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Autistic Disorder is an early-onset developmental disorder with severe lifelong impact on social functioning, communication, and behavior. There is currently no marker or cure. The pathophysiology and etiology are obscure. Evidence for abnormal gamma-aminobutyric acid (GABA) function in Autistic Disorders is limited. A few case-reports and small studies have reported differences in GABA levels in plasma, platelets, and urine, compared to controls. Further studies on abnormalities of GABA function in Autistic Disorder are warranted. Plasma GABA levels were measured using a new and sensitive technique, based on gas chromatography/mass spectrometry, in a small group of youngsters with Autistic Disorder and Attention-Deficit/Hyperactivity Disorder. Participants were outpatients between ages 5-15, satisfying modern criteria for these disorders. Elevated plasma GABA levels were found in youngsters with Autistic Disorder. Psychotropic medications did not seem to affect plasma GABA levels in this study. Plasma GABA levels decreased with age. Elevated plasma GABA levels may be a biochemical marker of Autistic Disorder. This study supports the hypothesis that GABAergic mechanisms play a role in the etiology or pathophysiology of Autistic Disorder. However, the hypothesis remains unspecified owing to lack of research. Future studies on the clinical associations of seizure disorders, mood disorders, and catatonia in autistic people may provide the necessary data to formulate a coherent theory of GABA dysfunction in Autistic Disorder. More trials of medication with known or suspected effects on GABA function are warranted.
Preliminary Report
Signature: Med Sci Monit, 2002; 8(8): PR1-6
PMID: 12165753
Elevated plasma gamma-aminobutyric acid (GABA)
levels in autistic youngsters: stimulus for a GABA
hypothesis of autism
Dirk Dhossche
abcdefg, Heather Applegate
def, Ann Abraham
Paul Maertens
bdg, Lorna Bland
ab, Aladar Bencsath
abd, José Martinez
Department of Psychiatry, University of South Alabama, USA
Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, USA
Mass Spectrometry Lab, College of Medicine, Mobile, Alabama, USA
Department of Neurology, College of Medicine, Mobile, Alabama, USA
Department of Medical Genetics, College of Medicine, Mobile, Alabama, USA
Background: Autistic Disorder is an early-onset developmental disorder with severe lifelong impact on
social functioning, communication, and behavior. There is currently no marker or cure. The
pathophysiology and etiology are obscure. Evidence for abnormal gamma-aminobutyric acid
(GABA) function in Autistic Disorders is limited. A few case-reports and small studies have
reported differences in GABA levels in plasma, platelets, and urine, compared to controls.
Further studies on abnormalities of GABA function in Autistic Disorder are warranted.
Material/methods: Plasma GABA levels were measured using a new and sensitive technique, based on gas chro-
matography/mass spectrometry, in a small group of youngsters with Autistic Disorder and
Attention-Deficit/Hyperactivity Disorder. Participants were outpatients between ages 5–15,
satisfying modern criteria for these disorders.
Results: Elevated plasma GABA levels were found in youngsters with Autistic Disorder. Psychotropic
medications did not seem to affect plasma GABA levels in this study. Plasma GABA levels
decreased with age.
Conclusions: Elevated plasma GABA levels may be a biochemical marker of Autistic Disorder. This study
supports the hypothesis that GABAergic mechanisms play a role in the etiology or pathophy-
siology of Autistic Disorder. However, the hypothesis remains unspecified owing to lack of
research. Future studies on the clinical associations of seizure disorders, mood disorders, and
catatonia in autistic people may provide the necessary data to formulate a coherent theory of
GABA dysfunction in Autistic Disorder. More trials of medication with known or suspected
effects on GABA function are warranted.
key words:
ADHD • autistic disorders • catatonia • GABA • mood disorders • plasma levels • seizure disorders
Full-text PDF:
Word count:
Received: 2002.03.27
Accepted: 2002.06.11
Published: 2002.08.07
Author’s address:
Dirk Dhossche MD, Department of Psychiatry & Human Behavior, University of Mississippi Medical Center,
2500 North State Street, Jackson, MS 39216, USA, email:
Authors’ Contribution:
Study Design
Data Collection
Statistical Analysis
Data Interpretation
Manuscript Preparation
Literature Search
Funds Collection
Med Sci Monit, 2002; 8(8): PR1-6Preliminary Report
Autistic disorder is a behavioral syndrome with a broad
range of severity, beginning before the age of 3, affec-
ting at least 1 or 2 in 1000 people, and characterized by
lifelong impaired communication, impaired social inter-
actions, and repetitive interests and behavior [1,2]. A
higher prevalence of more than 1 per 500 people has
been found when using a broader definition, including
all the pervasive developmental disorders.
There is currently no reliable marker for this syndrome.
The diagnosis is made clinically. No cure has been
found yet. Various behavioral and pharmacological
interventions are considered beneficial for decreasing
behavioral or psychiatric problems. A small proportion
of autistic individuals is diagnosed with known medical
illnesses or genetic syndromes that may increase some
liability for autistic symptoms. However, the majority of
autistic people have idiopathic conditions, some of
which are now thought to have a genetic component.
A bewildering array of psychological, physiological, bio-
chemical, immunological, and genetic differences have
been reported between autistic people and control
groups [3]. Some differences have been replicable;
others have been attributed to the cognitive deficits that
often occur in autistic people; a few may mark core
deficits of autistic symptoms. Understandably, specula-
tions on the basic deficit(s) and etiological factor(s) are
abounding as definitive findings and a comprehensive
framework to fit all data are probably not forthcoming
soon. In addition, any viable hypothesis should consider
the protean nature of symptoms, course, and outcome
in autistic people. Based on findings in the current
study and literature, we, along with others [4,5], believe
that a hypothesis of GABA dysfunction provides a rea-
sonable alternative to organize many developmental,
clinical, and biochemical key issues in Autistic Disorder.
However, empirical evidence of GABAergic mechanisms
in Autistic Disorders is limited.
One study has reported low platelet GABA levels in
autistic children [6]. Elevated levels of plasma and urine
GABA have recently been reported in an autistic child
[4]. Borgatti et al. [7] reported no significant differences
in plasma GABA levels between autistic children, aged
4–14, with inverted duplicated chromosome 15 and
normal controls. However, mean plasma GABA levels
were higher (but not significantly higher) in the autistic
group (22 ng/ml, SD 5.95 ng/ml) compared to normal
controls (18.8 ng/ml, SD 4.5 ng/ml). Particulars of the
study sample and the small sample size (N=8) may
explain the negative finding. No other systematic data
on plasma GABA levels in autistic children have been
published to our knowledge.
In the current pilot study, plasma GABA levels were
measured in youngsters with Attention-Deficit Hyperac-
tivity Disorder (ADHD) and Autistic Disorder. Implica-
tions for a GABA hypothesis of Autistic Disorders are
Study subjects were recruited from outpatient clinics in
the Departments of Psychiatry, Neurology, and Medical
Genetics at the University of South Alabama. Inclusion
criteria were: 1) age between 5–15; 2) a chart diagnosis
of Autism; 3) DSM-IV diagnosis of Autistic Disorder
after extensive interviews with an experienced child psy-
chiatrist (DD) and child neurologist (PM); and 4) no
chromosomal abnormalities on karyotype analysis.
Control subjects were outpatients in the same age
range, with chart diagnoses of ADHD, who were exten-
sively interviewed by two psychiatrists and met DSM-IV
[8] criteria for ADHD (without affective or anxious dis-
The study sample consisted of 9 children with Autistic
Disorder (8 males, 1 female; mean age 7.8, SD 3.4; age
range 5–15) and 9 children with ADHD (6 males, 3
females; mean age 10.5, SD 1.8; age range 5–15). All but
one of the autistic children were prescribed at least one
psychotropic medication including antipsychotics
(olanzepine, quetiapine, risperidone, thioridazine)
(N=7) antidepressants (amitriptyline, citalopram, fluoxe-
tine, paroxetine) (N=3), anticonvulsants (N=2) (one
child on valproic acid and one on lamotrigine), and va-
rious other medications (stimulants, guanfacine, cloni-
dine). One autistic patient was diagnosed with petit mal
seizures. This condition was well controlled with lamot-
rigine. All children diagnosed with ADHD were pre-
scribed methylphenidate (N=8) or dextroamphetamine
(N=1), but no other medications.
Blood was drawn between 8–9 a.m. Children were
allowed to have a light breakfast and no medications
were given until after the blood drawing. Plasma was
deproteinzed and stored at -70°C until assayed. The
Institutional Review Board at the University of South
Alabama approved the protocol, and written informed
consent was obtained from each parent or legal
The concentration of free GABA in plasma is very low.
Analytic methods for free GABA need to be more sensi-
tive than commonly used analytical methods. A new and
sensitive technique, based on gas chromatography/mass
spectrometry (CG/MS) was developed by our group
(Abraham A, Dhossche D, Bland L, Bencsath A. Electron
capture GC/MS determination of gamma-aminobutyric acid in
plasma. Poster presented at the 49th annual meeting of the
American Association of Mass Spectrometry, Chicago, IL,
2001) and was used in the current study. GABA is
extracted with a mixture of acetone and heptane. The
dried extract is derivatized into N-Pentafluoropropi-
onlyl-GABA-pentafluorobenzyl ester in a one step reac-
tion and then analyzed by electron capture GC/MS. The
internal standard is di-deuterated GABA.
The boxplot (Figure 1) shows the median, range, quar-
tiles, and outliers of plasma GABA levels by diagnosis.
Med Sci Monit, 2002; 8(8): PR1-6 Dhossche D et al – Elevated plasma gamma-aminobutyric acid (GABA) levels…
There was one outlier, i.e, a case with values between
1.5 and 3 box lengths from the upper or lower edge of
the box (the box length represents the middle 50% of
the data), in the ADHD group with a plasma GABA
level of 56 ng/ml. Information from the lab leads us to
believe that this extreme value may be due to a technical
The median plasma GABA level of the remaining 8 sub-
jects with ADHD was 7.7 ng/ml (mean 8.4, SD 3.7,
range 3.3–15.6) compared with a median level of 12.8
ng/ml (mean 15.4, SD 6.2, range 7.4–27.2) in the autistic
group. Plasma GABA levels were significantly higher in
youngsters with Autism than in youngsters with ADHD
(excluding the outlier of 56 ng/ml) (T-test; t=–2.8,
df=15, p=0.01).
Plasma GABA levels differed by age (linear regression;
F=6.9, df=1, p=0.02), but not by sex (T-test; t=1.1,
df=15, p=0.3). In Figure 2, the scatter plot shows that
plasma GABA levels tended to decrease with age. How-
ever, after controlling for age, diagnosis remained sig-
nificantly associated with plasma GABA level (p=0.01).
Findings in this pilot study suggest that mean plasma
GABA levels are higher in children with Autism than in
children with ADHD. The possibility that plasma GABA
level is a marker of autism should be explored further
in larger samples.
Plasma GABA levels tended to decrease with age. An
inverse relation between plasma GABA levels and age
was also found in a study of child and adolescent psychia-
tric inpatients, at least in those with behavior disorders
[9]. The significance of this finding is unclear.
The use of psychotropic medications is a potential con-
founding factor. Inspection of plasma GABA levels by
type of psychotropic medication used did not reveal a
distinct pattern, however. The literature on changes of
plasma GABA due to medications is limited. A definite
increase in plasma GABA has only been shown after
treatment with divalproic sodium in healthy volunteers
[10] and in neurological patients [11]. A decrease of CSF
GABA after neuroleptic treatment in schizophrenics has
been reported in one study [12] and an increase in
another study [13]. The effect of atypical neuroleptics
on CSF or plasma GABA levels has not been assessed to
our knowledge. The effect of psychotropic medications
on plasma GABA levels needs to be addressed in larger
and controlled studies in the future.
Another limitation is the lack of a normal control group.
In a study of child psychiatric inpatients [9], plasma
GABA levels were measured using high performance
liquid chromatography (HPLC). Levels in psychiatrical-
ly normal controls (mean 14.1 ng/ml; SD 3.9) were simi-
lar as in youngsters with ADHD (mean 14 ng/ml; SD
2.6). This suggests that plasma GABA levels are not dif-
ferent between normal controls and youngsters with
ADHD, but replication is necessary in other samples.
In the study of Prosser et al. [9], plasma GABA levels in
youngsters with ADHD (mean 14 ng/ml; SD 2.6) were
higher than levels found in children with ADHD in our
study (mean 8.4 ng/ml; SD 3.7). In the study of Borgatti
et al. [7], plasma GABA levels of normal controls (mean
18.8 ng/ml; SD 4.5) were higher than the levels in con-
trols in the study of Prosser et al. [9] (mean 14.1 ng/ml,
SD 3.9), and also higher than the levels found in autistic
children in our sample (mean 15.4 ng/ml, SD 6.2).
These discrepancies are not easily explained but may be
due to differences in patient samples, medication status,
and analytic method to assay plasma GABA. Until these
factors are better understood, differences between plas-
ma GABA levels across studies are difficult to interpret.
Elevated plasma GABA levels suggest alterations of cen-
tral GABA metabolism. However, there is no direct evi-
dence of this assumption so far. The meaning of eleva-
ted plasma GABA levels for central GABA function is dif-
ADHD Autism
Plasma GABA (ng/ml)
Figure 1. Plasma GABA levels in children with Attention Deficit/Hyper-
activity Disorder and Autistic Disorder (Median, range, the
box length represents the middle 50% of the data)
= outlier of 56 ng/ml (probably due to a technical error)
Figure 2. Scatter plot of plasma GABA levels and age.
Med Sci Monit, 2002; 8(8): PR1-6Preliminary Report
ficult to assess as the relations between brain, CSF, and
plasma GABA levels are unclear. Correlations between
plasma and CSF GABA levels and correlations between
changes in plasma and CSF GABA levels under specific
pharmacological conditions [9,11] or (patho)physiologi-
cal states [14] have been reported in some studies, but
not all [15,16]. New findings may be expected from
studies using in vivo measures of brain GABA levels e.g,
magnetic resonance spectrometry [17]. The simulta-
neous assessment of levels of brain, CSF, and plasma
GABA levels in future studies may clarify their correla-
tions in different disorders and under different condi-
GABA neurotransmission is widespread and defects may
be localized in certain brain areas with compensatory
changes in other brain areas. One possibility among
many is for example that elevated plasma levels in Autis-
tic Disorder, if confirmed, reflect a compensatory
increase in presynaptic GABA release in response to
hyposensitivity of a subset of GABA receptors. This in
turn could produce increased postsynaptic activation of
other normal GABA receptor subtypes, resulting in
complex alterations of GABAergic function throughout
the brain in autistic people.
This study adds to the small body of evidence suppor-
ting a role of GABA in the etiology or pathophysiology of
Autistic Disorders. Others have elaborated on biological,
anatomic, and genetic findings pointing towards
decreased or abnormal GABA inhibition in autism [4,5].
We have added a few clinical observations, also in sup-
port of a role of GABA in autism.
First, there is increasing evidence that GABA neuronal
dysfunction is implicated in various psychiatric disor-
ders including schizophrenia [18], mood disorders [19],
and anxiety disorders [20]. In some disorders, GABA
dysfunction may occur in conjunction with abnormali-
ties in reelin, a glycoprotein involved in the develop-
mental regulation of GABAergic transmission [21]. Varia-
tions in the gene coding for reelin have recently been
associated with Autistic Disorder [22]. Reductions of
reelin in the cerebellar cortex of people with autism
have also been reported [23].
Second, abnormalities on the long arm of chromosome
15 have been found in a small proportion of autistic
people [24]. A cluster of genes coding for GABAA recep-
tor subunits have been identified in that location (chro-
mosome 15q11-13). The GABA receptor beta-3 subunit
gene has been implicated as an autism susceptibility
locus in previous genetic studies, although the evidence
is far from conclusive [25,26]. It is possible that in a sub-
group of autistic people, GABA dysfunction is present in
some brain areas owing to abnormalities of the assembly
of GABAA receptor subunits into the GABA receptor
Third, a few reports have suggested that benzodia-
zepines, i.e., positive modulators of GABA metabolism,
have a negative and even paradoxical effect in autistic
people. Marrosu et al. [27] have reported that adminis-
tration of diazepam increased anxiety and a variety of
aggressive behaviors in young autistic children. In a sur-
vey of 66 autistic young people (<25 years) with seizure
disorders, treatment of seizures with benzodiazepines,
barbiturates, and phenytoin was often ineffective and
was accompanied by worsening of autistic symptoms,
confusion, and behavioral dyscontrol [28]. This suggests
that some autistic people respond abnormally to benzo-
diazepines possibly because of pre-existing GABAergic
dysfunction or abnormalities in the GABA-benzodia-
zepine receptor complex [29]. In addition, reduced
[H]-flunitrazepam labeled benzodiazepine bindings
sites and
[H]-muscimol labeled GABA
receptors were
recently reported in the hippocampus of autistic people
[30]. This finding provides direct evidence of abnormal
benzodiazepine receptor complexes in the hippocampus
of autistic people.
Fourth, there are at least two important clinical observa-
tions that suggest a role of GABA in Autistic Disorder.
The first clinical argument concerns the frequent occur-
rence of seizure disorders [31,32] and mood abnormali-
ties [33,34] in autistic people. GABAergic dysfunction
[35] may be the common substrate underlying the asso-
ciation between Autistic Disorder and seizure disorders
and between Autistic Disorder and mood disorders. An
unusual proportion of cases (up to 35%) of depressed
autistic youngsters had their first onset of mood prob-
lems in childhood, i.e., before age 11 [34]. No studies
have examined the relationship between autism, seizure
disorder, and mood disorders [36]. Abnormalities of
GABA function have independently been implicated in
the etiology of mood disorders [19,37] and seizure dis-
orders [38]. These studies have reported low brain
GABA levels in patients with mood disorders and
seizure disorders. This seems contradictory to finding
elevations of plasma GABA levels in autistic people.
However, as mentioned previously, the relation between
brain and plasma GABA levels has not been clarified yet
and may vary across different disorders, developmental
stages, and (patho-)physiological states. Further inquiry
into the role of GABA in autistic people with seizure dis-
orders and mood disorders is called for.
The second clinical clue is the occurrence of catatonic
symptoms in autistic people as described in a few case-
reports [39–43] and in one systematic survey [44]. Cata-
tonia is currently viewed as a distinct syndrome of psy-
chomotor signs across different disorders including
Schizophrenia, atypical psychotic disorders, primary
Mood Disorders, and a variety of medical conditions.
The clinical picture is dominated by at least two of the
following symptoms: motoric immobility as evidenced
by catalepsy or stupor, excessive motor activity (‘excited
catatonia’), extreme negativism or mutism, peculiarities
of voluntary movements as evidenced by posturing,
stereotypical movements, prominent mannerisms or gri-
macing, and echolalia or echopraxia [8]. Almost every
autistic person has a few catatonic symptoms but not all
meet criteria for the full-blown syndrome. For example,
in the survey of Wing & Shah [44], 17% of all patients,
age 15 and older, attending a tertiary referral center for
autism in the U.K. met full criteria for the catatonic
Med Sci Monit, 2002; 8(8): PR1-6 Dhossche D et al – Elevated plasma gamma-aminobutyric acid (GABA) levels…
syndrome. None of those under age 15 met criteria for
catatonia although isolated catatonic symptoms were
often observed. Catatonia may thus possibly arise in
adolescence as a late complication of autism. However,
further corroboration is needed that there is a specific
association between autism and catatonia [39,41,44,45].
Findings in a benzodiazepine ligand-binding study of
catatonics have shown GABAergic abnormalities [46].
Any increased risk for catatonia in autistic people could
be due to underlying GABAergic abnormalities. In addi-
tion, catatonia often responds dramatically to treatment
with benzodiazepines, i.e, positive modulators of GABA
neurotransmission [47]. This positive response has also
been observed in an autistic adolescent with catatonia
[41]. Further studies on catatonia in people with Autistic
Disorder should be done to clarify the role of GABA in
the catatonia and Autistic Disorder.
Finally, if a GABA hypothesis of autism has merit, evi-
dence should be forthcoming that developmental
changes of GABAergic function shape the clinical course
of autism and its comorbid conditions. We believe there
is preliminary support for this and will summarize perti-
nent data from the literature in the following sections.
GABA is regarded as the main inhibitory neurotrans-
mitter in the mature brain as perhaps 25–40% of all ter-
minals contain GABA [48]. Other roles of GABA include
paracrine signaling molecule, metabolic intermediate,
but also trophic or morphogenetic factor during early
human development. Developmental changes in pedi-
atric patients have been shown for the distribution of
the GABA transporter (GAT-1) using postmortem
immunohistochemical methods [49] and for the distri-
bution of the GABAA receptor complex using positron
emission tomography (PET) [50]. Developmental data
are not available in normal children and adolescents.
Interference with the trophic role of GABA may affect
development of neuronal wiring, plasticity of neuronal
network, and neural organization [51–53]. For example,
in mice, developmental changes in inhibitory synaptic
currents in cerebellar neurons are determined primarily
by developmental changes in GABAA receptor subunit
expression. Overall, the effects of abnormal trophic
GABA function are compatible with brain abnormalities
reported so far in autistic people [54,55].
Another tantalizing observation concerns the increased
rate of seizure disorders [28,31], catatonia [44], and
worsening of autistic symptoms or overall behavioral
deterioration after puberty [56,57]. A ghost of hormonal
changes may account for these phenomena. However,
decreased GABA inhibition in the hypothalamus is now
seen as an important trigger for onset of puberty [58,59].
Adaptive changes in GABA function at the onset of or
during puberty may worsen or induce disorders associa-
ted with underlying abnormalities of GABA function. In
addition, reconciliation of discrepant findings that ben-
zodiazepine treatment has detrimental effects in younger
autistic children and young autistic people with seizures
versus that benzodiazepine treatment is beneficial in
autistic people with catatonia may come from studies
assessing developmental changes of GABA receptors and
their functional properties in autistic people of different
ages. Data on all these areas are currently not available.
1. Elevated plasma GABA levels may be a biochemical
marker of Autistic Disorder.
2. Replication of findings in a larger sample is warranted.
3. The possible role of GABA in the etiology, symptoma-
tology, and clinical course of this disorder remains
unspecified owing to lack of research.
4. Future studies on autistic people with comorbid
seizure disorders, mood disorders, and catatonia may
give further clues on the role of GABA in Autistic
5. More trials of medications with known or putative
effects on GABA function in autistic people are war-
The authors thank Sam Strada, PhD, Wladimir Wert-
elecki, MD, and Charles Rich, MD, from the University
of South Alabama, College of Medicine, Mobile, Alaba-
ma, for their support.
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... During the second postnatal week, arachidonic acid and estradiol production peak. It has been shown that inflammation or nonsteroidal anti-inflammatory drugs (NSAIDs) result in impaired play behavior in males [106]. Even though it is still assumed that the cerebellum is not sexually dimorphic, as opposed to the preoptic area, for example, specific subregions such as lobules VI and VII have been demonstrated to represent a particular sexual orientation dimorphism related to emotion and sensation [106]. ...
... It has been shown that inflammation or nonsteroidal anti-inflammatory drugs (NSAIDs) result in impaired play behavior in males [106]. Even though it is still assumed that the cerebellum is not sexually dimorphic, as opposed to the preoptic area, for example, specific subregions such as lobules VI and VII have been demonstrated to represent a particular sexual orientation dimorphism related to emotion and sensation [106]. In the cerebellum, prostaglandins stimulate aromatase and local estradiol production. ...
... Indeed, E2 induced BDNF expression at physiological levels and promoted PC dendritic growth, spinogenesis and synaptogenesis during neonatal life. High E2 levels stop dendritic growth and reduce excitatory synapses number [89,106]. Given that E2 is the primary hormone in females, this raises the hypothesis that E2 could protect females from environmental insults, whether toxic, pharmacologic or immune. ...
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Autism spectrum disorders (ASD) are complex conditions that stem from a combination of genetic, epigenetic and environmental influences during early pre- and postnatal childhood. The review focuses on the cerebellum and the striatum, two structures involved in motor, sensory, cognitive and social functions altered in ASD. We summarize clinical and fundamental studies highlighting the importance of these two structures in ASD. We further discuss the relation between cellular and molecular alterations with the observed behavior at the social, cognitive, motor and gait levels. Functional correlates regarding neuronal activity are also detailed wherever possible, and sexual dimorphism is explored pointing to the need to apprehend ASD in both sexes, as findings can be dramatically different at both quantitative and qualitative levels. The review focuses also on a set of three recent papers from our laboratory where we explored motor and gait function in various genetic and environmental ASD animal models. We report that motor and gait behaviors can constitute an early and quantitative window to the disease, as they often correlate with the severity of social impairments and loss of cerebellar Purkinje cells. The review ends with suggestions as to the main obstacles that need to be surpassed before an appropriate management of the disease can be proposed.
... Human evidence from proton magnetic resonance spectroscopy (1H-MRS), neuroimaging, enzyme-linked immunosorbent assay (ELISA), and postmortem brain studies reported altered levels of GABA metabolites and the ratio of GABA to metabolites, such as glutamate and creatine (Rolf et al., 1993;Dhossche et al., 2002;Thatcher et al., 2009;Al-Otaish et al., 2018). A study showed that the electroencephalogram (EGG) phase reset of 54 patients with ASD showed reduced number and/or strength of thalamocortical connections comparing with healthy subjects (Thatcher et al., 2009). ...
... Earlier evidence showed increased serotonin levels and decreased levels of amino acids, namely, aspartic acid, glutamine, glutamic acid, and GABA, in patients with autism in comparison with controls (Rolf et al., 1993). However, contradictory results exist that young autism patients exhibited higher plasma GABA levels which decreased with age (Dhossche et al., 2002). Several evidence also reported higher plasma GABA levels and lower glutamate/GABA levels in autistic subjects than in controls (El-Ansary and Al-Ayadhi, 2014;Al-Otaish et al., 2018). ...
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Autism spectrum disorder (ASD) refers to a series of neurodevelopmental diseases characterized by two hallmark symptoms, social communication deficits and repetitive behaviors. Gamma-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the central nervous system (CNS). GABAergic inhibitory neurotransmission is critical for the regulation of brain rhythm and spontaneous neuronal activities during neurodevelopment. Genetic evidence has identified some variations of genes associated with the GABA system, indicating an abnormal excitatory/inhibitory (E/I) neurotransmission ratio implicated in the pathogenesis of ASD. However, the specific molecular mechanism by which GABA and GABAergic synaptic transmission affect ASD remains unclear. Transgenic technology enables translating genetic variations into rodent models to further investigate the structural and functional synaptic dysregulation related to ASD. In this review, we summarized evidence from human neuroimaging, postmortem, and genetic and pharmacological studies, and put emphasis on the GABAergic synaptic dysregulation and consequent E/I imbalance. We attempt to illuminate the pathophysiological role of structural and functional synaptic dysregulation in ASD and provide insights for future investigation.
... Several invasive studies have already demonstrated different levels of Glu and GABA in the autistic brain. In these studies increased levels of GABA (Dhossche et al., 2002;El-Ansary and Al-Ayadhi, 2014) and Glu (Aldred et al., 2003;El-Ansary and Al-Ayadhi, 2014;Tu et al., 2012) and decreased levels of the Glu/GABA ratio (El-Ansary and Al-Ayadhi, 2014) were reported in blood plasma. Moreover, previous non-invasive 1 H-MRS studies reported increased cerebral concentrations of Glu in Heschl's gyrus and the anterior cingulate cortex (Brown et al., 2013;Joshi et al., 2013). ...
... Decreases of GABAergic activity has been reported in several previous 1 H-MRS ASD studies (Gaetz et al., 2014;Harada et al., 2011;Kubas et al., 2012;Rojas et al., 2014). Also, elevated plasma GABA levels in ASD have been previously reported (Dhossche et al., 2002;El-Ansary and Al-Ayadhi, 2014). However, as GABA is also unable to cross the blood-brain barrier, a straightforward relationship between the plasma levels and the measured neurotransmitter concentrations is complicated. ...
... For example, abnormal GABA and glutamate concentrations in blood have been associated with depression, autism, schizophrenia and bipolar disorder. [47][48][49][50][51][52][53][54][55][56][57][58] For each individual, we collected 4 samples at least one week apart. Their analyses show the individual variation of GABA and glutamate plasma concentrations over time. ...
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Gamma-aminobutyric acid (GABA) and its precursor glutamate play signaling roles in a range of tissues. Both function as neurotransmitters in the central nervous system, but they also modulate pancreatic and...
... GABAergiques (Dhossche et al., 2002;Rubenstein et Merzenich, 2003). Des études précliniques ont d'ailleurs montré qu'un traitement court à la bumétanide permettait d'améliorer les phénotypes électrophysiologiques et comportementaux aberrants sur deux modèles animaux différents d'autisme (Tyzio et al., 2014). ...
L’éthanol, molécule tératogène, affecte le développement et la maturation du système nerveux central qui s’étendent depuis la vie fœtale jusqu’à la fin de l’adolescence. L’exposition à l’alcool pendant la vie fœtale entraîne des déficits d’apprentissages irréversibles et à l’adolescence, les alcoolisations de type Binge Drinking induisent également des pertes de mémoire. Cependant les mécanismes cellulaires dans ces deux cas d’expositions sont encore mal connus. L’hippocampe, une structure cérébrale, est impliqué dans la mémoire et les apprentissages par le biais des phénomènes de plasticité synaptique entre les neurones. Ici, nous avons étudié les effets de l’éthanol i) pendant la vie fœtale et ii) à l’adolescence sur la plasticité synaptique dans l’hippocampe de rat adolescent à l’aide de techniques d’électrophysiologie, de pharmacologie et de biochimie. Nous montrons que le glutamate et le GABA sont fortement impliqués dans la perturbation à long terme de la plasticité synaptique après alcoolisation fœtale. A l’adolescence, seul le glutamate est perturbé après un binge drinking, entraînant l’abolition rapide et prolongée de la plasticité synaptique ainsi que des déficits d’apprentissages. De manière intéressante, un diurétique, la bumétanide, restaure les perturbations après alcoolisation fœtale. L’éthanol pendant le développement cérébral perturbe les apprentissages en induisant un déséquilibre entre excitation et inhibition au sein du réseau neuronal de l’hippocampe
... On the other hand, in the ASD cases from Saudi Arabia, significantly increased plasma GABA concentration and lower plasma glutamate/GABA ratios were reported compared to the controls (Al-Otaish et al. 2018; El-Ansary and Al-Ayadhi 2014). Additionally, young American autistic subjects with elevated plasma GABA levels remained unaffected by treatment with psychotropic medications (Dhossche et al. 2002). In the Indian ASD probands, we have observed significantly higher plasma GABA concentration compared to the neurotypical control subjects. ...
Full-text available
Altered signaling of the chief inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), has been speculated in the etiology of autism spectrum disorder (ASD). We have investigated the association of six GABAA-receptor genetic variants and plasma GABA levels with ASD. Subjects were recruited based on the DSM, and CARS2-ST and ADI-R assessed disease severity. Peripheral blood was collected from the ASD probands (N = 251), their parents, and ethnically matched controls (N = 347). A positive correlation between the CARS2-ST and ADI-R scores was observed; domain scores of ADI-R were higher in the severe group categorized by the CARS2-ST. GABRB3 rs1432007 “A,” GABRG3 rs897173 “A,” and GABRA5 rs140682 “T” showed significant association with ASD. Trait scores were influenced by rs1432007 “AA” and rs140682 “TT.” GABA level was significantly higher in the probands than the age-matched controls. Our findings indicate an influence of GABA in the etiology of ASD in the Indian probands.
... To date, increasing evidence of dysfunction in the GABAergic neurotransmission system has been reported in patients and animal models of ASD [276,277]. In vivo 1H-MRS measurements have revealed a significant increase in plasma levels of GABA in children with ASD compared to controls [81,85,278]. Conversely, analyses of brain areas reported a reduced GABA/Glu ratio in the frontal lobes of autistic children [279], in the occipital brain areas of adolescent patients with high-functioning ASD [280], and the PFC of adult patients in response to riluzole [281]. ...
Full-text available
Disturbances in the glutamatergic system have been increasingly documented in several neuropsychiatric disorders, including autism spectrum disorder (ASD). Glutamate-centered theories of ASD are based on evidence from patient samples and postmortem studies, as well as from studies documenting abnormalities in glutamatergic gene expression and metabolic pathways, including changes in the gut microbiota glutamate metabolism in patients with ASD. In addition, preclinical studies on animal models have demonstrated glutamatergic neurotransmission deficits and altered expression of glutamate synaptic proteins. At present, there are no approved glutamatergic drugs for ASD, but several ongoing clinical trials are currently focusing on evaluating in autistic patients glutamatergic pharmaceuticals already approved for other conditions. In this review, we provide an overview of the literature concerning the role of glutamatergic neurotransmission in the pathophysiology of ASD and as a potential target for novel treatments.
... The β-alanine can cross the blood-brain barrier and canbe used in the brain as a partial antagonist, blocking the receptor sites for GABA, thus facilitating the production of more GABA to achieve equilibrium [118]. An excess of GABA [128] and reduced GABA A receptors in brain regions [129] was proposed as a possible contributor to autism. Unfortunately, confirmation of this hypothesis through a biochemical analysis of the reaction between propionic acid and ammonia in the context of the human body, as well as further research in terms of the dependency of β-alanine and GABA in the brain patients with autism, should be conducted. ...
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The purpose of this review is to summarize the current acquiredknowledge of Candida overgrowth in the intestine as a possible etiology of autism spectrum disorder (ASD). The influence of Candida sp. on the immune system, brain, and behavior of children with ASD isdescribed. The benefits of interventions such as a carbohydrates-exclusion diet, probiotic supplementation, antifungal agents, fecal microbiota transplantation (FMT), and microbiota transfer therapy (MTT) will be also discussed. Our literature query showed that the results of most studies do not fully support the hypothesis that Candida overgrowth is correlated with gastrointestinal (GI) problems and contributes to autism behavioral symptoms occurrence. On the one hand, it was reported that the modulation of microbiota composition in the gut may decrease Candida overgrowth, help reduce GI problems and autism symptoms. On the other hand, studies on humans suggesting the beneficial effects of a sugar-free diet, probiotic supplementation, FMT and MTT treatment in ASD are limited and inconclusive. Due to the increasing prevalence of ASD, studies on the etiology of this disorder are extremely needed and valuable. However, to elucidate the possible involvement of Candida in the pathophysiology of ASD, more reliable and well-designed research is certainly required.
Recent reports illustrated the increasing universal occurrence of autism and attention-deficit hyperactivity disorder (ADHD). Much of the pathogenesis and etiology of autism and ADHD remain unclear. Autism has a prevalence of 1:59 children in the United States, while ADHD affects almost 3% of adults worldwide. Presently, there are no reliable diagnostic biomarkers for autism and ADHD. Also, the most acceptable documented treatment is stimulant medication for autism and ADHD. The side effects and adverse reactions connected with stimulant medications are significant and grave, hampering growth and possibly being life-threatening. The pharmacological treatment choices are available; however, the relative benefits and adverse effects of individual treatments remain largely unknown. Inadequate availability of behavioral therapies and worries over adverse effects of pharmacological treatments provoked research for alternative strategies for management of autism and ADHD involving amino acid supplementation.Amino acids have a significant function in brain functioning and development. In addition, many of the amino acids have been demonstrated to exert direct or indirect effects on the levels of specific neurotransmitters. Thus, amino acids are anticipated to be effective in the management of autism and ADHD. There are several scientific reports about the significant functions of some amino acids in neurobiology and treatment of autism and ADHD. In this chapter, the authors exemplify the abnormalities in the profile of few amino acids in autism and ADHD patients, the pathways affected by amino acid imbalance in the brain, changes in the neuroactive amino acids which might have a role in pharmacotherapy and pathogenesis, amino acid supplementation therapy, and dysregulated amino acid metabolism which might considerably interfere with autism and ADHD.KeywordsAutismASDAttention-deficit hyperactive disorderADHDAmino acidsAmino acid supplementationTherapy
Stress is a major risk factor for neurodevelopmental and neuropsychiatric disorders, with the capacity to impact susceptibility to disease as well as long-term neurobiological and behavioral outcomes. Parvalbumin (PV) interneurons, the most prominent subtype of GABAergic interneurons in the cortex, are uniquely responsive to stress due to their protracted development throughout the highly plastic neonatal period and into puberty and adolescence. Additionally, PV + interneurons appear to respond to stress in a sex-specific manner. This review aims to discuss existing preclinical studies that support our overall hypothesis that the sex-and age-specific impacts of stress on PV + interneurons contribute to differences in individual vulnerability to stress across the lifespan, particularly in regard to sex differences in the diagnostic rate of neurodevelopmental and neuropsychiatric diseases in clinical populations. We also emphasize the importance of studying sex as a biological variable to fully understand the mechanistic and behavioral differences between males and females in models of neuropsychiatric disease.
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Catatonia in children and adolescents has received little research attention. Treatment and course of catatonia in an adolescent patient with Prader-Willi Syndrome are presented. Clinical features of a small series of published case reports of catatonia in children and adolescents are reported. The association between catatonia, Prader-Willi Syndrome, and other neurodevelopmental disorders is discussed.
The presentation of affective disorders in people with autism and autistic-like disorders is discussed based upon a review of 17 published cases. Half of the patients were female and almost all of the patients had IQs in the mentally retarded range. 35% of the patients had the onset of affective disorder in childhood. Of the cases mentioning family history, 50% had a family history of affective disorder or suicide. Changes in mood, self-attitude, and vital sense were rarely reported by the patients. A change in mood, attitude toward self and others, and vegetative changes were inferred based on the observations of others. Difficulties in diagnosing affective disorders in autistic people are presented and suggestions are made for diagnosis, treatment, and research.
Autistic disorder is a complex genetic disease. Because of previous reports of individuals with autistic disorder with duplications of the Prader-Willi/Angelman syndrome critical region, we screened several markers across the 15q11-13 region, for linkage disequilibrium. One hundred forty families, consisting predominantly of a child with autistic disorder and both parents, were studied. Genotyping was performed by use of multiplex PCR and capillary electrophoresis. Two children were identified who had interstitial chromosome 15 duplications and were excluded from further linkage-disequilibrium analysis. Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the gamma-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014). No evidence was found for parent-of-origin effects on allelic transmission. The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder.
Article abstract—Objective: To quantify developmental abnormalities in cerebral and cerebellar volume in autism. Methods: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. Results: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 6 1.3 cm versus clinical norms: 34.6 6 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI-VII than normal controls. Conclusions: Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism. NEUROLOGY 2001;57:245-254
The authors examined 183 children with autistic symptoms and found that the age-specific incidence rates of seizures in this sample were between 3 and 28 times the rates for children in the general population. The subjects classified as totally autistic were at high risk of developing seizure from early childhood well into adolescence, but especially so at puberty. The partially autistic children had an increased risk of seizures only up to age 10. The authors suggest that the high incidence of seizures at puberty observed in this study may be specific to children with total autistic symptomatology and may represent a distinct pathological process associated with autism.