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Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment / A. BANERJEE in Molecular Autism, 7 (2016)
[article]
Titre : Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment Type de document : Texte imprimé et/ou numérique Auteurs : A. BANERJEE, Auteur ; J. A. LUONG, Auteur ; A. HO, Auteur ; A. O. SAIB, Auteur ; J. E. PLOSKI, Auteur Article en page(s) : 16p. Langues : Anglais (eng) Mots-clés : Acoustic Stimulation Animals Autism Spectrum Disorder/etiology Basolateral Nuclear Complex/drug effects/metabolism Carrier Proteins/biosynthesis/genetics/physiology Conditioning, Classical/physiology Disease Models, Animal Electroshock Exploratory Behavior/drug effects/physiology Fear/drug effects/physiology Female Freezing Reaction, Cataleptic Gene Expression Regulation/drug effects Genetic Vectors/administration & dosage/genetics Homer Scaffolding Proteins Nerve Tissue Proteins/biosynthesis/genetics/physiology Pregnancy Prenatal Exposure Delayed Effects RNA, Messenger/biosynthesis Rats Recombinant Fusion Proteins/biosynthesis/genetics Social Behavior Teratogens/pharmacology Transduction, Genetic Valproic Acid/pharmacology Amygdala Autism Emotion Homer1a Learning Memory Pavlovian fear conditioning Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASDs) represent a heterogeneous group of disorders with a wide range of behavioral impairments including social and communication deficits. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety, and some studies indicate that a subset of ASD individuals have a reduced ability to be fear conditioned. Deciphering the molecular basis of ASD has been considerably challenging and it currently remains poorly understood. In this study we examined the molecular basis of autism-like impairments in an environmentally induced animal model of ASD, where pregnant rats are exposed to the known teratogen, valproic acid (VPA), on day 12.5 of gestation and the subsequent progeny exhibit ASD-like symptoms. We focused our analysis on the basal and lateral nucleus of the amygdala (BLA), a region of the brain found to be associated with ASD pathology. METHODS: We performed whole genome gene expression analysis on the BLA using DNA microarrays to examine differences in gene expression within the amygdala of VPA-exposed animals. We validated one VPA-dysregulated candidate gene (Homer1a) using both quantitative PCR (qRT-PCR) and western blot. Finally, we overexpressed Homer1a within the basal and lateral amygdala of naive animals utilizing adeno-associated viruses (AAV) and subsequently examined these animals in a battery of behavioral tests associated with ASD, including auditory fear conditioning, social interaction and open field. RESULTS: Our microarray data indicated that Homer1a was one of the genes which exhibited a significant upregulation within the amygdala. We observed an increase in Homer1a messenger RNA (mRNA) and protein in multiple cohorts of VPA-exposed animals indicating that dysregulation of Homer1a levels might underlie some of the symptoms exhibited by VPA-exposed animals. To test this hypothesis, we overexpressed Homer1a within BLA neurons utilizing a viral-mediated approach and found that overexpression of Homer1a impaired auditory fear conditioning and reduced social interaction, while having no influence on open-field behavior. CONCLUSIONS: This study indicates that dysregulation of amygdala Homer1a might contribute to some autism-like symptoms induced by VPA exposure. These findings are interesting in part because Homer1a influences the functioning of Shank3, metabotropic glutamate receptors (mGluR5), and Homer1, and these proteins have previously been associated with ASD, indicating that these differing models of ASD may have a similar molecular basis. En ligne : http://dx.doi.org/10.1186/s13229-016-0077-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 16p.[article] Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment [Texte imprimé et/ou numérique] / A. BANERJEE, Auteur ; J. A. LUONG, Auteur ; A. HO, Auteur ; A. O. SAIB, Auteur ; J. E. PLOSKI, Auteur . - 16p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 16p.
Mots-clés : Acoustic Stimulation Animals Autism Spectrum Disorder/etiology Basolateral Nuclear Complex/drug effects/metabolism Carrier Proteins/biosynthesis/genetics/physiology Conditioning, Classical/physiology Disease Models, Animal Electroshock Exploratory Behavior/drug effects/physiology Fear/drug effects/physiology Female Freezing Reaction, Cataleptic Gene Expression Regulation/drug effects Genetic Vectors/administration & dosage/genetics Homer Scaffolding Proteins Nerve Tissue Proteins/biosynthesis/genetics/physiology Pregnancy Prenatal Exposure Delayed Effects RNA, Messenger/biosynthesis Rats Recombinant Fusion Proteins/biosynthesis/genetics Social Behavior Teratogens/pharmacology Transduction, Genetic Valproic Acid/pharmacology Amygdala Autism Emotion Homer1a Learning Memory Pavlovian fear conditioning Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASDs) represent a heterogeneous group of disorders with a wide range of behavioral impairments including social and communication deficits. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety, and some studies indicate that a subset of ASD individuals have a reduced ability to be fear conditioned. Deciphering the molecular basis of ASD has been considerably challenging and it currently remains poorly understood. In this study we examined the molecular basis of autism-like impairments in an environmentally induced animal model of ASD, where pregnant rats are exposed to the known teratogen, valproic acid (VPA), on day 12.5 of gestation and the subsequent progeny exhibit ASD-like symptoms. We focused our analysis on the basal and lateral nucleus of the amygdala (BLA), a region of the brain found to be associated with ASD pathology. METHODS: We performed whole genome gene expression analysis on the BLA using DNA microarrays to examine differences in gene expression within the amygdala of VPA-exposed animals. We validated one VPA-dysregulated candidate gene (Homer1a) using both quantitative PCR (qRT-PCR) and western blot. Finally, we overexpressed Homer1a within the basal and lateral amygdala of naive animals utilizing adeno-associated viruses (AAV) and subsequently examined these animals in a battery of behavioral tests associated with ASD, including auditory fear conditioning, social interaction and open field. RESULTS: Our microarray data indicated that Homer1a was one of the genes which exhibited a significant upregulation within the amygdala. We observed an increase in Homer1a messenger RNA (mRNA) and protein in multiple cohorts of VPA-exposed animals indicating that dysregulation of Homer1a levels might underlie some of the symptoms exhibited by VPA-exposed animals. To test this hypothesis, we overexpressed Homer1a within BLA neurons utilizing a viral-mediated approach and found that overexpression of Homer1a impaired auditory fear conditioning and reduced social interaction, while having no influence on open-field behavior. CONCLUSIONS: This study indicates that dysregulation of amygdala Homer1a might contribute to some autism-like symptoms induced by VPA exposure. These findings are interesting in part because Homer1a influences the functioning of Shank3, metabotropic glutamate receptors (mGluR5), and Homer1, and these proteins have previously been associated with ASD, indicating that these differing models of ASD may have a similar molecular basis. En ligne : http://dx.doi.org/10.1186/s13229-016-0077-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 Postweaning positive modulation of ?5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner / Anja SANTRAC in Autism Research, 15-5 (May 2022)
[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