A type of protein that regulates the expression of genes and fulfils a key role in neuronal plasticity

In technical terms, which will be explained below, CREB, cAMP-response element-binding protein, is a protein that modulates the transcription of genes with cAMP-response elements in their promoters. CREB is one of the most commonly used acronyms in neurobiology these days, and also one of the few words in the jargon of molecular biology that even experimental psychologists and computational neuroscientists might have encountered. And if they didn't, they should. Because the more we advance our knowledge in molecular neurobiology, the more we realize that CREB plays a pivotal role in the response of neurons to external stimuli. CREB is a transcription factor. This means that it participates in the control of gene expression at the level of transcription, i.e. the production of RNA

complementary to a strand of DNA. Transcription factors bind to specific DNA elements in the promoter (the region that binds or facilitates the binding of RNA polymerase, which is the enzyme that synthesizes RNA), or in other regions that control transcription (e.g. enhancers; Lewin 1994). These elements, because they permit a gene to respond to regulatory factors, are called 'response elements'. Multiple families of response elements are known. Genes are controlled by the conjoint regulation of multiple response elements, belonging to the same or different families.

One type of response elements is the cAMP-response element (abbreviated CRE; Sassone-Corsi 1995). It mediates transcriptional regulation in response to altered levels of the "intracellular signal cAMP (cyclic adenosine monophosphate). CRE is found in the promoter region of many genes. A related element is the activating transcription factor element (ATF). Therefore the terms CRE/ATF, or CRE-like elements, are also in use. CREB binds to CRE, and is a member of the CREB/ATF family of transcription factors. Multiple genes encode these transcription factors, and alternative splicing yields an even larger number of factors.

All the members of the CREB/ATF family have in their carboxy terminus a conserved 'leucine zipper' dimerization domain (i.e. a stretch of amino acids with interspersed residues of the amino acid leucine, which interacts with a 'zipper' in another polypeptide to form a dimer), juxtaposed to a DNA-binding domain rich in basic amino acids (Brindle and Montminy 1992; Sassone-Corsi 1995). Different CREB/ATF transcription factors are able to heterodimerize with each other in certain combinations. Proteins that bind to CRE act as both activators and repressors. For example, CREB, CREMt (CRE-modulator, alternatively spliced variant t), and ATF1 are transcriptional activator, whereas CREB-2 and CREMa antagonize cAMP-induced transcription. Unless otherwise specified, the common usage of the term CREB in memory literature refers to the activator form.

At this point molecular biologists may already feel that they have taken enough revenge on psychologists in the contest for the most graceless terminology. Yet what should interest us is not the competition between scientific "cultures, but rather the relevance of all this to learning and memory. There are many members in the CREB/ATF family; unless otherwise indicated, we will limit ourselves here to the discussion of CREB only. CREB is present in cells under nonstimulated conditions, mostly in a nonactivated form (some other members of the CREB/ATF family are expressed only in response to a stimulus, see "immediate early genes). Appropriate extracellular stimuli activate CREB by phosphorylating it. CREB can be phosphorylated on multiple sites by multiple "protein kinases. Phosphorylation on residue Serine-133 is critical for activation, and is mediated via an increase in the level of intracel-lular cAMP and activation of cAMP-dependent protein kinase (PKA; Brindle and Montminy 1992; Sassone-Corsi 1995), or via an increase in intracellular "calcium and activation of calcium/calmodulin-activated protein kinase (Sheng et al. 1991; Bito et al. 1996; Deisseroth et al. 1998).1 The phosphorylation and dephosphorylation of CREB by different intracellular signalling pathways provides a mechanism for signal convergence and "coincidence detection (e.g. Perkinton et al. 1999). Phosphorylated CREB binds to the CREB-binding protein, recruits other components of the transcription machinery on the promoter, and initiates transcription, e.g. of other transcription factors (Figure 22).

It is this initiation of transcription in response to cAMP that has placed CREB in the spotlight of memory research (Silva et al. 1998). In recent years, multiple lines of evidence have shown that: (a) the cAMP cascade is stimulated in learning (e.g. "Aplysia, "Drosophila), and (b) "protein synthesis and modulation of gene expression are required for "consolidation. CREB links these two lines of evidence. The first to implicate CREB in neuronal "plasticity were Dash et al. (1990), in Aplysia neurons. Subsequent studies in a variety of species have indicated that the involvement of CREB, and CRE-regulated gene expression in general, in neuronal plasticity and memory formation, is possibly universal, and that CREB activation is correlated with, and necessary for, the formation of "long-term memory (e.g. Bourtchuladze et al. 1994; Bartch et al. 1995; Yin et al. 1995; Bito et al. 1996; Impey et al. 1996,1998; Guszowski and McGaugh 1997; Lamprecht et al. 1997).2 The experience-dependent balance between the activator and repressor isoforms of CREB may be critical in determining the fate of a memory. On the one hand, it could switch on very fast acquisition and consolidation of robust long-term memory (Yin et al. 1995; "flashbulb memory). On the other, it could culminate in the suppression of memory storage (Bartsch et al. 1995;Abel and Kandel 1998).

The CREB story leads us to the interface of "developmental and behavioural plasticity. It is now well established that CRE-regulated gene expression plays a key part in developing tissues (e.g. Davis et al. 1996; Liu and Graybiel 1996; Pham et al. 1999). The resemblance of CREB-related mechanisms in developmental and adult plasticity is so striking, that it was used as an argument in favour of the conceptual "paradigm of long-term-memory = /(growth) (Martin and Kandel 1996; "zeitgeist). But at the same time, these shared mechanisms imply that we are looking at a very basic "level of cellular response, which is not unique to learning and memory. CREB is probably essential in retaining cellular "homeostasis and in the protective response to stressful stimuli. It is clearly important in promoting the survival of many types of cells, not only neurons (Finkbeiner 2000; Walton and Dragunow 2000). The question thus remains what is the relevance of CREB to memory: Is the role permissive, supportive, or causal (see "criterion)? CREB could actually fulfil any of these roles, depending on the physiological and molecular "context. Understanding the functional implications of the fine tuning of the CREB machinery, might also cast light on pathological conditions in which neuronal homeostasis and plasticity malfunction. Such conditions could contribute to neurodegenerative disease ("dementia). Future drugs that target CREB might hence find multiple uses, including neuroprotection, the

CREB-1 activated

CREB-1 repressed





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Kinase or phosphatase?

CAAT Late effectors

Creb Early Response Late Response



Fig. 22 A highly simplified scheme of the proposed mechanism by which CREB regulates modulation of gene expression and the subsequent growth processes that accompany long-term use-dependent neuronal *plasticity. The box represents a pre*synaptic terminal; the postsynaptic membrane is across the synaptic cleft at the bottom. CAAT, or 'CAAT box', a conserved nucleotide sequence located upstream of the start point of a gene transcription unit, recognized by a variety of transcription factors; CBP, CREB-binding protein; C/EBP, CAAT/enhancer binding protein; CRE, cAMP response element; CREB-1, CREB-2, activator and repressor isoforms of CREB, respectively. CREB-2 is here depicted as a direct repressor of CREB-1, for simplicity; PKA, *protein kinase A, the cAMP-dependent protein kinase; RNApol, RNA polymerase, an enzyme that synthesizes RNA from a DNA template; TATA, or 'TATA Box', a conserved nucleotide sequence that may be involved in positioning RNApol for correct initiation; TFIIb, TFIId, general transcription factors. According to this scheme, the balance between the activator and repressor isoforms of CREB, which is regulated by a variety of intracellular signal transduction cascades (of which only the one involving cAMP is partially depicted in the scheme), determines whether remodelling of the synapse will indeed take place. Hence, certain combinations of inputs could lead to long-term change, whereas others may not, or could even abort memory at its outset. This property may pave the way to novel specific memory-blocking drugs, which target CREB and might be used, for example, in treating some types of trauma (e.g. *fear conditioning). (Adapted from Carew 1996.)

blocking of undesired memories (*lotus), or the enhancement of desired ones (*nootropics).

Selected associations: Consolidation, Immediate early genes, Protein synthesis, Reduction, Spaced training

'CREB should therefore better be termed 'cAMP/calcium response element-binding protein'.

2For a dissident claim that the role of CREB in neuronal plasticity is, however, dispensable, see Frey et al. (2000).

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