Long-Term Behavioral Programming Induced by Peripuberty Stress in Rats Is Accompanied by GABAergic-Related Alterations in the Amygdala

Stamatina Tzanoulinou,Esther Castillo-Gómez,Vandana Veenit,Clara García-Mompó,Carmen Sandi,Juan Nacher,Mathias V Schmidt

doi:10.1371/journal.pone.0094666

Stamatina Tzanoulinou, Esther Castillo-Gómez + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0094666

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Abstract

Stress during childhood and adolescence is a risk factor for psychopathology. Alterations in γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, have been found following stress exposure and fear experiences and are often implicated in anxiety and mood disorders. Abnormal amygdala functioning has also been detected following stress exposure and is also implicated in anxiety and social disorders. However, the amygdala is not a unitary structure; it includes several nuclei with different functions and little is known on the potential differences the impact of early life stress may have on this system within different amygdaloid nuclei. We aimed here to evaluate potential regional differences in the expression of GABAergic-related markers across several amygdaloid nuclei in adult rats subjected to a peripuberty stress protocol that leads to enhanced basal amygdala activity and psychopathological behaviors. More specifically, we investigated the protein expression levels of glutamic acid decarboxylase (GAD; the principal synthesizing enzyme of GABA) and of GABA-A receptor subunits α2 and α3. We found reduced GAD and GABA-A α3, but not α2, subunit protein levels throughout all the amygdala nuclei examined (lateral, basolateral, basomedial, medial and central) and increased anxiety-like behaviors and reduced sociability in peripubertally stressed animals. Our results identify an enduring inhibition of the GABAergic system across the amygdala following exposure to early adversity. They also highlight the suitability of the peripuberty stress model to investigate the link between treatments targeting the dysfunctional GABAergic system in specific amygdala nuclei and recovery of specific stress-induced behavioral dysfunctions.

Highlights

Exposure to stress during early life is a known risk factor for the development of mental illness [1,2,3]
Using a peripuberty stress protocol in rats that leads to increased activity throughout the amygdala at adulthood [9], we show here that protein levels of both the Gamma-aminobutyric acid (GABA) marker, glutamic acid decarboxylase (GAD), and the GABA-A a3, but not a2, subunit are reduced throughout all the amygdala nuclei examined (i.e., lateral amygdaloid nucleus (LA), basolateral amygdaloid nucleus (BLA), basomedial amygdaloid nucleus (BMA), medial amygdaloid nucleus (MeA) and central amygdaloid nucleus (CeA))
We show that these changes are present in the context of increased anxiety-like behaviors and reduced sociability displayed by peripuberty stress (PPS) animals

Summary

Introduction

Exposure to stress during early life is a known risk factor for the development of mental illness [1,2,3]. Childhood and adolescence are periods of high vulnerability to long-lasting programming of psychopathologies –including anxiety disorders– by stress [4], as reported in a variety of species, including humans [2,5,6], non-human primates [7,8], and rodents [9,10,11]. Enhanced amygdala reactivity can be detected in individuals with high state and trait anxiety levels exposed to emotionally arousing stimuli (for a review, see [17]) and has emerged as a hallmark in a variety of anxiety disorders, including post-traumatic stress disorder (PTSD) and social phobia [18,19]. Neuroimaging studies in PTSD patients indicate that increased amygdala activation is observed following exposure to disorder-relevant stimuli [20,21,22], and at rest [23] and during the completion of non-emotional tasks [24,25]

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