Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment

Abstract

BackgroundAutism 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.MethodsWe 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 naïve 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.ResultsOur 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0077-9) contains supplementary material, which is available to authorized users.

Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity

“…The role for both Homer1a and Ania3 on encoding and retrieval-mediated memory processes remains to be fully understood and needs to consider the contribution across the network supporting memory processing in different behavioral tasks. Indeed, unlike the hippocampus, overexpression of Homer1a in the adult amygdala results in impairments in fear conditioning [125], suggesting that high and low levels of Homer1a impair learning when these occur in different brain regions, that may reflect the underlying differences in the way the amygdala and hippocampus support fear learning [126, 127]. …”

Age- and Sex-Specific Fear Conditioning Deficits in Mice Lacking Pcdh10, an Autism Associated Gene

“…Like Pcdh10 +/mice, several mouse models associated with ASD exhibit fear conditioning deficits, including CD38, Homer1a, and Scn1a mutants (Han et al, 2012;Banerjee et al, 2016;Kim et al, 2016), as well as a number of others (Markram et al, 2008;Stapley et al, 2013;Howell et al, 2017;Nolan et al, 2017;Fricano-Kugler et al, 2019). Reports of fear conditioning in individuals with ASD have been varied, with some reporting impairments, and some failing to find differences compared to controls (Bernier et al, 2005;Gaigg and Bowler, 2007;Sterling et al, 2013).…”

“…Pcdh10 +/males are known to have abnormalities in the BLA and deficits in social behaviors that engage the BLA (Ferri et al, 2015;Schoch et al, 2017). This raises the question of whether Pcdh10 +/males might have deficits in fear conditioning, a behavior that involves the BLA (Ressler and Maren, 2019), and that is disrupted in several in mouse models relevant to ASD (Han et al, 2012;Banerjee et al, 2016;Kim et al, 2016), and in autistic humans (Gaigg and Bowler, 2007;Top Jr. et al, 2016). We hypothesized that fear conditioning would be disrupted in Pcdh10 +/mice, and we tested juvenile and adult male and female Pcdh10 +/and WT littermate mice in both contextual and cued fear conditioning paradigms.…”

The role of imbalance between urinary hexanoyl-lysine and total antioxidant capacity levels and its relation to plasma superoxide dismutase levels in autism spectrum disorder

“…ASD symptoms usually appear during early development and generally lead to serious lifelong limitations in function; thus, both genetic and environmental factors may contribute to its development [2,3]. The shift in the balance between oxidants and antioxidants in favor of oxidants is termed "oxidative stress" [4].…”