[article]
| Titre : |
Postweaning positive modulation of ?5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner |
| Type de document : |
Texte imprimé et/ou numérique |
| Auteurs : |
Anja SANTRAC, Auteur ; Dunja BIJELIC, Auteur ; Vladimir STEVANOVI?, Auteur ; Marija BANI?EVI?, Auteur ; Jovana ARAN?ELOVI?, Auteur ; Bojan BATINI?, Auteur ; Dishary SHARMIN, Auteur ; James M. COOK, Auteur ; Miroslav M. SAVI?, Auteur |
| Article en page(s) : |
p.806-820 |
| Langues : |
Anglais (eng) |
| Mots-clés : |
Animals Autism Spectrum Disorder/chemically induced/drug therapy Autistic Disorder Behavior, Animal/physiology Calcium/metabolism/pharmacology Disease Models, Animal Female Male Pregnancy Prenatal Exposure Delayed Effects Rats Rats, Wistar Receptors, GABA-A/metabolism Social Behavior Valproic Acid/pharmacology gamma-Aminobutyric Acid Kcc2 Nkcc1 autism spectrum disorder neuron maturity valproic acid animal model ?5GABAA receptor |
| Index. décimale : |
PER Périodiques |
| Résumé : |
Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA(A) receptors that contain the ?5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for ?5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD. Postweaning rats of both sexes were treated for 7?days with vehicle or MP-III-022 at two doses pharmacokinetically determined as selective, and thereafter tested in a behavioral battery (social interaction test, elevated plus maze, spontaneous locomotor activity, and standard and reverse Morris water maze). Additional rats were used for establishing a primary neuronal culture and performing calcium imaging, and determination of hippocampal mRNA levels of GABRA5, NKCC1, and KCC2. MP-III-022 prevented impairments in many parameters connected with social, repetitive and restrictive behavioral domains. The lower and higher dose was more effective in males and females, respectively. Intriguingly, MP-III-022 elicited certain changes in control animals similar to those manifested in valproate animals themselves. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of ?5GABAA receptors in pathophysiology of ASD, and suggest a potential application of selective PAMs in its treatment, that needs to be researched in a sex-specific manner. LAY SUMMARY: In rats prenatally exposed to valproate as a model of autism, a modulator of ?5GABAA receptors ameliorated social, repetitive and restrictive impairments, and, intriguingly, elicited certain autism-like changes in control rats. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, and partly in gene expression changes. This shows a role of ?5GABAA receptors in pathophysiology of ASD, and a potential application of their selective modulators in its treatment. |
| En ligne : |
http://dx.doi.org/10.1002/aur.2699 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 |
in Autism Research > 15-5 (May 2022) . - p.806-820
[article] Postweaning positive modulation of ?5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner [Texte imprimé et/ou numérique] / Anja SANTRAC, Auteur ; Dunja BIJELIC, Auteur ; Vladimir STEVANOVI?, Auteur ; Marija BANI?EVI?, Auteur ; Jovana ARAN?ELOVI?, Auteur ; Bojan BATINI?, Auteur ; Dishary SHARMIN, Auteur ; James M. COOK, Auteur ; Miroslav M. SAVI?, Auteur . - p.806-820. Langues : Anglais ( eng) in Autism Research > 15-5 (May 2022) . - p.806-820
| Mots-clés : |
Animals Autism Spectrum Disorder/chemically induced/drug therapy Autistic Disorder Behavior, Animal/physiology Calcium/metabolism/pharmacology Disease Models, Animal Female Male Pregnancy Prenatal Exposure Delayed Effects Rats Rats, Wistar Receptors, GABA-A/metabolism Social Behavior Valproic Acid/pharmacology gamma-Aminobutyric Acid Kcc2 Nkcc1 autism spectrum disorder neuron maturity valproic acid animal model ?5GABAA receptor |
| Index. décimale : |
PER Périodiques |
| Résumé : |
Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA(A) receptors that contain the ?5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for ?5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD. Postweaning rats of both sexes were treated for 7?days with vehicle or MP-III-022 at two doses pharmacokinetically determined as selective, and thereafter tested in a behavioral battery (social interaction test, elevated plus maze, spontaneous locomotor activity, and standard and reverse Morris water maze). Additional rats were used for establishing a primary neuronal culture and performing calcium imaging, and determination of hippocampal mRNA levels of GABRA5, NKCC1, and KCC2. MP-III-022 prevented impairments in many parameters connected with social, repetitive and restrictive behavioral domains. The lower and higher dose was more effective in males and females, respectively. Intriguingly, MP-III-022 elicited certain changes in control animals similar to those manifested in valproate animals themselves. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of ?5GABAA receptors in pathophysiology of ASD, and suggest a potential application of selective PAMs in its treatment, that needs to be researched in a sex-specific manner. LAY SUMMARY: In rats prenatally exposed to valproate as a model of autism, a modulator of ?5GABAA receptors ameliorated social, repetitive and restrictive impairments, and, intriguingly, elicited certain autism-like changes in control rats. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, and partly in gene expression changes. This shows a role of ?5GABAA receptors in pathophysiology of ASD, and a potential application of their selective modulators in its treatment. |
| En ligne : |
http://dx.doi.org/10.1002/aur.2699 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 |
|
Postweaning positive modulation of ?5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner in Autism Research, 15-5 (May 2022)
