Trends in Molecular Medicine
Protein kinase A as a therapeutic target for memory disorders: rationale and challenges
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
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