TY  - JOUR
AU  - Santrač, Anja
AU  - Bijelić, Dunja
AU  - Stevanović, Vladimir
AU  - Banićević, Marija
AU  - Aranđelović, Jovana
AU  - Batinić, Bojan
AU  - Sharmin, Dishary
AU  - Cook, James
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4071
AB  - 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 α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for α5GABAA 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 activ- ity, 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 ani- mals themselves. Behavioral results were mirrored in GABA switch and spontane- ous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of α5GABAA 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.
PB  - John Wiley and Sons Inc
T2  - Autism Research
T1  - Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner
DO  - 10.1002/aur.2699
ER  - 

@article{
author = "Santrač, Anja and Bijelić, Dunja and Stevanović, Vladimir and Banićević, Marija and Aranđelović, Jovana and Batinić, Bojan and Sharmin, Dishary and Cook, James and Savić, Miroslav",
year = "2022",
abstract = "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 α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for α5GABAA 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 activ- ity, 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 ani- mals themselves. Behavioral results were mirrored in GABA switch and spontane- ous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of α5GABAA 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.",
publisher = "John Wiley and Sons Inc",
journal = "Autism Research",
title = "Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner",
doi = "10.1002/aur.2699"
}

Santrač, A., Bijelić, D., Stevanović, V., Banićević, M., Aranđelović, J., Batinić, B., Sharmin, D., Cook, J.,& Savić, M.. (2022). Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner. in Autism Research
John Wiley and Sons Inc..
https://doi.org/10.1002/aur.2699

Santrač A, Bijelić D, Stevanović V, Banićević M, Aranđelović J, Batinić B, Sharmin D, Cook J, Savić M. Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner. in Autism Research. 2022;.
doi:10.1002/aur.2699 .

Santrač, Anja, Bijelić, Dunja, Stevanović, Vladimir, Banićević, Marija, Aranđelović, Jovana, Batinić, Bojan, Sharmin, Dishary, Cook, James, Savić, Miroslav, "Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner" in Autism Research (2022),
https://doi.org/10.1002/aur.2699 . .