Studies of mice with cyclic AMP-dependent protein kinase (PKA) defects reveal the critical role of PKA’s catalytic subunits in anxiety

• Alterations of total PKA activity in the amygdala regulate the anxiety response.
• Both R1α and Cα subunit activity regulate PKA signaling in the amygdala and anxiety.
• Cα activity is not the sole determinant of PKA’s cAMP signaling effects.

Cyclic adenosine mono-phosphate-dependent protein kinase (PKA) is critically involved in the regulation of behavioral responses. Previous studies showed that PKA’s main regulatory subunit, R1α, is involved in anxiety-like behaviors. The purpose of this study was to determine how the catalytic subunit, Cα, might affect R1α’s function and determine its effects on anxiety-related behaviors.The marble bury (MB) and elevated plus maze (EPM) tests were used to assess anxiety-like behavior and the hotplate test to assess nociception in wild type (WT) mouse, a Prkar1a heterozygote (Prkar1a+/−) mouse with haploinsufficiency for the regulatory subunit (R1α), a Prkaca heterozygote (Prkaca+/−) mouse with haploinsufficiency for the catalytic subunit (Cα), and a double heterozygote mouse (Prkar1a+/−/Prkaca+/−) with haploinsufficiency for both R1α and Cα. We then examined specific brain nuclei involved in anxiety.Results of MB test showed a genotype effect, with increased anxiety-like behavior in Prkar1a+/− and Prkar1a+/−/Prkaca+/− compared to WT mice. In the EPM, Prkar1a+/− spent significantly less time in the open arms, while Prkaca+/− and Prkar1a+/−/Prkaca+/− mice displayed less exploratory behavior compared to WT mice. The loss of one Prkar1a allele was associated with a significant increase in PKA activity in the basolateral (BLA) and central (CeA) amygdala and ventromedial hypothalamus (VMH) in both Prkar1a+/− and Prkar1a+/−/Prkaca+/− mice.Alterations of PKA activity induced by haploinsufficiency of its main regulatory or most important catalytic subunits result in anxiety-like behaviors. The BLA, CeA, and VMH are implicated in mediating these PKA effects in brain.