46 chromosomes, 2 are gametes or sex cells and 44 create everything
from hair color to inherited illnesses. Chromosomes are the home of the genes. Each gene has
a location on the chromosome called a loci or locus (Mosby’s 2013). The graphic presentation of
this mapping of the locations of the genes on the chromosome and the relative distance
between each gene is called genetic or linkage mapping (Mosby’s 2013). The importance of
chromosomal mapping may allow us to see specific chromosomes that are being affected that
cause autism, which is why linkage region studies are done. Linkage region or analysis studies
find genes that are thought to be part of the pathology for a disease, and scientists have found
more often than not that two or more genes are seen together on the same chromosome
(Mosby’s 2013).
Chromosomes associated with autism:
Chromosome 7 has two genes that are shown to be contributing causes of autism as well as the
regulator gene for both. Two of the genes researched are on chromosome 7: CNTNAP2 and
MET as well as their regulator FOXP2. CNTNAP2 is the largest gene in the human genome.
This gene takes up 1.5% of the entire chromosome it is on measuring 2.30 kb across (NCBI
2015). A KB is a kilobase, a measurement of 1000 nucleotides or base pairs (Mosby’s 2015).
Chromosome 7 is responsible for the instructions for making proteins and growth of tissues and
organs before birth, which has also associated it with cancer (Hillier et al. 2003, Nakabayashi K
et al. 2008). This chromosome was also one of the largest that was sequenced in the original
human genome study in 2003 (Washington University School of Medicine 2003). Overall, it
represents more than five percent of the total DNA in cells. The size of this chromosome and
the size of the genes on it make chromosome 7 a very important gene in the autistic research in
as much as this particular chromosome and the genes on it infiltrate a very large portion of the
overall DNA. Any deletions, frame shift mutations, or CNVs could upset the balance of the body
as a whole (Nakabayashi K, et al. 2008). NLGN 3 and 4 are located on the X gamete (Yu, et al.
2011) this is directly inherited along the sex cells. This would also explain why more males
present autism than females (Yu et al. 2011). Basic biology tells us that females have a
possibility of inheriting a normal X chromosome alongside of the abnormal X. Males only have
one X chromosome, the other is a Y. MTOR is located on chromosome 1 and is directly related
cell responses to DNA damage (NCBI 2015), to deprive cells of nutrients so they will induce
autophagy (Guomei Tang., et al. 2014). Chromosome 1 is the largest chromosome in the
human genome (NCBI 2015). NRXN1 is located on chromosome 2 (NCBI 2015) and is part of
the neurexin family of genes that are responsible for building a bridge to the neuroligins for
transmission of impulses across synapses (Südhof, 2008).
9. The Genes:
Met
According to a study done in 2014, this gene is thought to relate to the autistic characteristics of
cognition, social and language skills and executive functions. The researchers go on to say that
this would lead to reduced connectivity to the temporoparietal lobes (the space where the
temporal lobes and the parietal lobes meet) which are thought to be the main area for MET
expression. It also goes further to say that MET influences many neurodevelopmental areas.
This gene is responsible for normal pathway integrity in humans in very early developmental
stages (Shenfeng Qiu, et al, 2014). Met is a gene that regulates dendritic spine and neural
morphogenesis (etymologically broken down to mean morpho (change), and genesis (creation).
According to Weinstein this also relates to the process of creating a nerve cell. This process is
called induction during early stages of development signals are sent from an organized cluster
of specialized cells that cause neural development (Weinstein DC, et al. 1999). In later
development too little of the MET gene leads to wildly growing dendrites. Which are more
complex than in normal humans, and to mutations of their formation, and the timing of the
glutamatergic synapses in the postsynaptic membranes. These synapses take in the amino acid
glutamate to open the ion channels so that the positively charged calcium ion particles can pass
into them. The loss or gain of MET in early development leads to changes that are opposite in
nature than one would expect. Changes in dendritic spine shape and complexity, spine creation
and change, and the timing of glutamatergic synapse maturation. Deletion of the gene shows
faster than expected growth of the excitatory synapses. Current studies have shown that MET
receptor signals are unique, and they have a role in controlling neurons and dendritic spine
morphology (Shenfeng Qiu, et al, 2014).
mTOR
mTOR is a gene that regulates cell growth. This gene is also a regulatory gene in autophagy,
has roles in cell proliferation (increase in cell numbers), cell motility or movement, cell survival,
protein synthesis that is RNA specific, and RNA transcription (Chang Hwa Jung, et al. 2010,
Joungmok Kim et al. 2103). It has been suggested by recent studies of the gene that it may be
responsible for failure in the pruning mechanism (autophagy of the cells) of excitatory synapses
in autism. This failure is thought to result in the social interaction deficits that are characteristics
of autism. This would increase neuronal pathways that lead to the frontal cortex of the brain
(Guomei Tang, et al. 2014). These excitatory synapses are the synapses that release the amino
acid glutamate which opens the positive calcium ion channels in the postsynaptic cell
membrane to increase likelihood of action potential (Medical Dictionary 2006). This increase
would allow for continued growth of dendrites increasing density. mTOR silences AMPK and
another gene UNK1 instead of being silenced enough for the autophagy process to complete
(Guomei Tang, et al. 2014). Most of the genes that make one susceptible to autism, seem to be
connected in some way to the presynaptic and postsynaptic pathways. This appears to be
10. specific to the pathways that send and those that receive the amino acid glutamate in
transmission of impulses. Tang and his colleagues go further to say that this would indicate
abnormally functioning spines of the dendrites. Spines are the main branch for the dendrites.
The researchers noticed that consistently increased spine density is observed in frontal,
temporal, and parietal lobes in ASD brains. This led to changes in synapse structures. Spinal
density begins to grow at birth, and then during childhood it peaks. During the teenage to adult
years, this number decreases dramatically. This enables the immature circuitry and cells to
mature. When the circuitry is forming in utero, the circuitry forms rapidly. This continues for a
short period during development and into early childhood. Then, in the normal brain after the
peak of neuronal circuitry is reached, the circuitry begins to decline by up to fifty percent by the
time the child has reached adulthood. In the autistic brain however, this density is only down by
sixteen percent. (Guomei Tang, et al. 2014). Synapses must be able to balance creation and
destruction in order to maintain homeostasis (Guomei Tang, et al. 2014). The overproduction of
mTOR inhibits some of the autophagy components to mature into a viable auto phage cell
(Guomei Tang, et al. 2014, Hall MN. 2008). To explain how this works it needs to be known that
AMPK is the “on” switch allowing the cell to activate ULK1 a gene that creates a protein used
early on in the autophagy creation process, and if it has been determined that if the cell is in a
state of ill health; AMPK starts creating autophagy cells. MTOR is the regulator gene for this
process. If mTOR is overproduced, the AMPK cannot create autophagy cells (Joungmok Kim, et
al. 2103). In a 2014 study, in dendritic spines, (dendrites being the “branches” for message relay
in nerve cells), autophagy was found to be necessary to remove unwanted connections. In early
development, excitatory cells are necessary in abundance for the brain to grow, however, they
start to degrade and decline in numbers from childhood to adulthood. However, these are
immature cells that formed during the growth process. They must be able to grow to correct size
in order to function. The process of removal for the brain circuits allows the synapses and
neuronal circuits to mature for proper function (Guomei Tang, et al. 2014). There is a noted
increase in population of dendrite spines in those with ASD (Hutsler JJ, et al. 2010).
CNTNAP2
CNTNAP2 is considered a focus of autism and is seen in many individuals with this disorder. Of
the times it has been studied specifically, several cases this gene is shown to be present in
those with ASD to not be functioning correctly. The protein this gene produces is involved with
language development: one of the key issues with autism. This, along with communication, and
cognitive processing are some of the key areas associated with autistic spectrum disorder. This
gene is also involved with synapse production, and dendrite formation which pass messages
along to other cells, or collect said information (Pedro Rodenas-Cuadrado et al. 2014). It is
suggested that deletion mutation of parts of the gene or over production are the causes for
autism (Pedro Rodenas-Cuadrado et al. 2014, Christiane Zweier, et al. 2009). This is still under
debate. This gene is an interneuron specific gene, meaning that it sends messages to other
central nervous system neurons only. CASPR2 is the protein that the CNTNAP2 codes for. This
particular gene is in a superfamily called neurexins, which aid in cell to cell interactions within
the nervous system. It has been suggested that those individuals with ASD who carry the risk
variant of this gene may have effects to the structure and function in the network of pathways
11. related to autism. These areas relate to cognitive processing in the brain (Pedro Rodenas-
Cuadrado et al. 2014).
NRNX1
A 2009 study of this gene in relation to autism found that the NRNX1 is a gene from the same
family as CNTNAP2, the neurexin family. NRXN1 has been shown that along with CNTNAP2, to
be among the largest genes. When there are too many CNVs (copy number variations or
duplications) of the genes, it reorganizes synaptic shape, and increases density in population of
synapses (Christiane Zweier, et al. 2009). Conversely, patients with deletions of NRXN1 have a
range of conditions including: autism, speech delay, social communication difficulties,
developmental delays, learning difficulties, ADHD, epilepsy, and behavior problems (Sarah
Curran et al. 2013).
NRXN1 and CNTNAP2 are nuerexins, and one of their function is to release neurotransmitters
that cause cellular growth. With too many CNVs of one or the other of the genes, synapses get
reorganized and therefore, can cause issues by allowing the post synaptic gene to receive more
glutamate simply because there are more genes producing it. If either this gene or CNTNAP2
are increased in number, it can reorganize the synapses, increasing density of the active zones
for glutamate, and allow for more glutamate to be in the brain (Christiane Zweier, et al. 2009).
The slightest changes to the synapses can result in too little or too much connectivity in the
brain. If it is moved slightly, connections may fail entirely because of reorganization. If synapses
are not perfectly aligned with each other, transmission of impulses will fail. If the synapses are
not forming correctly, or if they are not aligning with their counterparts, the impulses cannot get
across. Too much production from the excitatory synapses means out of control growth. The
study went on to say that no growth inhibition points to a lack of communication between the
synapses (Christiane Zweier, et al. 2009). If it causes extra branches, or too few branches of
those nerve cells to appear, the GABA neurotransmitter fails to issue a stop command for action
potential. This can increase the overall number of cells to unexpected amounts in areas of the
brain that they are located in, and cause too much production of neurotransmitters. This as has
been said will cause an increase in density as the synapses are unable to get enough GABA to
combat the glutamate. When this neurotransmitter (glutmate) is overproduced, it allows for
growth. The theory that synapse impulse communication, which is a suspect in autism, may be
caused by either the overexpression of this or the CNTNAP2 gene. This can cause abnormal
neuronal excitability, processing of external information and complex information, as well as
issues with anxiety and issues with social interactions (Pat Levitt, et al. 2004). This could lead to
behaviors such as anxiety and difficulty in social interactions, which are two of the ASD
phenotypes. It can also lead to cognitive and speech delays (Wiśniowiecka-Kowalnik, et al.
2010).
12. NLGN3 and NLGN4
As these genes are frequently listed together, in various studies, so this paper will be focused
on them as a unit as well. These genes are located on the post synaptic membrane, and as with
many nueroligins their function is cell adhesion in the receptor sites; providing a bridge between
the presynaptic and postsynaptic membranes. NLGN3 and NLGN4 are neuroligin genes on the
postsynaptic membrane and may be involved with formation and remodeling of the central
nervous system synapses (Jindan Yu, et al. 2011). Synapse development is imperative to a
normally functioning brain. Without it, and without the messages being able to cross the space
between synapses, messages such as a crucial start or stop are prevented. According to a
study in 2011, frame shift mutation of both of these genes seems to contribute to developmental
delay. This delay in autistics is generally seen as language delays, or delays in speech. The
study went on to say the researchers also found that a NLGN3 specific frame shift mutation has
also been thought to affect information processing. The theory they proposed in this study is
that these genes are affecting neuronal networks by changing networks structure, architecture
and synchronization (Jindan Yu, et al. 2011). Another study in 2009 on the NLGN4 gene
specifically suggested that NLGN4 is prevented from traveling to the membrane disabling its
ability to transport the impulse into the cell. It went on to show that there is a direct correlation of
functional effects of NL4 mutation in the clinical phenotype in humans. This supports the trans
synaptic theory interaction hypothesis of ASD (Chen Zhang, et al. 2009).
CONCLUSIONS:
The genes associated with autism all seem to converge on the mechanisms responsible for the
glutamate excitatory synapses. There is an autophagy regulatory gene, the dendrite and neuron
growth gene, as well as genes that are associated with the transmission of the amino acid
glutamate. There were two families which were researched using various genes: the neurexin
family, responsible for the presynaptic membrane transmission of glutamate to the post synapse
and the neuroligin family which is located in the postsynaptic membranes. The neurexins and
neuroligins are bridges between the synapses at the cleft, a space that is 10-20 nm wide.
Autophagy malfunction of the mTOR, which prevents the dendritic pruning associated with the
frontal cortex region of the brain, and is also believed to cause the social interaction deficits
frequently seen in autism. MET, which is thought to aid in cognition, social and language skills
and executive functions. MET is responsible for the normal circuitry integrity in humans in very
early developmental stages (Shenfeng Qiu, et al, 2014). MET is believed to be a gene that aids
in neuron and dendrite formation and change. MET is another gene responsible for cognition,
social and language skills and executive functions. The job of MET is to aid in creation and
morphogenesis of the neurons and dendrites. This gene also encodes for the placement of the
axons, as well as decisions in cell fate. The CNTNAP2 gene is involved with language
development, communication, and cognitive processing. These are key areas associated with
autistic spectrum disorder. This is the largest gene in the genome and comprises about five
percent of all the DNA in the body. This gene is also involved with synapse and dendrite
13. formation (Pedro Rodenas-Cuadrado, et al. 2014). NRXN1, a member of the nuerexin family,
and is a cause of anxiety, social interaction issues, speech and cognitive delays, social
communication difficulties, and learning difficulties. NLGN3 and NLGN4, which are a part of the
neuroligin family and are responsible for the reception of the neurotransmitters that the neurexin
family sends. This then allows the ion gate channels to open or close in order to allow action
potential of the nerve to change to either favor impulse send, or to decrease the ability for it to
send. These genes are concerning various parts of developmental delays in speech and
language, and in information processing.
There is research being done on the glutamate pathways, however, more research
needs to be done on these pathways. Perhaps this is the next phase in solving the puzzle of
autism. One might also look into the possible locations of the activity in the brain that these
pathways lead to. Researchers could review articles that referred to more connections than
necessary in the brain. Another possible area of research might be to consider the theories that
neuronal connections while greater in number near the frontal cortex and hippocampus, but the
longer term connections to the tempopariatal lobes may be lacking (Shenfeng Qiu, et al, 2014).
One might research more into those areas of the brain, and determine if the glutamate
pathways actually led to those regions theorized. One must be able to build from the
foundations up. This paper was a start, a base. More research needs to be done to determine
the paths, rather than just being a theory, to being actuality. Now that the groundwork has been
laid, it is time to continue research on where that groundwork leads to.
What are the implications of those pathways? Can the pathways be tested to find
evidence for what the studies are suggesting? Is there even the slightest clinically significant
differences between ASD brains and normal brains in the areas in the brain thought to be
affected by ASD? Is there a way to find this or even look into the neuronal connections and see
if there is indeed a pattern to it? Studies have shown some hyper connectivity in certain studies
already. One might wonder then is there a pattern to it? Do they actually connect back to the
glutamate pathways?
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