1. Duszczyk-Budhathoki M, Olczak M, Lehner M, Majewska MD. {{Administration of Thimerosal to Infant Rats Increases Overflow of Glutamate and Aspartate in the Prefrontal Cortex: Protective Role of Dehydroepiandrosterone Sulfate}}. {Neurochem Res};2011 (Oct 21)
Thimerosal, a mercury-containing vaccine preservative, is a suspected factor in the etiology of neurodevelopmental disorders. We previously showed that its administration to infant rats causes behavioral, neurochemical and neuropathological abnormalities similar to those present in autism. Here we examined, using microdialysis, the effect of thimerosal on extracellular levels of neuroactive amino acids in the rat prefrontal cortex (PFC). Thimerosal administration (4 injections, i.m., 240 mug Hg/kg on postnatal days 7, 9, 11, 15) induced lasting changes in amino acid overflow: an increase of glutamate and aspartate accompanied by a decrease of glycine and alanine; measured 10-14 weeks after the injections. Four injections of thimerosal at a dose of 12.5 mug Hg/kg did not alter glutamate and aspartate concentrations at microdialysis time (but based on thimerosal pharmacokinetics, could have been effective soon after its injection). Application of thimerosal to the PFC in perfusion fluid evoked a rapid increase of glutamate overflow. Coadministration of the neurosteroid, dehydroepiandrosterone sulfate (DHEAS; 80 mg/kg; i.p.) prevented the thimerosal effect on glutamate and aspartate; the steroid alone had no influence on these amino acids. Coapplication of DHEAS with thimerosal in perfusion fluid also blocked the acute action of thimerosal on glutamate. In contrast, DHEAS alone reduced overflow of glycine and alanine, somewhat potentiating the thimerosal effect on these amino acids. Since excessive accumulation of extracellular glutamate is linked with excitotoxicity, our data imply that neonatal exposure to thimerosal-containing vaccines might induce excitotoxic brain injuries, leading to neurodevelopmental disorders. DHEAS may partially protect against mercurials-induced neurotoxicity.
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2. Esposito G, Yoshida S, Venuti P, Kuroda KO. {{Three lessons from Philip Teitelbaum and their application to studies of motor development in humans and mice}}. {Behav Brain Res};2011 (Oct 14)
In this paper we present a number of studies, some with humans and some with animals that have been directly influenced by the work of Philip Teitelbaum. As appropriate for a festschrift, we integrate a number of contributions from different fields (specifically, clinical psychopathology and neurobiology) and present the studies, not so much chronologically, but in ways that illustrate some of the key lessons that we have learned from Philip Teitelbaum. We would summarize these lessons as follows: (1) Complex and precise tools are required to assess the complexity of specific behaviors; using simplified tools will bias our understanding of the behavior itself. (2) Studying a specific behavior in atypical brain conditions is required to fully understand that behavior and how the brain controls it. (3) Considering the evolutionary basis of human behavior, studying corresponding behaviors in other mammalian species is required to strengthen and deepen our knowledge of specific human behaviors. In this paper we describe studies on motor development in humans and mice and their implication for the diagnosis of autism and early parental care that illustrate these three lessons.
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3. Makkonen I, Kokki H, Kuikka J, Turpeinen U, Riikonen R. {{Effects of Fluoxetine Treatment on Striatal Dopamine Transporter Binding and Cerebrospinal Fluid Insulin-Like Growth Factor-1 in Children with Autism}}. {Neuropediatrics};2011 (Oct 20)
A positive effect of fluoxetine has been shown in some children with autism. The present study was undertaken to correlate striatal dopamine transporter (DAT) binding and cerebrospinal fluid insulin-like growth factor-1 (CSF-IGF-1) with clinical response in autistic children (n=13, age 5-16 years) after a 6-month fluoxetine treatment. Good clinical responders (n=6) had a decrease (p=0.031) in DAT binding as assessed using single-photon emission computed tomography with [123I]-nor-beta-CIT, whereas poor responders had a trend to an increase. An increase in CSF-IGF-1 (p=0.003) was detected after the treatment period, but no correlation between the clinical response and CSF-IGF-1 was found. In conclusion, fluoxetine decreases DAT binding indicating alleviation of the hyperdopaminergic state and increases CSF-IGF-1 concentration, which may also have a neuroprotective effect against dopamine-induced neurotoxicity in autistic children.
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4. Mehta MV, Gandal MJ, Siegel SJ. {{mGluR5-Antagonist Mediated Reversal of Elevated Stereotyped, Repetitive Behaviors in the VPA Model of Autism}}. {PLoS One};2011;6(10):e26077.
Autism spectrum disorders (ASD) are highly disabling developmental disorders with a population prevalence of 1-3%. Despite a strong genetic etiology, there are no current therapeutic options that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of glutamatergic signaling, in particular through metabotropic glutamate receptor 5 (mGluR5) receptors, may contribute to phenotypic deficits and may be appropriate targets for pharmacologic intervention. This study assessed the therapeutic potential of 2-methyl-6-phenylethyl-pyrididine (MPEP), an mGluR5-receptor antagonist, on repetitive and anxiety-like behaviors in the valproic acid (VPA) mouse model of autism. Mice were exposed prenatally on day E13 to VPA and assessed for repetitive self-grooming and marble burying behaviors as adults. Anxiety-like behavior and locomotor activity were measured in an open-field. VPA-exposed mice displayed increased repetitive and anxiety-like behaviors, consistent with previously published results. Across both marble burying and self-grooming assays, MPEP significantly reduced repetitive behaviors in VPA-treated mice, but had no effect on locomotor activity. These results are consistent with emerging preclinical literature that mGluR5-antagonists may have therapeutic efficacy for core symptoms of autism.
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5. Salyakina D, Cukier HN, Lee JM, Sacharow S, Nations LD, Ma D, Jaworski JM, Konidari I, Whitehead PL, Wright HH, Abramson RK, Williams SM, Menon R, Haines JL, Gilbert JR, Cuccaro ML, Pericak-Vance MA. {{Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk}}. {PLoS One};2011;6(10):e26049.
Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology.
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6. Walum H, Lichtenstein P, Neiderhiser JM, Reiss D, Ganiban JM, Spotts EL, Pedersen NL, Anckarsater H, Larsson H, Westberg L. {{Variation in the Oxytocin Receptor Gene Is Associated with Pair-Bonding and Social Behavior}}. {Biol Psychiatry};2011 (Oct 17)
BACKGROUND: In specific vole and primate species the neuropeptide oxytocin plays a central role in the regulation of pair-bonding behavior. Here we investigate the extent to which genetic variants in the oxytocin receptor gene (OXTR) are associated with pair-bonding and related social behaviors in humans. METHODS: We first genotyped twelve single nucleotide polymorphisms (SNPs) in the TOSS (Twin and Offspring Study in Sweden) (n = 2309) and the TCHAD (Swedish Twin Study of Child and Adolescent Development) (n = 1240), comprising measures of self-reported pair-bonding behavior. In the TOSS sample we further investigated one of the SNPs for measures of marital status and quality. Moreover, in the TCHAD sample we explored the longitudinal relationship between precursors of pair-bonding during childhood and subsequent behavior in romantic relationships. Finally, in the TCHAD study and in the Child and Adolescent Twin Study of Sweden (CATSS) (n = 1771), the association between the same SNP and childhood behaviors was investigated. RESULTS: One SNP (rs7632287) in OXTR was associated with traits reflecting pair-bonding in women in the TOSS and TCHAD samples. In girls the rs7632287 SNP was further associated with childhood social problems, which longitudinally predicted pair-bonding behavior in the TCHAD sample. This association was replicated in the CATSS sample in which an association between the same SNP and social interaction deficit symptoms from the autism spectrum was detected. CONCLUSION: These results suggest an association between variation in OXTR and human pair-bonding and other social behaviors, possibly indicating that the well-described influence of oxytocin on affiliative behavior in voles could also be of importance for humans.
