1 THE JOURNAL OF NEUROBEHAVIORAL SCIENCES VOLUME 1 / NUMBER 3 / 2014
JNBS 2014 Published by Üsküdar Universitywww.jnbs.org
THE JOURNAL OF
NÖRODAVRANIŞ BİLİMLERİ DERGİSİ
Year : 2014
Volume : 1
Issue Number : 3
Doi Number : 10.5455/JNBS.1408369302
Received 18 August 2014
Received in revised form 29 August 2014
Accepted 18 September 2014
1 Üsküdar University, Health Sciences Institute, Neuroscience Master Program
2 Üsküdar University, Faculty of Engineering and Natural Sciences, Bioengineering Program.
3 Üsküdar University, Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics.
*Address for Correspondance: Zeynep Kalkan, Üsküdar University, Health Sciences Institute, Neuroscience Master Program Department of Psychology,
Üsküdar University, Altunizade Mh. Haluk Türksoy Sk. No:14 İstanbul, Türkiye 34662.Phone:+90 5074929287 E-mail: firstname.lastname@example.org
RECENT STUDIES ON GENETIC AND ENVIRONMENTAL BASIS
The disorders are characterized by impaired social
interaction, communication andverbal communication
and language impairments, and repetitive behaviors and
interests. Autism has an increasing prevalence in recent
years. From 2007 to 2011–2012, the incidence of ASD
rose from 1.16% to 2.00% in the United States of America
(Blumberg et al., 2013).
Most researches shows that both genetic and
environmental factors play a role in the development
of ASD. High concordance of ASD among boys and girls
cannot be explained by genetic heritability alone; shared
environmental factors explain a large proportion of the
variance in liability. In addition, prenatal exposure to
organophosphates has been related to a signicant
reduction in childhood IQ.
2. Glutamate and Autism
Glutamate is a major excitatory neurotransmitter, is
highly concentrated throughout the brain and is crucial
to neuronal plasticity and the maintenance of cognitive
Autism is a neurodevelopmental disorder that affects
1–2 in 100 children, according to recent data on the broad
array of autism spectrum disorders . Autism is diagnosed
when a child or adult has abnormalities in a ‘‘triad’’ of
behavioral domains: social development, communication,
and repetitive behavior/obsessive interests. Autism can
occur at any point on the IQ continuum, and IQ is a strong
predictor of outcome (Baron-Cohen et al., 2009). Unusual
social development becomes apparent early in childhood.
Autistic infants show less attention to social stimuli, smile
and look at others less often, and respond less to their
own name. Autistic toddlers differ more strikingly from
social norms; for example, they have less eye contact
and turn taking, and do not have the ability to use simple
movements to express themselves, such as the deciency
to point at things.
Autism is one of the subtypes of autism spectrum
disorders (ASD) which refers to a group of childhood
neurodevelopmental disorders with polygenic etiology.
Autism is a childhood neurodevelopmental disorder that affects 1–2 in 100 children, according to recent data on the broad array of
autism spectrum disorders. It is a neurodevelopmental disorder, genetic and environmental factors playing role in autism. Molecular
and mechanistic basis of autism started to be enlightened. As a genetic basis of disease, glutamate gene mechanisms supposed to
develop a new method for diagnosing and treatment of autism. Aim of this mini-review is to gain a general knowledge about genetic and
environmental reasons of autism.
Keywords: autism, glutamate, immune system, genetic, neurodevelopment.
Zeynep Kalkan*1, Hazal Gür2, Belkis Atasever Arslan3
Otizm, son verilere gore, 100 çocuktan 1-2 sinde görülen bir çocuklukçağı nörogelişimsel hastalığıdır.Nörogelişimsel bir hastalık olan otizmde genetik
ve çevresel faktörler rol oynar. Otizmin moleküler ve mekanistik temelleri aydınlatılmaya başlanmıştır. Hastalığın genetik altyapılarından biri olarak,
glutamat gen mekanizması, teşhis ve tedavisi için yeni bir metod geliştirilmesine olanak sağlayabilir. Bu kısa derlemenin amacı, otizmin genetik ve
çevresel nedenleri ile ilgili yapılan son çalışmalardan faydalanılarak hastalık hakkında bilgi edinmektir.
Anahtar Kelimeler: otizm, glutamate, immune system, genetik, nörogelişim
OTİZMİN GENETİK VE ÇEVRESEL TEMELLERİ HAKKINDAKİ SON ÇALIŞMALAR
VOLUME 1 / NUMBER 3 / 2014 THE JOURNAL OF NEUROBEHAVIORAL SCIENCES 2
JNBS 2014 Published by Üsküdar Universitywww.jnbs.org
functioning. However, excess glutamate has been shown
to be a potent neurotoxin that leads to neuronal cell
death (Manev et al., 1989) and is deemed to play a role in
the pathophysiology of some neuropsychiatric disorders
(Sheldon et al., 2007). Recently, a hyperglutamatergic
hypothesis of autism was proposed (Blaylock et al.,
2009) based on evidence of hyperglutamatergia in the
brain of individuals with autism. For instance, in a study,
levels of GAD 65 kDa and GAD 67 kDa proteins, both of
which are involved in converting glutamate to GABA, are
reduced in the brains of individuals with autism, resulting
in increased levels of glutamate in the brain substrate
(Fatemi et al, 2002). In addition, in another study that
contains neuroimaging magnetic resonance spectroscopy
has demonstrated that individuals with ASD have
signicantly higher concentrations of glutamate in the
amygdala- hippocampal region than do healthy controls
(Page et al., 2006). The high level of plasma glutamate
level especially in children with normal IQ is supposed
to be biomarker to diagnose autism (Shimmura et al.,
2011). Higher glutamate level is not limited to plasma,
and some studies conrmed its higher level in some brain
regions (amygdala-hippocampal regions) of patients with
autism compared to the controls (Page et al., 2006).
Most psychiatric and neurodevelopmental disorders
(PNDD) have a strong heritable component (Sullivan et al.,
2012). Twin studies have proved that neurodevelopmental
disorders, such as (ASD) (Posthuma et al., 2013).
Glutamate receptors (GluRs) mediate excitatory synaptic
transmission and plasticity in the brain (Traynelis et al.,
2010). Glutamate receptors encode GRIK2, GRIN3B
and GRIA3 genes which are related to ASD. In addition,
anomalies in regions on chromosomes six and seven,
encoding Glu receptors, have been related to ASD (Yang
et al., 2013). Abnormalities in the glutamatergic system
might therefore be implied in ASD. Indeed, epileptic
seizures which have been related to excitatory Glu and
decreased GABA, are common in ASD (Ballaban et al.,
3. Effects of environmental factors against autism
In addition to genetic basis of glutamate level,
environmental components also play role increased
glutamate level children with autism. Many children
with autism are picky eaters. They do not like a variety
of different foods. Eating problems are risk factors for
nutritional deciencies. Some of these children do not like
to try new foods and have food selectivity (Kral et al.,
Last ndings support that many children with autism
suffer from amino acids metabolism impairment.
Nearly, all the studies reported higher levels of plasma
glutamate in children with autism than those of the
controls. Hyperglutamatergic state causes excitotoxicity
and neurodegeneration (Sheldon et al., 2007). Moreover,
this increased glutamate level is compatible with the
ndings that the level of proteins involved in transforming
glutamate to GABA is decreased. A study compared
plasma level of 25 amino acids between high-functioning
autism children and the healthy controls. The study
showed that only the levels of glutamate and glutamine
were different between the two groups. While the level
of glutamate was increased, the level of glutamine was
decreased (Shimmura et al., 2011).
4. Immunologic system and autism
There is increasing evidence supporting that an immune
insult during pregnancy can have a signicant effect on
the developing fetus (Brown, 2012). For over 30 years,
epidemiological research has continued to nd associations
between maternal infection and increased risk of autism
(Atladottir et al., 2010). A recent large case-control
population based study revealed an increased risk of
developing autism spectrum disorder (ASD) with maternal
fever, which was attenuated if pregnant mothers used a
fever reducing agent (Zerbo et al., 2013). In addition,
reports highlight associations between risk of having a
child with autism and increased levels of inammatory
mediators in both the maternal sera and amniotic uid.
These increased inammatory markers, interleukins (IL)-
4, IL-5, and interferon (IFN)-γ. (Abdallah et al., 2012),
supporting a relationship between maternal immune
activation (MIA), aberrant fetal neurodevelopment, and
risk for neurodevelopmental disorders such as autism.
Also inammatory markers are playing role in another
neurological disorders such as panic disorder. A supporting
study has shownIL-12and IFN-γ were signicantly lower in
panic disorder group when compared to the controls and
IFN-γ values were signicant predictors of the presence of
panic disorder (Tukel et al., 2012).
Autism is not only result from genetic factors but
also environmental factors play signicant role in the
development of autism. From the beginning of individual’s
existence all factors can be effective. There are many
questions waiting to be answered about autism. Is it an
untreatable genetic destiny? Is there a chance to diagnose
autism before childhood?
It is still nebulous the underlying mechanisms of autism.
With understanding the role of molecular and mechanistic
basis of autism more details will be enlightened about
disease. Glutamate mechanism is only one of the
molecular reasons of autism. All knowledge in this area,
throw a new light on developing new genetic treatment
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