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Targeting the CREB pathway for memory enhancers

Key Points

  • Memory enhancers are drugs that can improve memory formation in clinical patients suffering memory loss due to age, injury, heredity or disease.

  • CREB is a transcription factor that is activated by neuronal activity. CREB isoforms function either as activators of gene expression or as repressors of the activators.

  • CREB is a key regulator of an increasingly complex biochemical pathway that produces changes in the strength and structure of synaptic connections between neurons of a defined brain circuit. These cellular changes are likely to underlie the formation of long-term memory.

  • Neurogenetic experiments in fruit flies and in rats have shown that overexpression of CREB activator enhances long-term memory formation by reducing the usual requirements for repetition and rest during training.

  • On the basis of these observations, a high-throughput screen was designed and executed in human neuroblastoma cells to search for drugs that modulate CREB-dependent gene expression.

  • One class of drug was inhibitors of phosphodiesterase 4 (PDE4), which were shown to enhance memory in mammals.

  • Methods and pitfalls to develop PDE4 for clinical study are outlined.

  • Potential clinical applications for CREB-based memory enhancers are discussed.

Abstract

Today, the clinical notion of 'memory disorder' is largely synonymous with 'Alzheimer's disease.' Only 50% of all dementias are of the Alzheimer's type though, and dementias represent only the more severe of all learning/memory disorders that derive from heredity, disease, injury or age. Perhaps as many as 30 million Americans suffer some type of clinically recognized memory disorder. To date, therapeutic drugs of only one class have been approved for the treatment of Alzheimer's disease. Fortunately, basic research during the past 25 years has begun to define a 'chemistry of brain plasticity,' which is suggesting new gene targets for the discovery of memory enhancers.

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Figure 1: Memory phases.
Figure 2: Neurobiology of memory.
Figure 3: The 'CREB signature' of memory enhancement.
Figure 4: Heritable forms of mental retardation with molecular lesions in the biochemistry of brain plasticity.

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Acknowledgements

We thank Josh Dubnau and Holly Cline for helpful comments and discussion.

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Correspondence to Tim Tully.

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DATABASES

Online Mendelian Inheritance in Man

Angelman syndrome

Coffin–Lowry syndrome

Down's syndrome

fragile-X mental retardation-1

myotonic dystrophy

neurofibromatosis-1

Rubinstein–Taybi syndrome

FURTHER INFORMATION

Scientific Learning Corp

Institute for the Study of Aging

Official site of the Human Genome Project

Glossary

NEUROHUMORAL SIGNALLING

A type of slow-acting chemical communication in the nervous system, which contrasts with the fast-acting communication of neurotransmitters. Neurohumoral signalling often occurs between the central nervous system and peripheral tissues and can influence motivational and emotional states.

CHOLINERGIC

Pertaining to acetylcholine neurotransmission.

CHOLINESTERASE

An enzyme that metabolizes the neurotransmitter acetylcholine. Cholinesterase inhibitors lead to increased levels of acetylcholine in the brain.

PAVLOVIAN CONDITIONING

A well-defined experimental paradigm to study simple associations between two stimuli. Such 'associative learning' is thought to be an elemental building block of more complex, experience-dependent behaviours.

GLUTAMATERGIC

Pertaining to glutamate neurotransmission.

SYNAPTIC PLASTICITY

A cellular process that results in lasting changes in the efficacy of neurotransmission. These changes are likely to be both functional (for example, changes in neurotransmitters, receptors, ion channels, signalling molecules and so on) and structural (for example, changes in the size and number of synaptic connections).

FORSKOLIN

A small-molecule agonist of adenylyl cyclase which binds to the active site of the enzyme and which stimulates the synthesis of the signalling molecule cAMP.

ADENYLYL CYCLASE

(AC). An enzyme that synthesizes cAMP from ATP and is involved in intracellular signalling, usually after neurotransmitter activation.

PHOSPHODIESTERASE

(PDE). An enzyme that hydrolyzes cAMP into AMP.

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Tully, T., Bourtchouladze, R., Scott, R. et al. Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2, 267–277 (2003). https://doi.org/10.1038/nrd1061

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