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

Briassoulis, George; Keil, Margaret F.; Naved, Bilal; Liu, Sophie; Starost, Matthew F.; Nesterova, Maria; Gokarn, Nirmal; Batistatos, Anna; Wu, Tao; Stratakis, Constantine A.

doi:10.1016/j.bbr.2016.03.001

Cited by 9 publications

(6 citation statements)

References 78 publications

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“…Our finding of a lack of a genotype effect in other behavioral assays of anxiety in adolescent mice suggest that the anxiety-like phenotype as noted in adult mice with loss of one Prkar1a allele (associated with increased PKA activity in the amygdala), is likely due to long-term exposure during critical developmental periods of brain development to alterations in PKA activity. PKA activity in brain areas of adolescent WT and HZ mice are similar to what has been reported for their adult counterparts (unpublished data); namely, increased PKA activity in the amygdala but no genotype differences in PKA activity in cortex, thalamus, or paraventricular hypothalamus [10, 11].…”

Section: Discussionsupporting

confidence: 65%

“…Previous studies have demonstrated that PKA’s main regulatory subunit, R1α, is involved in the expression of anxiety-like behaviors; the loss of one Prkar1a allele in mice ( Prkar1a +/− ) led to an augmentation of anxiety-like behaviors in association with an increase in PKA activity in both the basolateral (BLA) and central amygdala (CeA) [10]. In a subsequent study, Briassoulis et al [11] studied the effects of deleting one allele of the main catalytic subunit (Cα) and compared anxiety-related behaviors in Prkar1a +/− and Prkar1a +/− /Prkaca +/− mice: the former spent significantly less time in the open arms of the elevated plus maze (EPM), while Prkaca +/− and Prkar1a +/− /Prkaca +/− mice displayed less exploratory behaviors [11].…”

Section: Introductionmentioning

confidence: 99%

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

Ugolini

Keil

Paradiso

et al. 2018

Behavioural Brain Research

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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.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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

Ugolini

Keil

Paradiso

et al. 2018

Behavioural Brain Research

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“…The alteration of PKA activity in these transgenic mice was not a ubiquitous effect, since PKA activity was found to be similar between heterozygotes and WT mice in some brain areas (e.g., prefrontal cortex, hippocampus, paraventricular hypothalamus, cerebellum, and neural sensory areas). These findings highlight the importance of even modest changes in PKA activity in modulating anxiety-like behaviors and also that catalytic subunit activity is not the sole determinant of PKA’s cAMP-signaling effects ( 89 , 90 ). It is also possible that compensatory mechanisms in remaining PKA subunits and PDE4 may be a factor in areas not showing any differences in PKA activity between Prkar1a +/− and Prkar1a +/− /Prkaca +/− and WT or Prkaca +/− mice.…”

Section: Effect Of Pka Defects On Anxiety-like Behaviormentioning

confidence: 96%

Protein Kinase A and Anxiety-Related Behaviors: A Mini-Review

et al. 2016

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This review focuses on the anxiety related to cyclic AMP/protein kinase A (PKA) signaling pathway that regulates stress responses. PKA regulates an array of diverse signals that interact with various neurotransmitter systems associated with alertness, mood, and acute and social anxiety-like states. Recent mouse studies support the involvement of the PKA pathway in common neuropsychiatric disorders characterized by heightened activation of the amygdala. The amygdala is critical for adaptive responses leading to fear learning and aberrant fear memory and its heightened activation is widely thought to underpin various anxiety disorders. Stress-induced plasticity within the amygdala is involved in the transition from normal vigilance responses to emotional reactivity, fear over-generalization, and deficits in fear inhibition resulting in pathological anxiety and conditions, such as panic and depression. Human studies of PKA signaling defects also report an increased incidence of psychiatric disorders, including anxiety, depression, bipolar disorder, learning disorders, and attention deficit hyperactivity disorder. We speculate that the PKA system is uniquely suited for selective, molecularly targeted intervention that may be proven effective in anxiolytic therapy.

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“…PKA mouse models have also demonstrated a role for PKA signaling in anxiety. Increased cAMP signaling has been associated with an anxiety phenotype in mice that were haploinsufficient for either Prkar1a (Keil et al 2012) or Prkaca (Briassoulis et al 2016). Similarly, in mice overexpressing G s α, enhanced striatal PKA enzymatic activity was associated with an anxiety phenotype (Favilla et al 2008).…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

PKA functions in metabolism and resistance to obesity: lessons from mouse and human studies

London

Bloyd

Stratakis

2020

Journal of Endocrinology

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Both direct and indirect evidence demonstrate a central role for the cAMP-dependent protein kinase (PKA) signaling pathway in the regulation of energy balance and metabolism across multiple systems. However, the ubiquitous pattern of PKA expression across cell types poses a challenge in pinpointing its tissue-specific regulatory functions and further characterizing its many downstream effects in certain organs or cells. Mouse models of PKA deficiency and over-expression and studies in living cells have helped clarify PKA function in adipose tissue (AT), liver, adrenal, pancreas, and specific brain nuclei, as they pertain to energy balance and metabolic dysregulation. Limited studies in humans suggest differential regulation of PKA in AT of obese compared to lean individuals and an overall dysregulation of PKA signaling in obesity. Despite its complexity, under normal physiologic conditions, the PKA system is tightly regulated by changes in cAMP concentrations upstream via adenylate cyclase and downstream by phosphodiesterase-mediated cAMP degradation to AMP and by changes in PKA holoenzyme stability. Adjustments in the PKA system appear to be important to the development and maintenance of the obese state and its associated metabolic perturbations. In this review we discuss the important role of PKA in obesity and its involvement in resistance to obesity, through studies in humans and in mouse models, with a focus on the regulation of PKA in energy expenditure, intake behavior, and lipid and glucose metabolism.

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

Cited by 9 publications

References 78 publications

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

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

Protein Kinase A and Anxiety-Related Behaviors: A Mini-Review

PKA functions in metabolism and resistance to obesity: lessons from mouse and human studies

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