Anxiety-like behavior and other consequences of early life stress in mice with increased protein kinase A activity

Abstract

Anxiety disorders are associated with abnormalities in fear-learning and bias to threat; early life experiences are influential to the development of an anxiety-like phenotype in adulthood. We recently reported that adult mice (Prkar1a+/-) with haploinsufficiency for the main regulatory subunit of the protein kinase A (PKA) exhibit an anxiety-like phenotype associated with increased PKA activity in the amygdala. PKA is the main effector of cyclic adenosine mono-phosphate signaling, a key pathway involved in the regulation of fear learning. Since anxiety has developmental and genetic components, we sought to examine the interaction of a genetic defect associated with anxiety phenotype and early life experiences. We investigated the effects of neonatal maternal separation or tactile stimulation on measures of behavior typical to adolescence as well as developmental changes in the behavioral phenotype between adolescent and adult wild-type (WT) and Prkar1a+/- mice. Our results showed developmental differences in assays of anxiety and novelty behavior for both genotypes. Adolescent mice showed increased exploratory and novelty seeking behavior compared to adult counterparts. However, early life experiences modulated behavior in adolescent WT differently than in adolescent Prkar1a+/- mice. Adolescent WT mice exposed to early life tactile stimulation showed attenuation of anxiety-like behavior, whereas an increase in exploratory behavior was found in Prkar1a+/- adolescent mice. The finding of behavioral differences that are apparent during adolescence in Prkar1a mice suggests that long-term exposure of the brain to increased PKA activity during critical developmental periods contributes to the anxiety-like phenotype noted in the adult animals with increased PKA activity.

Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome

“…Data from studies in mice also showed that decreased PKA, which is an effector molecule downstream of the cAMP regulatory unit (PKA reg), was associated with increased anxiety and higher PKA activity in the basolateral and central amygdala, as well as in the ventromedial hypothalamus (125,126). Consistently, increased PKA level from early life stress has been observed (117). Therefore, it remains unclear how PDE inhibitors could exert anxiolytic effects via the regulation of cAMP signaling.…”

“…As for mGluR inhibitors, PDE inhibitors have been linked to having anxiolytic effects, influencing neurogenesis, and mitigating the effects of corticosteroids (117)(118)(119)(120)(121). Evidently, the study of Beer et al (122) has shown how PDE inhibitors could reduce anxiety by elevating cAMP levels.…”

Bile acid signalling and its role in anxiety disorders

“…The activation of the TGR5-cAMP-protein kinase A (PKA) axis exerts an anti-inflammatory effect on microglia, which in turn promotes the phosphorylation of the target protein CREB. The cAMP/PKA/CREB signaling pathway is closely associated with anxiety (63)(64)(65)(66). The anti-anxiety effect of INT-777 is elicited through the activation of microglial cells, which modulate the TGR5/cAMP/PKA/CREB axis.…”