Inhibition of purinergic P2 receptors prevents synaptic and behavioral alterations in a rodent model of autism spectrum disorders / Lidia BABIEC in Research in Autism Spectrum Disorders, 112 (April 2024)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 112 (April 2024) . - p.102353 Titre : Inhibition of purinergic P2 receptors prevents synaptic and behavioral alterations in a rodent model of autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Lidia BABIEC, Auteur ; Anna WILKANIEC, Auteur ; El?bieta GAWINEK, Auteur ; Wojciech HILGIER, Auteur ; Agata ADAMCZYK, Auteur Article en page(s) : p.102353 Langues : Anglais (eng) Mots-clés : Autism spectrum disorders  Valproic acid  Extracellular nucleotides  Purinergic receptors  IsoPPADS  PPADS Index. décimale : PER Périodiques Résumé : Background Extracellular nucleotides acting through specific purinergic receptors play a key role in synaptic transmission and neuromodulation. Therefore, any deregulation of purine-dependent signaling may lead to synaptic dysfunction and the development of autism-like behaviors. Method Here, we used a well-established autism spectrum disorders (ASD) model of a single prenatal exposure to valproic acid (VPA). Wistar female rats received an i.p. injection of VPA (450 mg/kg body weight) at gestational day 12.5. To study the involvement of purinergic signaling in the alterations of the key synaptic proteins and the development of ASD-like behaviors in VPA offspring at 52. post-natal day, we performed a single i.p. injection of the non-selective P2-purinoceptor antagonists PPADS and isoPPADS (12.5 mg/kg body weight) 24 h before behavioral tests. Results The results showed an increased level of ATP and its metabolites, ADP, and AMP in the cerebrospinal fluid of VPA offspring indicating significant dysregulation in extracellular nucleotides- signaling, that may result in synaptic aberrations. Treatment with isoPPADS significantly prevented alterations of the selected synaptic proteins evoked by prenatal VPA exposure along with prevention of the overactivation of mTOR kinase, while both purinergic antagonists reversed autism-like behavior. This suggests that apart from the activation of the mTOR signaling cascade, purinergic deregulation may influence molecular pathways other than synaptic protein imbalance. Conclusions Disturbances in the ATP turnover and overstimulation of purinergic receptors are responsible for synaptic proteins' dyshomeostasis and the appearance of ASD-like behaviors. mTOR kinase might be partially responsible for the development of autistic symptoms evoked by hyperpurinergia. En ligne : https://doi.org/10.1016/j.rasd.2024.102353 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=524 [article] Inhibition of purinergic P2 receptors prevents synaptic and behavioral alterations in a rodent model of autism spectrum disorders [Texte imprimé et/ou numérique] / Lidia BABIEC, Auteur ; Anna WILKANIEC, Auteur ; El?bieta GAWINEK, Auteur ; Wojciech HILGIER, Auteur ; Agata ADAMCZYK, Auteur . - p.102353. Langues : Anglais (eng) in Research in Autism Spectrum Disorders > 112 (April 2024) . - p.102353 Mots-clés : Autism spectrum disorders  Valproic acid  Extracellular nucleotides  Purinergic receptors  IsoPPADS  PPADS Index. décimale : PER Périodiques Résumé : Background Extracellular nucleotides acting through specific purinergic receptors play a key role in synaptic transmission and neuromodulation. Therefore, any deregulation of purine-dependent signaling may lead to synaptic dysfunction and the development of autism-like behaviors. Method Here, we used a well-established autism spectrum disorders (ASD) model of a single prenatal exposure to valproic acid (VPA). Wistar female rats received an i.p. injection of VPA (450 mg/kg body weight) at gestational day 12.5. To study the involvement of purinergic signaling in the alterations of the key synaptic proteins and the development of ASD-like behaviors in VPA offspring at 52. post-natal day, we performed a single i.p. injection of the non-selective P2-purinoceptor antagonists PPADS and isoPPADS (12.5 mg/kg body weight) 24 h before behavioral tests. Results The results showed an increased level of ATP and its metabolites, ADP, and AMP in the cerebrospinal fluid of VPA offspring indicating significant dysregulation in extracellular nucleotides- signaling, that may result in synaptic aberrations. Treatment with isoPPADS significantly prevented alterations of the selected synaptic proteins evoked by prenatal VPA exposure along with prevention of the overactivation of mTOR kinase, while both purinergic antagonists reversed autism-like behavior. This suggests that apart from the activation of the mTOR signaling cascade, purinergic deregulation may influence molecular pathways other than synaptic protein imbalance. Conclusions Disturbances in the ATP turnover and overstimulation of purinergic receptors are responsible for synaptic proteins' dyshomeostasis and the appearance of ASD-like behaviors. mTOR kinase might be partially responsible for the development of autistic symptoms evoked by hyperpurinergia. En ligne : https://doi.org/10.1016/j.rasd.2024.102353 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=524

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