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

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.

Qualitatively different effect of repeated stress during adolescence on principal neuron morphology across lateral and basal nuclei of the rat amygdala

“…Our results suggest that other factors may be driving increased anxiety and fear behavior after repeated stress in adolescent rats. For instance, reduced GABAergic function and increased membrane excitability could increase BLA neuronal responsivity, and both have been previously observed in adolescent rats after repeated stress (Braga et al, 2004; Hetzel and Rosenkranz, 2014; Jacobson-Pick and Richter-Levin, 2012; Jiang et al, 2009; Liu et al, 2014; Tzanoulinou et al, 2014; Maslova et al, 2002; McCormick et al, 2008; Toth et al, 2008). However, the loss of spines, perhaps reflective of loss of specific glutamatergic inputs, layered on top of those changes in adolescent rats may lead to a loss of specificity of responses.…”

Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala

“…Repeated stress also leads to decreased responsiveness of BLA interneurons, as measured by c-Fos and GABA efflux in response to acute stress (Reznikov et al, 2008;Reznikov et al, 2009), reduces GAD67, and induces dendritic atrophy of BLA interneurons (Gilabert-Juan et al, 2011). Repeated stress applied to juvenile rats can lead to changes of GABA function in adult rats, such as reduced GAD (Tzanoulinou et al, 2014) as well as changes observed as juveniles, such as reduced 5-HT and noradrenergic facilitation of sIPSCs (Braga et al, 2004;Jiang et al, 2009). However, the current study is the first to demonstrate directly the age bias in the effects of stress on GABAergic regulation of LAT neurons.…”

“…This may be due to alterations of GABA A receptor subunit composition. Indeed, stress exposure can induce significant alteration in GABA A receptor subunit expression in the amygdala (Caldji et al, 2003;Jacobson-Pick and Richter-Levin, 2012;Tzanoulinou et al, 2014). Reduced sensitivity to GABA combined with impaired function of LAT interneurons may contribute to the observed reduction of ongoing GABAergic inhibition of the LAT.…”

“…However, little is known about the effects of stress on GABAergic function during adolescence. There are, again, hints towards impaired GABAergic regulation of the BLA after repeated stress applied to juvenile rats that can be measured in adult rats (Jacobson-Pick and Richter-Levin, 2012;Tzanoulinou et al, 2014) as well as changes observed as juveniles (Braga et al, 2004;Jiang et al, 2009). However, there is little direct evidence that repeated stress alters GABAergic function in the BLA, and there has been no comparison of BLA GABAergic function between adolescent exposure and adult exposure to repeated stress.…”

Are Anxiety and Depression the Same Disorder?

“…50,51,52,53 In rats developmental stresses facilitated and increased glutamate release in the amygdala. 54 Considering the amygdala's connectivity to various regions of the brain, 55 such sensitisation may trigger a cascading fear/anxiety response throughout the brain. Furthermore chronic stress also reduces functioning and damages neurons in the hippocampus and PFC, the precise areas found damaged in depressive disorders.…”