Serotonin changes in ASD |
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Serotonin in autismIt is remarkable that 5-hydroxytryptamine (serotonin, 5HT) is found in excess in the blood of ASD children as a relatively reliable element in them although in around 60%. The rise in serotonin is found to be in the platelets throughout the lifespan of the autistic person. In other words this effect is taking place many years after any specific damage has taken place in the brain. It is unlikely that the platelet serotonaemia is caused by the brain, and indeed that the platelet carriage of serotonin affects the brain because the blood brain barrier is almost impenetrable to 5-HT. As a result we must consider that an original effect is causing both effects separately. Serotonin in the bloodIt appears that
Serotonin in the brain
Genetics of serotonin
Serotonin and treatment?This simply is unclear at the moment. Many reports of improvements with drugs acting against 5HT have come along with others that suggest the opposite.
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Production of
5HT from tryptophan |
Serotonin:
The biochemistry in autism (this one of the most reliable factors in
autism biochemistry and so the literature is large and goes back until the
1970s. I have not increased all the
literature here but ones that appear to be of value in allowing a reader to get
a good idea as to where things have got to.
There is large amounts of literature quoted in the articles of Janusonis, and Harnilovic,
which are recent.
Singh VK, Singh EA, Warren RP. Hyperserotoninemia and serotonin receptor antibodies in children with autism but not mental retardation. Biol Psychiatry. 1997 Mar 15;41(6):753-5. (Not useful on PubMed).
Burgess NK, Sweeten TL, McMahon WM, Fujinami RS. Hyperserotoninemia and altered immunity in autism. J Autism Dev Disord. 2006 Jul;36(5):697-704. Review (just puts the point forward that 5HT is known to alter immunity but no data showing cause and effect in autism)
Anderson
GM, Gutknecht
L, Cohen
DJ, Brailly-Tabard
S, Cohen
JH, Ferrari
P, Roubertoux
PL, Tordjman
S. Serotonin transporter promoter variants in autism: functional effects
and relationship to platelet hyperserotonemia.
Mol Psychiatry. 2002;7(8):831-6. (but they were not the
cause of the autism!)
Hranilovic D, Bujas-Petkovic Z, Vragovic R, Vuk T, Hock K, Jernej B. Hyperserotonemia in adults with autistic disorder.J Autism Dev Disord. 2007 Nov;37(10):1934-40. (shows that the high serotonin factor is one of the most commonly reliable ones found in autism, and that currently there is no specific reason for it)
Janusonis S. Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities. Theor Biol Med Model. 2005 Jul 19;2:27. (they try to show how the build up of platelet serotonin takes place statistically and whether it is predictable…their data tries hard but does not come up with perfect results)
McNamara IM, Borella AW, Bialowas LA, Whitaker-Azmitia PM. Further studies in the developmental hyperserotonemia model (DHS) of autism: Social, permutation and peptide changes. Brain Res. 2007 (the model is that high serotonin in the blood and low in the brain – as is found in autism – would cause embryological brain to be exposed to high serotonin and they showed in rats that this effect caused a change in the developing animal’s psychology)
Urinary 5-hydroxyindoleacetic acid and whole blood
serotonin and tryptophan in autistic and normal subjects. Minderaa RB, Anderson GM, Volkmar FR,
Akkerhuis GW, Cohen DJ. Biol Psychiatry. 1987 Aug;22(8):933-40. Urinary 5-hydroxyindoleacetic acid (5-HIAA)
excretion in two consecutive collection periods (5:00 PM-11:00 PM and 11:00
PM-8:00 AM) and whole blood serotonin (5-HT) and tryptophan (TRP) were measured
in groups of unmedicated autistics (n = 16), medicated autistics (n = 20), and
normal controls (n = 27). Whole blood 5-HT values were significantly higher in
unmedicated autistics compared to normal controls. No significant differences
were found in 5-HIAA excretion (microgram/mg creatinine, mean +/- SD) between
unmedicated autistics (4.07 +/- 1.52) and normal controls (3.50 +/- 1.07), or
between medicated (5.35 +/- 2.93) and drug-free autistic individuals. No
correlations were found between 5-HT values and urinary 5-HIAA excretion.
Peripheral markers of serotonergic and noradrenergic
function in post-pubertal, caucasian males with autistic disorder.
Croonenberghs J, Delmeire L, Verkerk R, Lin AH, Meskal A, Neels H, Van der
Planken M, Scharpe S, Deboutte D, Pison G, Maes M. Neuropsychopharmacology.
2000 Mar;22(3):275-83. This study
examines serotonergic and noradrenergic markers in a study group of 13 male,
post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13
matched volunteers. [3H]-paroxetine binding Kd values were significantly higher
in patients with autism than in healthy volunteers. Plasma concentrations of
tryptophan, the precursor of 5-HT, were significantly lower in autistic
patients than in healthy volunteers. There were no significant differences between
autistic and normal children in the serum concentrations of 5-HT, or the 24-hr
urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline,
noradrenaline, and dopamine.
Croonenberghs J, Verkerk R, Scharpe S,
Deboutte D, Maes M. Serotonergic disturbances in
autistic disorder: L-5-hydroxytryptophan administration to autistic youngsters
increases the blood concentrations of serotonin in patients but not in
controls. Life Sci. 2005 Mar 25;76(19):2171-83
Croonenberghs J, Wauters A, Deboutte D, Verkerk R, Scharpe S, Maes M. Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test. Neuro Endocrinol Lett. 2007 Aug;28(4):449-55. (this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children.) This is actually quite important, showing specifically poor response in a manner that would suggest the lack of 5-HTP modification or some other factor.
Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol. 1999 Mar;45(3):287-95. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children.
Martineau J, Barthélémy C, Jouve J, Muh JP, Lelord G. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age-related changes and drug effects. Dev Med Child Neurol. 1992 Jul;34(7):593-603. 156 autistic children aged two to 12 years 6 months, compared with matched mentally retarded and normal controls. Very significant group and age effects were found for dopamine (DA), Homovanillinic acid (HVA), 3methoxy-tryptamine (3MT), norepinephrine and epinephrine (NE + E) and serotonin (5HT). High HVA, 3MT, NE + E and 5HT levels were found in autistic and non-autistic children. The DA, HVA, 3MT, NE + E, 5HT and its metabolite 5HIAA levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol)
Israngkun
PP, Newman
HA, Patel
ST, Duruibe
VA, Abou-Issa
H. Potential biochemical markers for infantile autism. Neurochem
Pathol. 1986 Aug;5(1):51-70. (raised
epinephrine, norepinephrine, serotonin in blood)
Toda Y, Mori K, Hashimoto T, Miyazaki M, Nozaki S, Watanabe Y, Kuroda Y, Kagami S. Administration of secretin for autism alters dopamine metabolism in the central nervous system. Brain Dev. 2006 Mar;28(2):99-103. (a complex study in which they gave 12 autistic children some i.v. secretin and looked for improvements in biopterin, 5HIAA, and homovanillinic acid –taken as signs of irritation, serotonin turnover and dopamine turnover- these were found in 7 but all of those with raised biopterin results initially)
Warren RP, Singh VK. Elevated serotonin levels in autism: association with the major histocompatibility complex. Neuropsychobiology. 1996;34(2):72-5.
Hranilović D, Novak R, Babić
M, Novokmet M, Bujas-Petković Z, Jernej B. Hyperserotonemia
in autism: the potential role of 5HT-related gene variants. Coll Antropol. 2008
Jan;32 Suppl 1:75-80
Huang CH, Santangelo SL.Autism
and serotonin transporter gene polymorphisms: A systematic review and
meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2008 Feb 19. [Epub ahead
of print]. Also have a look at Sutcliffe
JS, Delahanty RJ, Prasad HC, McCauley
JL, Han Q, Jiang L, Li C, Folstein SE, Blakely RD. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet. 2005 Aug;77(2):265-79.
Tsujino
N, Nakatani Y, Seki Y, Nakasato A, Nakamura M, Sugawara M, Arita H. Abnormality of circadian rhythm accompanied
by an increase in frontal cortex serotonin in animal model of autism. Neurosci Res. 2007 Feb;57(2):289-95. Epub 2006 Dec 6.
Croonenberghs J, Spaas K, Wauters A, Verkerk R, Scharpe S, Deboutte D, Maes M. Faulty serotonin--DHEA interactions in autism: results of the 5-hydroxytryptophan challenge test. Neuro Endocrinol Lett. 2008 Jun;29(3):385-90. (The present study examines plasma dehydroepiandrosterone-sulphate (DHEA-S) and the cortisol/DHEA-S ratio following administration of L-5-hydroxytryptophan (5-HTP). The 5-HTP-induced DHEA-S responses were significantly higher in autistic patients than in controls. In baseline conditions, the cortisol/DHEA-S ratio was significantly higher in autistic patients than in controls. Discussion: The results suggest that autism is accompanied by a major disequilibrium in the serotonergic system.)
Relationships among body mass, brain size, gut length, and
blood tryptophan and serotonin in young wild-type mice. Albay R 3rd, Chen A,
Hyperserotonemia in autism: activity of 5HT-associated
platelet proteins. Hranilović D, Bujas-Petković Z,
Tomicić M, Bordukalo-Niksić T, Blazević S, Cicin-Sain L. J Neural Transm. 2009 Apr;116(4):493-501. Disturbances in serotonin (5HT)
neurotransmission have been indicated as biological substrates in several
neuropsychiatric disorders including autism. Blood 5HT concentrations, elevated
in about one-third of autistic subjects, are regulated through the action of
peripheral 5HT-associated proteins. We have measured the activity of two
platelet 5HT-associated proteins: 5HT transporter (5HTT) and monoamine oxidase
B (MAOB), and indirectly studied the activity of 5HT(2A) receptor (5HT(2A)r) in
15 hyperserotonemic (HS) and 17 normoserotonemic (NS) autistic subjects, and 15
healthy controls (C) While mean velocities
of 5HTT kinetics did not significantly differ among the groups, significant
elevation in the mean velocity of MAOB kinetics was observed in NS subjects and
was even more pronounced in HS subjects.
The results suggest a possibility of upregulation of monoaminergic
synthesis/degradation and, probably consequential, downregulation of 5HT(2A)
receptors in autistic subjects.
Dopamine and serotonin levels following prenatal viral
infection in mouse--implications for psychiatric disorders such as
schizophrenia and autism. Winter C, Reutiman TJ, Folsom TD, Sohr R,
Wolf RJ, Juckel G, Fatemi SH. Eur Neuropsychopharmacol.
2008 Oct;18(10):712-6. Neurochemical
analysis following infection on E18 using this model has revealed significantly
altered levels of serotonin, 5-hydroxyindoleacetic acid, and taurine, but not
dopamine. In order to monitor these different patterns of monoamine expression
in exposed offspring in more detail and to see if there are changes in the
dopamine system at another time point, pregnant C57BL6J mice were infected with
a sublethal dose of human influenza virus or sham-infected using vehicle
solution on E16. When compared to controls, there was a significant decrease in
serotonin levels in the cerebella of offspring of virally exposed mice at P14.
No differences in levels of dopamine were observed in exposed and control mice,
although there was a significant decrease in dopamine at P14 and P56 when
compared to P0.
Cortical serotonin type-2 receptor density in parents of
children with autism spectrum disorders. Goldberg J, Anderson GM,
Zwaigenbaum L, Hall GB, Nahmias C, Thompson A, Szatmari P. J Autism Dev Disord. 2009 Jan;39(1):97-104. Parents (N
= 19) of children with autism spectrum disorders (ASD) and adult controls (N =
17) underwent positron emission tomography (PET) using [(18)F]setoperone to
image cortical serotonin type-2 (5-HT2) receptors. Lower cortical 5-HT2 receptor density in
parents of children with ASD is consistent with reports of diminished 5-HT2
expression and functioning in individuals with ASD.
Serotonin in the brain
The idea is that in autism there is a change in the production of serotonin and that this may be concerning the genetics is unclear in that some of the patients without any of the serotonin transporter polymorphisms seem to have the same effect (poor data). However, in brain neurochemistry this is an interesting finding. It is clear that changes take place during development and that this is also different in autistic children from controls.
Chugani DC. Serotonin in autism and pediatric epilepsies. Ment Retard Dev Disabil Res Rev. 2004;10(2):112-6. Review. (this suggests that there are problems that associate brain changes with other epilepsies. An argument is made that cortical malformation leads to abnormalities of thalamocortical connectivity, and that serotonin plays a critical role in this process. Finally, a role for altered metabolism of the serotonin precursur, tryptophan, in both epilepsy and autism is discussed. )
Nabi R, Serajee FJ, Chugani DC, Zhong H, Huq AH. Association of tryptophan 2,3 dioxygenase gene polymorphism with autism. Am J Med Genet B Neuropsychiatr Genet. 2004 Feb 15;125B(1):63-8. (Haplotype analysis also demonstrated significant difference in the transmission of TDO2 haplotypes to autistic subjects (P = 0.0027). Our results suggest the presence of a susceptibility mutation in the TDO2 or a nearby gene, but may also represent a chance finding.)
Chugani DC. Role of altered brain serotonin mechanisms in autism. Mol Psychiatry. 2002;7 Suppl 2:S16-7. Review. (a lot of this is basically theory but may be of significance)
Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, da Silva EA, Chugani HT. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol. 1997 Oct;42(4):666-9. (Using alpha-[11C]methyl-L-tryptophan as a tracer for serotonin synthesis with positron emission tomography, we now report unilateral alterations of serotonin synthesis in the dentatothalamocortical pathway in autistic boys. They did this using siblings or non-autistics as controls)
Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children Ann Neurol. 1999 Mar;45(3):287-95.For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity.)
Martineau J, Barthélémy C, Jouve J, Muh JP, Lelord G. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age-related changes and drug effects. Dev Med Child Neurol. 1992 Jul;34(7):593-603. (Very significant group and age effects were found for DA, HVA, 3MT, NE + E and 5HT. High HVA, 3MT, NE + E and 5HT levels were found in autistic and non-autistic children. The dopamine, homovanillic acid, methyltryptamine, norepinephrine + epinephrine, 5HT and 5-hydroxyiminoacetic acid levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol, compared with non-medicated autistic children.
Goldberg J, Anderson GM, Zwaigenbaum L, Hall GB, Nahmias C, Thompson A, Szatmari P. Cortical Serotonin Type-2 Receptor Density in Parents of Children with Autism Spectrum Disorders. J Autism Dev Disord. 2008 Jul 1. Cortical serotonin-2 binding potentials (BPs) were significantly lower in parents compared to controls and platelet 5-HT levels were significantly negatively correlated with cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents of children with ASD is consistent with reports of diminished 5-HT2 expression and functioning in individuals with ASD.
Cortical serotonin type-2 receptor density in parents of
children with autism spectrum disorders.
Goldberg J,
Serotonin associated genes
This is important in that the reasons why the serotonin has
built up and has specific pharmacokinetics when injected must surely be to do
with the way in which it is produced and moved inside cells. Serotonin: Many genes associated with its formation,
transport and reception Part of this was as a result of genetic findings, but
also claims were made of the advantages for SSRI compounds as treatment (now
this is shown not to be true). The
compounds that are most used are citalopram or fluoxitine. The genetics, however still seems to remain
to be of significance. These involve the
SERT gene (SERotonin Transporter) and protein, which depends on
the sodium and potassium ion concentrations between the outside and the inside
of the nerve wall to provide the energy for serotonin transportation. Amazingly the gene is fairly well retained
genetically from fairly low animals, but only in higher simian apes does the
strange format appear that is found in humans.
This involves multiple changes (called polymorphism) in the gene within
the genetic make up of the animal and these modifications are found in the
protein itself. Below you will find
various groups arguing as to whether the gene or potential treatments have
anything to do with autism.
Ramoz
N, Reichert JG, Corwin TE, Smith CJ, Silverman JM, Hollander E, Buxbaum JD. Lack of evidence for association of the serotonin
transporter gene SLC6A4 with autism. Biol Psychiatry. 2006 Jul 15;60(2):186-91.
Epub 2006 Apr 17.
Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco AP. Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. The International Molecular Genetic Study of Autism Consortium. Am J Med Genet. 1999 Oct 15;88(5):492-6.
Nabi
R, Serajee FJ, Chugani DC, Zhong H, Huq AH. Association of tryptophan 2,3 dioxygenase gene polymorphism with autism.
Am J Med Genet B Neuropsychiatr Genet. 2004 Feb 15;125B(1):63-8. (Haplotype analysis also
demonstrated significant difference in the transmission of TDO2 haplotypes to
autistic subjects (P = 0.0027). Our results suggest the presence of a
susceptibility mutation in the TDO2 or a nearby gene, but may also represent a
chance finding.)
Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Murphy DL, Lerner A, Rudnick G, Lesch KP. Mol Interv. 2004 Apr;4(2):109-23. Review. This is actually quite a good article and tries to go through the various conditions that the changes in the gene may produce. It says little about ASD but explains very well the gene itself.
Coutinho
AM, Oliveira
G, Morgadinho
T, Fesel
C, Macedo
TR, Bento
C, Marques
C, Ataíde
A, Miguel
T, Borges
L, Vicente
AM. Variants of the serotonin
transporter gene (SLC6A4) significantly contribute to hyperserotonemia in
autism Mol Psychiatry.
2004 Mar;9(3):264-71
Coutinho
AM, Sousa
I, Martins
M, Correia
C, Morgadinho
T, Bento
C, Marques
C, Ataíde
A, Miguel
TS, Moore
JH, Oliveira
G, Vicente
AM. Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and
in the determination of platelet serotonin levels Hum Genet. 2007 Apr;121(2):243-56. Epub 2007
Jan 3. (these are two proteins that are
linked in manufacture by cells).
Cross S, Kim SJ, Weiss LA, Delahanty RJ, Sutcliffe JS, Leventhal BL, Cook EH Jr, Veenstra-Vanderweele J Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism. Neuropsychopharmacology. 2008 Jan;33(2):353-60. Epub 2007 Apr 4 (Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT.)
Wassink TH, Hazlett HC, Epping EA, Arndt S, Dager SR, Schellenberg GD, Dawson G, Piven J. Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism. Arch Gen Psychiatry. 2007 Jun;64(6):709-17. (The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism)
Brune CW, Kim SJ, Salt J, Leventhal BL, Lord C, Cook EH Jr 5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism.Am J Psychiatry. 2006 Dec;163(12):2148-56 (this is a locus of the serotonin transporter protein gene)
Hranilović
D, Novak R, Babić M, Novokmet M, Bujas-Petković Z, Jernej B. Hyperserotonemia in autism: the potential
role of 5HT-related gene variants. Coll Antropol. 2008 Jan;32
Suppl 1:75-80.
(they looked at the effect of the MAOA gene and others in increasing the
serotonin levels of the platelets).
Goldberg
J, Anderson GM, Zwaigenbaum L, Hall GB, Nahmias C, Thompson A, Szatmari P.
Cortical Serotonin Type-2 Receptor Density in Parents of Children with Autism
Spectrum Disorders. J Autism Dev Disord. 2008 Jul 1. Cortical serotonin-2
binding potentials (BPs) were significantly lower in parents compared to
controls and platelet 5-HT levels were significantly negatively correlated with
cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents
of children with ASD is consistent with reports of diminished 5-HT2 expression
and functioning in individuals with ASD
Serotonin transporter genotype and neuroanatomy in autism
spectrum disorders. Raznahan A, Pugliese L, Barker GJ, Daly E,
Powell J,
Examination of association of genes in the serotonin
system to autism. Anderson BM, Schnetz-Boutaud NC, Bartlett J,
Wotawa AM, Wright HH, Abramson RK, Cuccaro ML, Gilbert JR, Pericak-Vance MA,
Haines JL. Neurogenetics. 2009 Jul;10(3):209-16. A number of researchers had suggested that
serotonin pathways might be involved in ASD.
They screened 403 autism families for 45 single nucleotide polymorphisms
in ten serotonin pathway candidate genes. Although genome-wide linkage scans in
autism have provided support for linkage to various loci located within the
serotonin pathway, our study does not provide strong evidence for linkage to
any specific gene within the pathway.
However…..
Functional coding variation in recombinant inbred mouse
lines reveals multiple serotonin transporter-associated phenotypes.
Carneiro AM, Airey DC, Thompson B, Zhu CB, Lu L, Chesler EJ, Erikson KM,
Blakely RD. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):2047-52. The human serotonin (5-hydroxytryptamine,
5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and
treatment of many prevalent neurobehavioral disorders including anxiety,
alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here,
we use naturally occurring polymorphisms in recombinant inbred (RI) lines to
identify multiple phenotypes associated with altered SERT function. Our studies
provide an example of the power of coordinated in vitro, in vivo, and in silico
approaches using mouse RI lines to elucidate and quantify the system-level
impact of gene variation in that what they were doing was to look at cell lines
with the right genetic changes, mice that carried them, and the genetics of
patients.
Genetic and expression analyses reveal elevated
expression of syntaxin 1A ( STX1A) in high functioning autism.
Nakamura K, Anitha A, Yamada K, Tsujii M, Iwayama Y, Hattori E, Toyota T, Suda
S, Takei N, Iwata Y, Suzuki K, Matsuzaki H, Kawai M, Sekine Y, Tsuchiya KJ,
Sugihara G, Ouchi Y, Sugiyama T, Yoshikawa T, Mori N. Int
J Neuropsychopharmacol. 2008 Dec;11(8):1073-84. Serotonin transporter
(5-HTT), which modulates serotonin levels, is a major therapeutic target in
autism. Therefore, factors that regulate 5-HTT expression might be implicated
in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein,
syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio
association study using DNA samples from 249 AGRE trios with autistic
probands. They looked at the RNA of the
gene specifically in lymphocytes and other cells from autistic patients and
suggested that it may be involved.
Analysis of serotonin receptor 2A gene (HTR2A):
Association study with autism spectrum disorder in the Indian population and
investigation of the gene expression in peripheral blood leukocytes.
Guhathakurta S, Singh AS, Sinha S, Chatterjee A, Ahmed S, Ghosh S, Usha R. Neurochem Int. 2009 Jul 29. The 5-HT receptor binding
studies using (3)H-lysergic acid diethylamide ((3)H-LSD) and linkage analysis
provided evidences to consider HTR2A as a potential candidate gene for ASD. The
three SNPs, -1438A/G (rs6311), 102T/C (rs6313) and 1354C/T (rs6314) of HTR2A
have been well studied in the etiology of various neuropsychiatric disorders.
But studies on association of this gene with ASD are limited to two reports
from American and Korean populations. Paternal imprinting of HTR2A with
expression from only one allele may take place.
This study investigates association of three markers of HTR2A with ASD
in Indian population using population and family-based approaches. The subsequent association analyses did not
show association of these markers with ASD. So, HTR2A is unlikely to be a
genetic marker for ASD in Indian population. The expression analyses showed
absence of mono allelic expression, suggesting lack of parental imprinting of
HTR2A gene.
Association and gene-gene interaction of SLC6A4 and ITGB3
in autism. Ma DQ, Rabionet R, Konidari I, Jaworski J, Cukier HN,
Wright HH, Abramson RK, Gilbert JR, Cuccaro ML, Pericak-Vance MA, Martin ER. Am J Med Genet B Neuropsychiatr Genet. 2009 Jul
8. two serotonin related genes: SLC6A4
and ITGB3 with a sex-specific genetic effect and interaction between the
genes. Our results indicate the
extensive heterogeneity within these two genes among families and a great
difficulty in nailing down specific effects.
Hyperserotonemia in autism: the potential role of
5HT-related gene variants. Hranilović D, Novak R, Babić M,
Novokmet M, Bujas-Petković Z, Jernej B. Coll
Antropol. 2008 Jan;32 Suppl 1:75-80.
A large-scale screen for coding variants in SERT/SLC6A4
in autism spectrum disorders.
Sakurai T, Reichert J, Hoffman EJ, Cai G, Jones HB, Faham M, Buxbaum JD.
Autism Res. 2008 Aug;1(4):251-7. Search for rare variants in SLC6A4 contribute
to autism susceptibility and to rigid-compulsive behaviors in autism. We made
use of a large number of unrelated cases with autism spectrum disorders
(approximately 350) and controls (approximately 420) and screened for rare
exonic variants in SLC6A4. These results
do not support a significant role for rare coding variants in SLC6A4 in autism
spectrum disorders, nor do they support a significant role for SLC6A4 in
rigid-compulsive traits in these disorders.
Basically they found no association, despite the high numbers of cases
tested.
Influence of the 5-HTTLPR polymorphism and environmental
risk factors in a Brazilian sample of patients with autism spectrum disorders.
Longo D, Schüler-Faccini L, Brandalize AP, dos Santos Riesgo R, Bau CH. Brain Res. 2009 Apr 24;1267:9-17. Epub 2009 Mar 10
Genotyping was achieved in 151 ASD patients, 179 unrelated controls and 105
complete trios. There was no evidence of association between the 5-HTTLPR with
ASD in both case-control and FBAT tests, but the LaLa 5-HTTLPR genotype was
associated with mood instability in patients (P=0.006).
Haploinsufficiency for Pten and Serotonin transporter
cooperatively influences brain size and social behavior. Page DT,
Kuti OJ, Prestia C, Sur M. Proc Natl Acad Sci U S A.
2009 Feb 10;106(6):1989-94. Two genes that have been implicated as conferring
susceptibility to ASD are PTEN and Serotonin transporter (SLC6A4). The PI3K and
serotonin pathways, in which these genes respectively act, are both potential
biomarkers for ASD diagnosis and treatment.
These findings provide insight into an interaction between two ASD
candidate genes during brain development and point toward the use of compound
mutant mice to validate biomarkers for ASD against biological and behavioral
phenotypes.
Serotonin transporter genotype and neuroanatomy in autism
spectrum disorders. Raznahan A, Pugliese L, Barker GJ, Daly E,
Powell J,
Examination of association of genes in the serotonin
system to autism. Anderson BM, Schnetz-Boutaud NC, Bartlett J,
Wotawa AM, Wright HH, Abramson RK, Cuccaro ML, Gilbert JR, Pericak-Vance MA,
Haines JL. Neurogenetics. 2009
Jul;10(3):209-16. Numerous studies have
suggested that variation in peripheral and central metabolism of serotonin
(5-hydroxytryptamine) may play a role in the pathophysiology of autism. We
screened 403 autism families for 45 single nucleotide polymorphisms in ten
serotonin pathway candidate genes. Although genome-wide linkage scans in autism
have provided support for linkage to various loci located within the serotonin
pathway, our study does not provide strong evidence for linkage to any specific
gene within the pathway. The most significant association (p = 0.0002; p = 0.02
after correcting for multiple comparisons) was found at rs1150220 (HTR3A)
located on chromosome 11 ( approximately 113 Mb).
HTR1B and HTR2C in autism spectrum disorders in Brazilian
families. Orabona GM, Griesi-Oliveira K, Vadasz E, Bulcão VL,
Takahashi VN, Moreira ES, Furia-Silva M, Ros-Melo AM, Dourado F, Matioli R,
Otto P, Passos-Bueno MR. Brain Res. 2009 Jan
23;1250:14-9. two serotonin receptor genes (HTR1B and HTR2C) in 252 Brazilian
male ASD patients of European ancestry.
These analyses showed evidence of undertransmission of the HTR1B
haplotypes containing alleles -161G and -261A at HTR1B gene to ASD (P=0.003),
but no involvement of HTR2C to the predisposition to this disease.
Enhanced activity of human serotonin transporter variants
associated with autism. Prasad HC, Steiner JA, Sutcliffe JS, Blakely
RD. Philos Trans R Soc Lond B Biol Sci. 2009 Jan
27;364(1514):163-73. To some degree this
is review in that it contains large
amounts of data concerning other articles.
The research that they carried out separately involved genetically
modified HeLa cells.
Genetic and expression analyses reveal elevated
expression of syntaxin 1A ( STX1A) in high functioning autism.
Nakamura K, Anitha A, Yamada K, Tsujii M, Iwayama Y, Hattori E, Toyota T, Suda
S, Takei N, Iwata Y, Suzuki K, Matsuzaki H, Kawai M, Sekine Y, Tsuchiya KJ,
Sugihara G, Ouchi Y, Sugiyama T, Yoshikawa T, Mori N. Int
J Neuropsychopharmacol. 2008 Dec;11(8):1073-84. Serotonin transporter
(5-HTT), which modulates serotonin levels, is a major therapeutic target in
autism. Therefore, factors that regulate 5-HTT expression might be implicated
in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein,
syntaxin 1A (STX1A). STX1A expression in the high functioning autism group was
significantly higher (p=0.001) than that of controls. During early childhood, there is a period of
high brain serotonin synthesis that is disrupted in autistic children; STX1A
might influence the serotonergic system during this stage of neurodevelopment.
Treatments concerning serotonin
It should be realised that there is a wide
range of drugs that are active against serotonin. They work in migraine, in allergy, and in
various psychological and psychotic conditions.
Nobody is claiming that they actually have jumped forward and pointed at
them as helping in autism, despite many having been: Also see treatments
Scott LJ, Dhillon S. Risperidone: a review of its use in the treatment of irritability associated with autistic disorder in children and adolescents. Paediatr Drugs. 2007;9(5):343-54. (goes through the mechanism of action of risperidone and its pharmacokinetics. Does not claim activity in autism).
Shea S, Turgay A, Carroll A, Schulz M, Orlik H, Smith I, Dunbar F Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics. 2004 Nov;114(5):e634-41. Epub 2004 Oct 18 Comment in:
Pediatrics. 2005 May;115(5):1447-8; author reply 1448. (they felt that there was no sign of problems in the children receiving the drug)
Kolevzon A, Mathewson KA, Hollander E. Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J Clin Psychiatry. 2006 Mar;67(3):407-14. (the most commonly used example is fluoxetine – Prozac – but little advantage is seen compared with side effects of the drugs. These were clearly not a major treatments and further research was required)
Hollander E, Phillips A, Chaplin W, Zagursky K, Novotny S, Wasserman S, Iyengar R. A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology. 2005 Mar;30(3):582-9.
Moore ML, Eichner SF, Jones JR. Treating functional impairment of autism with selective serotonin-reuptake inhibitors. Ann Pharmacother. 2004 Sep;38(9):1515-9. Epub 2004 Aug 3. Review.
Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol. 1999 Mar;45(3):287-95. (it changes in the rate of growth compared with controls and adults) see the section of PET.
Review of the evidence for treatment of children with autism
with selective serotonin reuptake inhibitors. West L, Brunssen SH,
Waldrop J. J Spec Pediatr Nurs. 2009
Jul;14(3):183-91. This basically is a
review of the research currently available.
The major problem is that the authors make it clear that there is simply
not good enough data to show that drugs such as fluoxetine (SSRIs) have
adequate effect in autism and what aspects are altered.
Lack of efficacy of citalopram in children with autism
spectrum disorders and high levels of repetitive behavior: citalopram
ineffective in children with autism. King BH, Hollander E, Sikich L,
McCracken JT, Scahill L, Bregman JD, Donnelly CL, Anagnostou E, Dukes K,
Sullivan L, Hirtz D, Wagner A, Ritz L; STAART Psychopharmacology Network. Arch Gen Psychiatry. 2009 Jun;66(6):583-90 The researchers tested quite a large number
of factors in 149 patients and found no advantage over control. Citaloparam is an SSRI
Evidence that oxytocin exerts anxiolytic effects via
oxytocin receptor expressed in serotonergic neurons in mice. Yoshida
M, Takayanagi Y, Inoue K, Kimura T, Young LJ, Onaka T, Nishimori K. J Neurosci. 2009 Feb 18;29(7):2259-71. They are trying to explain how serotonin and
other transmitter substances may actually
be involved in almost the same action and how potentially treatment may
be looked for in a different manner.
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