Chapter 6 Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase

https://doi.org/10.1016/S0079-6123(07)00006-4Get rights and content

Abstract

The hippocampus is crucial for the consolidation of new declarative long-term memories. Genetic and behavioral experimentation have revealed that several protein kinases are critical for the formation of hippocampus-dependent long-term memories. Cyclic-AMP dependent protein kinase (PKA) is a serine–threonine kinase that has been strongly implicated in the expression of specific forms of hippocampus-dependent memory. We review evidence that PKA is required for hippocampus-dependent memory in mammals, and we highlight some of the proteins that have been implicated as targets of PKA. Future directions and open questions regarding the role of PKA in memory storage are also described.

Introduction

Protein kinases modulate a plethora of important processes, including synaptic plasticity, learning, and memory. Multiple chemical neurotransmitters, hormones, and other signaling substances use cyclic adenosine 3′,5′ monophosphate (cAMP) as an intracellular second messenger. The principal target for cAMP in mammalian cells is cAMP-dependent protein kinase (PKA), which is ubiquitously expressed and mediates intracellular signal transduction. Pioneering work by Earl Sutherland identified cAMP as the first intracellular second messenger (Sutherland and Rall, 1957; Sutherland et al., 1965). Subsequently, Edwin Krebs, Paul Greengard, and their colleagues purified PKA from rabbit skeletal muscle (Walsh et al., 1968; Reimann et al., 1971), and they showed that PKA activity was stimulated by cAMP (Miyamoto et al., 1968, Miyamoto et al., 1969; Walsh et al., 1968; Beavo et al., 1974). Other advances, made possible by genetic, molecular, and cell biological techniques, have shed light on the molecular characteristics, dynamics, and functional plurality of the PKA holoenzyme (reviewed by McKnight et al., 1988; Beebe, 1994; Skalhegg and Tasken, 2000). It is now well established that PKA regulates many biological processes through its phosphorylation of proteins. Also, phosphatases such as protein phosphatase 1 and the calcium-regulated phosphatase, calcineurin, can dephosphorylate proteins that had been phosphorylated by PKA, thus allowing PKA signaling events to be reversible (Fig. 1).

A fundamental process that is modulated by PKA is synaptic transmission, which can be modified by the electrical activity of a neuron — a process termed “activity-dependent synaptic plasticity” (reviewed by Nguyen and Woo, 2003). Because synaptic plasticity involves long-lasting modifications of intercellular signaling in the nervous system, it plays significant roles in regulating learning and memory (Castellucci et al., 1970; Kupfermann et al., 1970; McKernan and Shinnick-Gallagher, 1997; Abraham et al., 2002; Whitlock et al., 2006). Not surprisingly, certain types of long-lasting synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), are believed to underlie some forms of learning and memory in the mammalian brain (Bliss and Lomo, 1973; Dudek and Bear, 1992; Martin et al., 2000; Abraham et al., 2002; Whitlock et al., 2006).

Cyclic AMP/PKA signaling has been shown to be pivotal for specific types of long-term synaptic plasticity and for long-term memory (Fig. 1), as demonstrated in the landmark studies of learning and memory in Aplysia and Drosophila (reviewed by Burrell and Sahley, 2001). In particular, electrophysiological and behavioral studies of the marine snail, Aplysia californica, have revealed a requirement for cAMP/PKA signaling in the establishment of short- and long-lasting forms of synaptic plasticity, learning, and memory (Kandel, 2001). These studies demonstrated an important role for PKA in mediating short-term synaptic facilitation (by reversible phosphorylation of ion channels), and long-term facilitation and long-term memory for behavioral sensitization (by modulation of gene expression and protein synthesis) (Kandel, 2001). Studies in Drosophila have also been instrumental in defining the role of PKA in learning and memory (reviewed by McGuire et al., 2005;Davis, 1996). The learning mutant, dunce, was the first learning mutant isolated in Drosophila, and dunce encodes a cAMP phosphodiesterase. Similarly, mutations in adenylyl cyclase (rutabaga) and mutations in PKA itself impair learning and memory in Drosophila. Overall, these landmark experiments have laid much of the conceptual foundations for subsequent research on the roles of PKA in learning and memory in the mammalian brain. In this article, the roles of PKA in hippocampus-dependent memory are reviewed. We focus only on the mammalian hippocampus, because of its pivotal roles in the consolidation of spatial and non-spatial long-term memories. We discuss studies that have shown a requirement for PKA signaling in the hippocampus. We then consider some of the downstream targets of PKA, emphasizing studies that have identified requirements for PKA-mediated phosphorylation and signaling in hippocampal LTP, a form of synaptic plasticity that has been linked to memory formation (Abel et al., 1997; Gruart et al., 2006; Whitlock et al., 2006).

Section snippets

cAMP-dependent protein kinase (PKA)

The mammalian PKA family consists of four regulatory (R) subunits (RIα, RIβ, RIIα, RIIβ) and three catalytic (C) subunits (Cα, Cβ, Cγ). Each subunit is encoded by a unique gene (McKnight et al., 1988; Doskeland et al., 1993) and they are all expressed in the mammalian brain (Cadd and McKnight, 1989). Two major isozymes of PKA, termed type I (with RIα and RIβ dimers) and type II (with RIIα and RIIβ dimers), have been characterized and were initially identified based on their patterns of

Properties of memory

Learning, the change in behavior as a result of experience, and memory, the retention of changes in behavior that result from learning, have been of great interest to neurobiologists. The psychological study of memory began over 100 years ago with the experiments of Herman Ebbinghaus; since then, researchers have sought to define the principles underlying memory storage. This work has defined three major properties of memory storage (Milner et al., 1998). First, the study of patients like H. M.

The role of the cAMP/PKA system in spatial memory

In rodents, the quintessential hippocampus-dependent behavioral task is spatial learning and memory in the hidden platform version of the Morris water maze. In this task, animals learn to use the distal cues located in the room to find the location of a submerged platform during repeated trials. Performance is measured by an increase in latency to find the platform during training trials and memory is tested in a probe (or transfer) test in which the platform is removed from the pool and

The role of the cAMP/PKA system in contextual conditioning

Experiments with spatial memory clearly establish the role of the cAMP/PKA pathway in hippocampus-dependent memory. However, because of the repeated training trials necessary for spatial learning, these tasks do not allow researchers to precisely define the role of this signaling pathway in short- and long-term memory. Since 1890, when William James made the distinction between short-term and long-term memory (James, 1890), researchers have sought to determine the relationship between these

The cAMP/PKA pathway as a target of cognition-enhancing drugs

Our discussion has focused on the impact of impairments in cAMP/PKA signaling, but researchers have also investigated the behavioral effects of increased activity in the cAMP/PKA pathway. Pharmacological experiments have revealed a time window of 3–6 h after training when treatment with drugs that directly or indirectly activate PKA can enhance memory storage (Bernabeu et al., 1997). Blockade of the degradation of cAMP by treatment with inhibitors of phosphodiesterases such as the PDE4

Synaptic tagging

Neurons typically receive inputs from thousands of synaptic contacts. However, L-LTP is input-specific (Andersen et al., 1977; Nguyen et al., 1994). To preserve the input specificity of L-LTP, a mechanism to mark, or “tag”, active synapses has been proposed to allow newly synthesized gene products to be captured and utilized at appropriately activated synapses (Sossin, 1996; Frey and Morris, 1997; Schuman, 1997). Frey and Morris (1997) first provided evidence for the synaptic tag theory in the

Downstream substrates for PKA in synaptic plasticity and memory storage

The cAMP/PKA signaling cascade has garnered much attention because of its critical requirement for both long-term memory and for specific forms of long-term synaptic plasticity that are believed to underlie memory storage. The precise molecular mechanisms underlying these processes have not been fully elucidated, but many proteins that are important mediators of synaptic plasticity are regulated by cAMP/PKA signaling (Fig. 1; reviewed by Nguyen and Woo, 2003). Here, we discuss several key

The role of PKA in shaping the essence of memory

Our review has highlighted multiple roles for PKA in hippocampal memory. However, much remains unexplored. For example, what are the specific roles of PKA in the distinct phases of memory processing? These phases include acquisition, consolidation, reconsolidation, and retrieval of memories, and their mechanistic definitions are essential goals that must be achieved before researchers can fully grasp the essence of memory in the mammalian brain. Reversible pharmacological inactivation of

Acknowledgments

Our research was supported by the Canadian Institutes of Health Research (PVN), the Alberta Heritage Foundation for Medical Research (PVN), the National Institutes of Health (TA), and the Human Frontiers Science Program (TA). PVN thanks the University of Pennsylvania Provost's Distinguished International Scholars Program for supporting a sabbatical visit during which this article was written. We thank Ted Huang (University of Pennsylvania) for his help with constructing the figure. We thank S.

References (170)

  • G. Buzsáki et al.

    Hippocampal network patterns of activity in the mouse

    Neuroscience

    (2003)
  • G. Cadd et al.

    Distinct patterns of cAMP-dependent protein kinase gene expression in mouse brain

    Neuron

    (1989)
  • P. Chavis et al.

    Visualization of cyclic AMP-regulated presynaptic activity at cerebellar granule cells

    Neuron

    (1998)
  • R.L. Clem et al.

    Pathway-specific trafficking of native AMPARs by in vivo experience

    Neuron

    (2006)
  • S.O. Doskeland et al.

    The genetic subtypes of cAMP-dependent protein kinase — functionally different or redundant?

    Biochim. Biophys. Acta

    (1993)
  • C.S. Gibbs et al.

    Systematic mutational analysis of cAMP-dependent protein kinase identifies unregulated catalytic subunits and defines regions important for the recognition of the regulatory subunit

    J. Biol. Chem.

    (1992)
  • M.G. Gold et al.

    Molecular basis of AKAP specificity for PKA regulatory subunits

    Mol. Cell.

    (2006)
  • G.A. Gonzalez et al.

    Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133

    Cell

    (1989)
  • P. Greengard et al.

    Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade

    Neuron

    (1999)
  • F. Helmchen et al.

    A miniature head-mounted two-photon microscope. high-resolution brain imaging in freely moving animals

    Neuron

    (2001)
  • H.C. Hemmings et al.

    DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated neuronal phosphoprotein. II. Comparison of the kinetics of phosphorylation of DARPP-32 and phosphatase inhibitor 1

    J. Biol. Chem.

    (1984)
  • D.G. Howe et al.

    Molecular and behavioral effects of a null mutation in all PKA C beta isoforms

    Mol. Cell Neurosci.

    (2002)
  • Y.Y. Huang et al.

    Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala

    Neuron

    (1998)
  • K. Kameyama et al.

    Involvement of a postsynaptic PKA substrate in expression of homosynaptic LTD

    Neuron

    (1998)
  • E. Korzus et al.

    CBP histone acetyltransferase activity is a critical component of memory consolidation

    Neuron

    (2004)
  • H. Lee et al.

    NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus

    Neuron

    (1998)
  • G. Lonart et al.

    Phosphorylation of RIM1alpha by PKA triggers presynaptic long-term potentiation at cerebellar parallel fiber synapses

    Cell

    (2003)
  • B.E. Lonze et al.

    Function and regulation of CREB family transcription factors in the nervous system

    Neuron

    (2002)
  • W. Lu et al.

    Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons

    Neuron

    (2001)
  • G. Malleret et al.

    Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin

    Cell

    (2001)
  • A.L. Mammen et al.

    Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II

    J. Biol. Chem.

    (1997)
  • H.Y. Man et al.

    Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization

    Neuron

    (2000)
  • K.C. Martin et al.

    Synapse-specific long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage

    Cell

    (1997)
  • W.C. Abraham et al.

    Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus

    J. Neurosci.

    (2002)
  • P.B. Allen et al.

    Protein phosphatase-1 regulation in the induction of LTP: heterogeneous molecular mechanisms

    J. Neurosci.

    (2000)
  • P. Andersen et al.

    Specific long-lasting potentiation of synaptic transmission in hippocampal slices

    Nature

    (1977)
  • J. Athos et al.

    Hippocampal CRE-mediated gene expression is required for contextual memory formation

    Nat. Neurosci.

    (2002)
  • M.E. Bach et al.

    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)
  • B.J. Bacskai et al.

    Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons

    Science

    (1993)
  • D. Balschun et al.

    Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory?

    J. Neurosci.

    (2003)
  • M. Barad et al.

    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)
  • J.A. Beavo et al.

    Activation of protein kinase by physiological concentrations of cyclic AMP

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

    (1974)
  • S.J. Beebe

    The cAMP-dependent protein kinases and cAMP signal transduction

    Semin. Cancer Biol.

    (1994)
  • R. Bernabeu et al.

    Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats

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

    (1997)
  • T.V. Bliss et al.

    A synaptic model of memory: long-term potentiation in the hippocampus

    Nature

    (1993)
  • T.V. Bliss et al.

    Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

    J. Physiol.

    (1973)
  • R.D. Blitzer et al.

    Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP

    Science

    (1998)
  • R. Bourtchouladze et al.

    Different training procedures for contextual memory in mice can recruit either one or two critical periods for memory consolidation that require protein synthesis and PKA

    Learn. Mem.

    (1998)
  • R. Bourtchouladze et al.

    Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein

    Cell

    (1994)
  • R. Bourtchouladze et al.

    A mouse model of Rubinstein–Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4

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

    (2003)
  • Cited by (157)

    • Many faces and functions of GSKIP: a temporospatial regulation view

      2022, Cellular Signalling
      Citation Excerpt :

      PKA causes Ser-9 phosphorylation and thus by PKA blocks its pathogenic effect in AD. Additionally, the PKA signaling pathway promotes neuron growth and long-term memory formation [79–81]. However, an increase in the crosslinking between PKA pathway and GSK3β pathways in evolution has been noted.

    View all citing articles on Scopus
    View full text