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Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

Kazim SF, Cardenas-Aguayo Mdel C, Arif M, Blanchard J, Fayyaz F, Grundke-Iqbal I, Iqbal K - PLoS ONE (2015)

Bottom Line: The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression.Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth.Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment.

View Article: PubMed Central - PubMed

Affiliation: Inge Grundke-Iqbal Research Floor, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities (NYSIBR), Staten Island, New York, United States of America; Neural and Behavioral Science Graduate Program, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America; SUNY Downstate/NYSIBR Center for Developmental Neuroscience (CDN), Staten Island, New York, United States of America.

ABSTRACT
Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

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Effects of autism and control sera in the presence or absence of P6 on ultrasonic vocalizations (USVs) from postnatal day 2–11 in rat pups.(A and B) Social communication in young Wistar rats injected intracerebroventricularly on P 0.5 with sham or 2% autism or control serum with or without 20 nM P6. Social communication was evaluated by the number (A) and duration (B) of isolation induced ultrasonic calls emitted by rat pups during the 5min test on postnatal days 3, 5, 7, 9, and 11. Data are presented as mean±S.E.M. in saline (sham) (n = 15–17), autism serum (n = 15–17), autism serum+P6 (n = 15–17), control serum (n = 15–17), and control serum+P6 (n = 15–17) treated pups. *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.
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pone.0118627.g004: Effects of autism and control sera in the presence or absence of P6 on ultrasonic vocalizations (USVs) from postnatal day 2–11 in rat pups.(A and B) Social communication in young Wistar rats injected intracerebroventricularly on P 0.5 with sham or 2% autism or control serum with or without 20 nM P6. Social communication was evaluated by the number (A) and duration (B) of isolation induced ultrasonic calls emitted by rat pups during the 5min test on postnatal days 3, 5, 7, 9, and 11. Data are presented as mean±S.E.M. in saline (sham) (n = 15–17), autism serum (n = 15–17), autism serum+P6 (n = 15–17), control serum (n = 15–17), and control serum+P6 (n = 15–17) treated pups. *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.

Mentions: Although rodents such as rats and mice do not use language, they emit auditory signals including USVs [71,72]. USVs emitted by rat pups upon separation from the dam and littermates can be used to assess the ability of social communication [71,72]. We found that number of isolation-induced ultrasonic calls was significantly lower in pups injected with sera from autistic children compared to saline injected sham group and control sera injected group on postnatal days 5, 7, and 9 [Fig. 4A; repeated measures 2-way ANOVA, group effect, F = 28.84 (4, 365), p<0.0001; postnatal day 5, sham vs. autism serum group, Bonferroni’s post-hoc test, p<0.001, autism serum vs control serum group, Bonferroni’s post-hoc test, p<0.001; postnatal day 7, sham vs. autism serum group, Bonferroni’s post-hoc test, p<0.05, autism serum vs control serum group, post-hoc test, p<0.05; postnatal day 9, sham vs. autism serum group, Bonferroni’s post-hoc test, p<0.01, autism serum vs control serum group, post-hoc test, p<0.01]. No significant effect of P6 treatment was found on USVs emitted by the rat pups. The mean duration of ultrasonic calls did not differ between groups [Fig. 4B; repeated measures 2-way ANOVA, group effect, F = 1.79 (4, 365), p = 0.1306]. The decreased number of ultrasonic calls emitted after maternal and littermate isolation in rat pups injected with sera from autistic children suggest decreased propensity towards their mothers as is also common in autistic infants.


Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

Kazim SF, Cardenas-Aguayo Mdel C, Arif M, Blanchard J, Fayyaz F, Grundke-Iqbal I, Iqbal K - PLoS ONE (2015)

Effects of autism and control sera in the presence or absence of P6 on ultrasonic vocalizations (USVs) from postnatal day 2–11 in rat pups.(A and B) Social communication in young Wistar rats injected intracerebroventricularly on P 0.5 with sham or 2% autism or control serum with or without 20 nM P6. Social communication was evaluated by the number (A) and duration (B) of isolation induced ultrasonic calls emitted by rat pups during the 5min test on postnatal days 3, 5, 7, 9, and 11. Data are presented as mean±S.E.M. in saline (sham) (n = 15–17), autism serum (n = 15–17), autism serum+P6 (n = 15–17), control serum (n = 15–17), and control serum+P6 (n = 15–17) treated pups. *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4359103&req=5

pone.0118627.g004: Effects of autism and control sera in the presence or absence of P6 on ultrasonic vocalizations (USVs) from postnatal day 2–11 in rat pups.(A and B) Social communication in young Wistar rats injected intracerebroventricularly on P 0.5 with sham or 2% autism or control serum with or without 20 nM P6. Social communication was evaluated by the number (A) and duration (B) of isolation induced ultrasonic calls emitted by rat pups during the 5min test on postnatal days 3, 5, 7, 9, and 11. Data are presented as mean±S.E.M. in saline (sham) (n = 15–17), autism serum (n = 15–17), autism serum+P6 (n = 15–17), control serum (n = 15–17), and control serum+P6 (n = 15–17) treated pups. *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.
Mentions: Although rodents such as rats and mice do not use language, they emit auditory signals including USVs [71,72]. USVs emitted by rat pups upon separation from the dam and littermates can be used to assess the ability of social communication [71,72]. We found that number of isolation-induced ultrasonic calls was significantly lower in pups injected with sera from autistic children compared to saline injected sham group and control sera injected group on postnatal days 5, 7, and 9 [Fig. 4A; repeated measures 2-way ANOVA, group effect, F = 28.84 (4, 365), p<0.0001; postnatal day 5, sham vs. autism serum group, Bonferroni’s post-hoc test, p<0.001, autism serum vs control serum group, Bonferroni’s post-hoc test, p<0.001; postnatal day 7, sham vs. autism serum group, Bonferroni’s post-hoc test, p<0.05, autism serum vs control serum group, post-hoc test, p<0.05; postnatal day 9, sham vs. autism serum group, Bonferroni’s post-hoc test, p<0.01, autism serum vs control serum group, post-hoc test, p<0.01]. No significant effect of P6 treatment was found on USVs emitted by the rat pups. The mean duration of ultrasonic calls did not differ between groups [Fig. 4B; repeated measures 2-way ANOVA, group effect, F = 1.79 (4, 365), p = 0.1306]. The decreased number of ultrasonic calls emitted after maternal and littermate isolation in rat pups injected with sera from autistic children suggest decreased propensity towards their mothers as is also common in autistic infants.

Bottom Line: The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression.Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth.Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment.

View Article: PubMed Central - PubMed

Affiliation: Inge Grundke-Iqbal Research Floor, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities (NYSIBR), Staten Island, New York, United States of America; Neural and Behavioral Science Graduate Program, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America; SUNY Downstate/NYSIBR Center for Developmental Neuroscience (CDN), Staten Island, New York, United States of America.

ABSTRACT
Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

Show MeSH
Related in: MedlinePlus