Thalidomide or Valproate drugs being taken by the mother early during pregnancy gives rise to an increase proportion of the children with autism

This was initially simply shown as an excess statistically but the attempts to look for the reason behind it were much more difficult. It was possible to show in rodents given the thalidomide or valproate during pregnancy, that the drugs modified the production of serotonergic neurones in the developing mouse foetus’ brain. They found also that other brain compounds (e.g. monoamines, encephalins) were also affected in concentration but what caused what is unclear. However, there was little demonstration that this was actually causing the symptoms in humans or that the withdrawal of the drugs continued to allow the brain modification. When the mother was taking valproate there was an increased chance of autism but that is all; it could not be guaranteed as it was in the rodent models.

Neither valproate nor thalidomide has continued to be used in pregnancy at all unless by accident. As such this effect could not be considered to have caused the apparent increase that has been reported in the last 20 years. However, the phenomenon might be useful to create an animal model for the condition.

It is fairly clear that these cases appeared to start with signs of illness fairly early, and they were not thought of as regressive autism. Also, because of all the other side effects of the drugs the damage seen may be part of something much more complex.

Hormones: There are indications of hypertesteronism prenatally in the autistic children: this is seen on another web page.

The 2D:4D ratio of significance in understanding prenatal hormones

1) Association with thalidomide embryopathy.

Autism in thalidomide embryopathy: a population study. Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C. Dev Med Child Neurol 1994;36:351-6.

Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Miyazaki K, Narita N, Narita M.. Int J Dev Neurosci. 2005 Apr-May;23(2-3):287-97. (this work was done in rats, and looked into the chemistry of the brain)

Increased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism. Narita N, Kato M, Tazoe M, Miyazaki K, Narita M, Okado N. Pediatr Res. 2002 Oct;52(4):576-9.

Linking etiologies in humans and animal models: studies of autism. Rodier PM, Ingram JL, Tisdale B, Croog VJ. Reprod Toxicol. 1997 Mar-Jun;11(2-3):417-22. Review. (reviews thalidomide association with autism)

Common increase of GATA-3 level in PC-12 cells by three teratogens causing autism spectrum disorders. Rout UK, Clausen P. Neurosci Res. 2009 Jun;64(2):162-9. In this study, a neuron-like PC-12 cell model was used to examine the effects of these compounds on the binding potential of 50 different transcription factors to understand the molecular mechanism/s that may be involved in the teratogenesis caused by these agents. Cells in culture were treated with low or high concentrations of teratogens within a range that are reported in the blood of individuals. A pronounced increase in GATA transcription factor binding was observed for all three teratogens (thalidomide, valproate and alcohol).

Thalidomide and misoprostol: Ophthalmologic manifestations and associations both expected and unexpected. Miller MT, Ventura L, Strömland K. Birth Defects Res A Clin Mol Teratol. 2009 Jul 28. When they looked back on a series of thalidomide associated cases of embryopathy they found that autism was also involved.

2) Association with prenatal valproate

This is an antiepileptic drug that is in full and extensive use currently and as such some women become pregnant but are unaware of the effect of the valproate. It penetrates throughout the body and does not disappear quickly after the drug is stopped. The exact mechanism by which the effect might be seen to cause the autism-like effect in humans and rat models has not been followed up greatly except in one paper which associates it with valproate being very much associated with a dramatic drop in neuroligin 3 production.

Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Schneider T, Przewłocki R. Neuropsychopharmacology. 2005 Jan;30(1):80-9.

Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism Schneider T, Ziòłkowska B, Gieryk A, Tyminska A, Przewłocki R.. Psychopharmacology (Berl). 2007 Sep;193(4):547-55.

Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Rinaldi T, Kulangara K, Antoniello K, Markram H. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13501-6. Epub 2007 Aug (N-methyl d-alanine receptors are involved in opioids and various others receptors)

Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Ingram JL, Peckham SM, Tisdale B, Rodier PM. Neurotoxicol Teratol. 2000 May-Jun;22(3):319-24. Compared to controls, rats exposed to a single dose of 600-mg/kg sodium valproate on embryonic day 12.5 had significantly fewer Purkinje cells in the cerebellar vermis and a reduction short of significant in the hemispheres

Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Miyazaki K, Narita N, Narita M. Int J Dev Neurosci. 2005 Apr-May;23(2-3):287-97. (this work was done in rats, and looked into the chemistry of the brain)

Increased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism. Narita N, Kato M, Tazoe M, Miyazaki K, Narita M, Okado N. Pediatr Res. 2002 Oct;52(4):576-9.

Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic Acid animal model of autism.Rinaldi T, Perrodin C, Markram H. Front Neural Circuits. 2008;2:4. Epub 2008 Oct 29. They basically used the model of the rat that had been in utero while the mother was taking valproate and then tried to look at the specific cells and circuits in the prefrontal cortex. Their claim to have found something is interesting but what is now needed is to find the same changes in the children with the same condition. They found an increase in hyper-connectivity neurone interaction sites. Hyper-connectivity and hyper-plasticity in the prefrontal cortex implies hyper-functionality of one of the highest order processing regions in the brain, and stands in contrast to the hypo-functionality that is normally proposed in this region to explain some of the autistic symptoms

Altered morphology of motor cortex neurons in the VPA rat model of autism. Snow WM, Hartle K, Ivanco TL. Dev Psychobiol. 2008 Nov;50(7):633-9. Pregnant Long-Evans rats were administered either valproic acid (VPA) or saline during fetal neural tube development. Morphological analyses of cells in layer II of the golgi impregnated motor cortex were done to determine dendritic length, volume, and complexity in both groups. No differences were found in length or volume of cortical dendrites, but dendritic arborization was more complex in apical dendrites of pyramidal cells in VPA-exposed animals than controls. Again this was like the hyperconnectivity found by Rinaldi et al.

Interstimulus interval (ISI) discrimination of the conditioned eyeblink response in a rodent model of autism. Murawski NJ, Brown KL, Stanton ME. Behav Brain Res. 2009 Jan 23;196(2):297-303. Rats exposed to valproic acid (VPA) on gestational day 12 (GD12) have been advanced as a rodent model of autism [Arndt TL, Stodgell, Rodier PM. The teratology of autism. Int J Dev Neurosci 2005;23: 189-99. and Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Schneider T, Przewłocki R. Neuropsychopharmacology. 2005 Jan;30(1):80-9]. These rats show cerebellar anomalies and alterations in eyeblink conditioning that are associated with autism. What they did was a standard set of tests concerning eye blinking and found that the VPA exposed rats were similar to autistic children in this respect.

Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Schneider T, Roman A, Basta-Kaim A, Kubera M, Budziszewska B, Schneider K, Przewłocki R. Psychoneuroendocrinology. 2008 Jul;33(6):728-40. A plethora of aberrations has been found in male VPA rats: lower sensitivity to pain, increased repetitive/stereotypic-like activity, higher anxiety, decreased level of social interaction, increased basal level of corticosterone, decreased weight of the thymus, decreased splenocytes proliferative response to concanavaline A, lower IFN-gamma/IL-10 ratio, and increased production of NO by peritoneal macrophages. Female VPA rats exhibited only increased repetitive/stereotypic-like activity and decreased IFN-gamma/IL-10 ratio. Sexual dimorphism characteristics for measured parameters have been observed in both groups of animals, except social interaction in VPA rats. Clearly they did this work to see if they can justify the excess of male children with autism compared with females. BALB/c mice injected on P14 with 400 mg/kg VPA engaged in fewer social interactions (including ano-genital sniffs, allogrooming, and crawl-under/over behaviors) than control mice. Treated mice also exhibited reduced motor activity in a social context but were not significantly different from controls when motor activity was assessed in non-social settings. This sort of work was backed by repeats from VPA-induced apoptosis and behavioral deficits in neonatal mice. Yochum CL, Dowling P, Reuhl KR, Wagner GC, Ming X. Brain Res. 2008 Apr 8;1203:126-32.

Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid. Rinaldi T, Silberberg G, Markram H. Cereb Cortex. 2008 Apr;18(4):763-70. We examined the postnatal effects of embryonic exposure to VPA on microcircuit properties of juvenile rat neocortex using in vitro electrophysiology. We found that a single prenatal injection of VPA on embryonic day 11.5 causes a significant enhancement of the local recurrent connectivity formed by neocortical pyramidal neurons. They did this using electrophysiology, which is not easy!

Abnormal fear conditioning and amygdala processing in an animal model of autism. Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H. Neuropsychopharmacology. 2008 Mar;33(4):901-12. The problem with this one is that it is not clear that the amygdala action is modified in autism.

A clinical study of 57 children with fetal anticonvulsant syndromes. Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, Dean JC. J Med Genet. 2000 Jul;37(7):489-97 Thirty four (60%) were exposed in utero to valproate alone, four (7%) to carbamazepine alone, four (7%) to phenytoin alone, and 15 (26%) to more than one anticonvulsant. Forty six (81%) reported behavioural problems, 22 (39%) with hyperactivity or poor concentration of whom four (7%) had a diagnosis of attention deficit and hyperactivity disorder. Thirty four (60%) reported two or more autistic features, of whom four had a diagnosis of autism and two of Asperger's syndrome. Forty four (77%) had learning difficulties, 46 (81%) had speech delay, 34 (60%) had gross motor delay, and 24 (42%) had fine motor delay. Nineteen (33%) had glue ear and 40 (70%) had joint laxity involving all sizes of joints. Of 46 who had formal ophthalmic evaluation, 16 (34%) had myopia. CONCLUSIONS: Speech delay, joint laxity, glue ear, and myopia are common in the fetal anticonvulsant syndromes and autistic features and hyperactivity form part of the behavioural phenotype. An important set of findings followed rapidly by a group in Spain that found similar results.

Valproic acid regulates catecholaminergic pathways by concentration-dependent threshold effects on TH mRNA synthesis and degradation. D'Souza A, Onem E, Patel P, La Gamma EF, Nankova BB. Brain Res. 2009 Jan 9;1247:1-10. They were looking to see if the tyrosine hydroxylase gene was modified by valproate as this was involved in brain structure and the use of catecholamine activity. They found that it did have an effect but that it varied during the mouse’s development .

Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Ornoy A. Reprod Toxicol. 2009 Jul;28(1):1-10.

Observation of fetal brain in a rat valproate-induced autism model: a developmental neurotoxicity study. Kuwagata M, Ogawa T, Shioda S, Nagata T. Int J Dev Neurosci. 2009 Jun;27(4):399-405. Rats were treated with sodium valproate (VPA, 800 mg/kg) orally on gestational day (GD) 9 or 11 (VPA9 or VPA11), and the fetal brains were examined on GD16 using immunohistochemistry for serotonin (5-HT), tyrosine hydroxylase (TH), and TuJ1 (neuron specific class III beta-tubulin). Hypoplasia of the cortical plate was induced in both VPA9 and VPA11 groups. Abnormal migration of TH-positive and 5-HT neurons, possibly due to the appearance of an abnormally running nerve tract in the pons, was observed only in the VPA11 group. The present results demonstrate that examination of the GD16 fetal brain was useful for detecting and characterizing abnormal development of the brain after VPA exposure.

Interstimulus interval (ISI) discrimination of the conditioned eyeblink response in a rodent model of autism. Murawski NJ, Brown KL, Stanton ME. Behav Brain Res. 2009 Jan 23;196(2):297-303. Rats exposed to valproic acid (VPA) on gestational day 12 (GD12) have been advanced as a rodent model of autism [Arndt TL, Stodgell, Rodier PM. The teratology of autism. Int J Dev Neurosci 2005;23: 189-99.]. These rats show cerebellar anomalies and alterations in eyeblink conditioning that are associated with autism. Autistic humans and VPA-exposed rats show normal responses to conditioned and unconditioned stimuli, but they show marked differences from comparison groups in acquisition, magnitude, and timing of the conditioned response (CR). They have tried using this to show an effect of valproate in various manners.

Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. Kolozsi E, Mackenzie RN, Roullet FI, Decatanzaro D, Foster JA. Neuroscience. 2009 Jul 14. Expression levels of NLGN1, NLGN2, NRXN1, NRXN2, and NRXN3 were observed to be similar in VPA and control mice. NLGN3 mRNA expression was found to be significantly lower in the VPA mice relative to control animals in hippocampal subregions, cornu ammonis (CA1) and dentate gyrus, and somatosensory cortex.

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