Protein kinase A as a therapeutic target for memory disorders: rationale and challenges

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cAMP-dependent protein kinase A (PKA) signaling has a key role in memory processes and has been identified as a potential therapeutic target for memory disorders. The activation of PKA signaling is crucial for the consolidation of long-term memories dependent on the hippocampus and/or the amygdala, By contrast, initial studies indicate that cAMP–PKA activation might impair the working memory and executive functions of the prefrontal cortex. Furthermore, PKA activation in the nucleus accumbens might increase sensitivity to addiction. These complexities must be heeded when designing medications aimed at altering PKA activity. PKA might be most practical as a therapeutic target in disorders with global alterations in cAMP–PKA activity due to genetic or environmental factors.

Introduction

The molecular basis of neuroplasticity was first addressed in simple nervous systems – those of Aplysia and Drosophila. The pioneering studies of Schacher, Kandel and colleagues [1] first demonstrated that the stimulation of cAMP-dependent protein kinase A (PKA; Box 1) was necessary for the consolidation of long-term memories in Aplysia [1]. This same pathway was subsequently found to be crucial for long-term memory formation in the mammalian hippocampus, validating this experimental approach [2]. Recent research has expanded this paradigm to other brain circuits contributing to cognitive function. This review identifies areas of progress in our understanding of cAMP–PKA actions in the mammalian brain, with focus on four interconnected brain regions that subserve varied forms of memory (Box 2): the hippocampus (memory consolidation), the amygdala (affective regulation of memory), the striatum, with particular focus on the nucleus accumbens (reward-motivated actions or habits relevant to drug addiction), and the prefrontal cortex (PFC; working memory and executive functions). The review emphasizes the recent controversy that not all brain regions are regulated by cAMP–PKA in a similar fashion, and that these differences must be respected if we are to develop effective therapeutics for disorders such as age-related cognitive decline, post-traumatic stress disorder (PTSD) and drug abuse. The review identifies arenas in which cAMP–PKA would probably be a beneficial therapeutic target and highlights challenges that must be overcome if we are to translate our understanding of molecular mechanisms governing memory processes into successful treatments.

Section snippets

The important role of PKA in the consolidation of long-term memories by the hippocampus

Studies of amnesic patients and experimental animals have demonstrated that the hippocampus is crucial for the formation of long-term memories [3]. Numerous studies have subsequently shown that cAMP–PKA activation has an essential role in the induction of long-term synaptic, physiological and behavioral changes. These PKA-dependent changes are required for learning and long-term memory consolidation in a variety of species, ranging from Aplysia 3, 4 to rodents 5, 6, 7, 8, 9. In rodents, genetic

PKA activation facilitates amygdala processing of emotion

Recent studies found that PKA signaling is essential for the mnemonic functions of the amygdala. The amygdala contributes to the emotional enhancement of memory and is crucial for affective conditioning, such as fear conditioning. The infusion of PKA inhibitors into the basal and lateral amygdala (BLA) immediately following fear-conditioning training dose-dependently blocked the consolidation of fear memory measured 24 h after training, but did not alter short-term memory measured 4 h after

PKA activation in the ventral striatum facilitates addictive behaviors and appetitive learning

Cortical-striatal circuits are essential for the selection, formation and execution of motor, cognitive and affective habits. As in the hippocampus and amygdala, PKA activation is crucial for striatal neuroplasticity [21]. The link between alterations in PKA and maladaptive learning and memory has been best studied in the nucleus accumbens, particularly in regard to drug addiction.

The compulsive aspects of addiction might result from pathological alterations in molecular mechanisms underlying

High levels of PKA activity impair the working memory functions of the PFC

The PFC guides behavior using working memory. Prefrontal dysfunction is commonly found in many human psychiatric disorders, including attention-deficit hyperactivity disorder, PTSD, the affective disorders and schizophrenia. Prefrontal cortical deficits also develop with advancing age and acutely during stress exposure [40].

Neuropharmacological studies have indicated that the PFC is modulated differently from the hippocampus and amygdala, and thus requires alternative treatment strategies. For

The aging brain: exaggeration of neurochemical differences

Agents that strengthen PKA signaling are being considered as therapeutics for the treatment of memory deficits in the elderly. A variety of studies have found that PKA signaling is reduced with age in the hippocampus, weakening LTP and impairing memory consolidation in aged rodents [7]. However, the opposite profile appears to emerge with age in the PFC: cAMP–PKA signaling appears to impair working memory by becoming overactive in the aged PFC [49].

Studies of PFC cognitive function in monkeys

Challenges to PKA as a therapeutic target

Given the universal nature of cAMP–PKA signaling, there will be several obstacles to consider when designing medications that target this pathway. Care will be needed when designing compounds for elderly subjects to ensure that prefrontal cortical cognitive functions are not worsened. The literature also suggests that PKA activators, when combined with certain other stimulant medications, might increase the susceptibility to addiction. Tempering doses might be sufficient to allay these

Concluding remarks

The research summarized illustrates that cAMP–PKA signaling can have powerful influences on varied brain regions and thus on varying types of memory. These findings are compelling, suggesting that intracellular targets might provide unique opportunities to strengthen mnemonic functions. However, the limitations of this approach are also apparent: PKA does not appear to have universally beneficial actions on all types of memory; thus, strengthening one type of memory might necessarily weaken

Acknowledgements

Supported by AG06036 and P50 MH068789 to AFTA and DA15222 to JRT.

Glossary

Progressive-ratio responding:
When an animal is required to work progressively harder to obtain each subsequent reward, or reinforcer, this is termed a progressive ratio schedule. For example, two responses are required to obtain a drug or food reward, then four, then eight, then 16, etc. The point at which that the subject stops responding has been termed ‘the breakpoint’ and is believed to be a sensitive measure of motivation for the reward.
Associative learning:
Pavlovian and instrumental

References (54)

  • M.J. Miserendino et al.

    Behavioral sensitization to cocaine: modulation of the cyclic AMP system in the nucleus accumbens

    Brain Res.

    (1995)
  • A.E. Kelley

    Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning

    Neurosci. Biobehav. Rev.

    (2004)
  • A.E. Baldwin

    Appetitive instrumental learning is impaired by inhibition of cAMP-dependent protein kinase within the nucleus accumbens

    Neurobiol. Learn. Mem.

    (2002)
  • A.F.T. Arnsten

    Catecholamine modulation of prefrontal cortical cognitive function

    Trends Cogn. Sci.

    (1998)
  • M. Genkova-Papazova

    Effects of flunarizine and nitrendipine on electroconvulsive shock- and clonidine-induced amnesia

    Pharmacol. Biochem. Behav.

    (1997)
  • A.F.T. Arnsten

    Stress impairs PFC function in rats and monkeys: Role of dopamine D1 and norepinephrine α-1 receptor mechanisms

    Prog. Brain Res.

    (2000)
  • B. Ramos

    Dysregulation of protein kinase A signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline

    Neuron

    (2003)
  • S. Schacher

    cAMP evokes long-term facilitation in Aplysia sensory neurons that requires new protein synthesis

    Science

    (1988)
  • E.R. Kandel

    The molecular biology of memory storage: a dialogue between genes and synapses

    Science

    (2001)
  • S.N. Duffy et al.

    Postsynaptic application of a peptide inhibitor of cAMP-dependent protein kinase blocks expression of long-lasting synaptic potentiation in hippocampal neurons

    J. Neurosci.

    (2003)
  • M. Barad

    Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • M.E. Bach

    Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • P. Ardenghi

    Late and prolonged post-training memory modulation in entorhinal and parietal cortex by drugs acting on the cAMP/protein kinase A signaling pathway

    Behav. Pharmacol.

    (1997)
  • G.E. Schafe et al.

    Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala

    J. Neurosci.

    (2000)
  • M.T. Koh

    Inhibition of protein kinase A activity interferes with long-term, but not short-term, memory of conditioned taste aversions

    Behav. Neurosci.

    (2002)
  • B. Ferry

    Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between β- and α-1-adrenoceptors

    J. Neurosci.

    (1999)
  • Y.Y. Huang

    Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis-dependent late phase of long-term potentiation

    J. Neurosci.

    (2000)
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