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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