Transcription factors in long-term memory and synaptic plasticity

Abstract

Transcription is a molecular requisite for long-term synaptic plasticity and long-term memory formation. Thus, in the last several years, one main interest of molecular neuroscience has been the identification of families of transcription factors that are involved in both of these processes. Transcription is a highly regulated process that involves the combined interaction and function of chromatin and many other proteins, some of which are essential for the basal process of transcription, while others control the selective activation or repression of specific genes. These regulated interactions ultimately allow a sophisticated response to multiple environmental conditions, as well as control of spatial and temporal differences in gene expression. Evidence based on correlative changes in expression, genetic mutations, and targeted molecular inhibition of gene expression have shed light on the function of transcription in both synaptic plasticity and memory formation. This review provides a brief overview of experimental work showing that several families of transcription factors, including CREB, C/EBP, Egr, AP-1, and Rel, have essential functions in both processes. The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation.

Figure 1. Transcription

To begin transcription, eucaryotic RNA polymerase II requires the general transcription factors. These transcription factors are called TFIIA, TFIIB, and so on. (A) The promoter contains a DNA sequence called the TATA box, which is located 25 nucleotides away from the site where transcription is initiated. (B) The TATA box is recognized and bound by transcription factor TFIID, which then enables the adjacent binding of TFIIB. (C) For simplicity the DNA distortion produced by the binding of TFIID is not shown. (D) The rest of the general transcription factors, as well as the RNA polymerase itself, assemble at the promoter. (E) TFIIH uses ATP to pry apart the double helix at the transcription start point, allowing transcription to begin. TFIIH also phosphorylates RNA polymerase II, releasing it from the general factors so it can begin the elongation phase of transcription. As shown, the site of phosphorylation is a long polypeptide tail that extends from the polymerase molecule. The exact order in which the general transcription factors assemble on each promoter is not known with certainty. In some cases, most of the general factors are thought to first assemble with the polymerase independent of the DNA, with this whole assembly then binding to the DNA in a single step. The general transcription factors have been highly conserved in evolution; some of those from human cells can be replaced in biochemical experiments by the corresponding factors from simple yeasts. [From Alberts et al. (16].

Figure 2. Genomic organization of the mammalian CREB family

The consensus alignment of the genomic organization of human cyclic AMP response element (CRE)-binding protein (CREB), the cAMP response element modulator (CREM) and the activating transcription factor 1 (ATF1) was obtained by BLAST analysis of human GenBank sequences against the human genome and against each other. In cases for which human sequences were unavailable for published isoforms, the mouse or rat sequences were used. Homologous domains are in color (see key). In the CREB and CREM genes, several alternatively spliced exons exist, creating in-frame stop codons (TAA or TGA) leading to carboxy-terminally truncated proteins or giving rise to amino-terminally truncated proteins by using internal transcription-initiation sites downstream of the stop-introducing exon. A partial list of alternative splice products with divergent activating properties is shown. [From Mayr & Montminy (151)].

Figure 3. An overview of signaling pathways that converge on CREB

Excitatory neurotransmitters, ligands for GPCRs, neuronal growth factors, and stress inducers are among the stimuli that activate signaling pathways that converge upon CREB. Multiple stimulus-dependent protein kinases have been implicated as CREB kinases in neurons, and a high degree of crosstalk exists between these signaling pathways. Stimulus-dependent CREB kinases include PKA, CaMKIV, MAPKAP K2, and members of the pp90RSK (RSK) and MSK families of protein kinases. Protein phosphatase 1 (PP1) has been implicated as the predominant phospho-CREB phosphatase. [From Lonze and Ginty (143)].

Figure 4. Genomic organization of the mammalian C/EBP family members

The leucine zipper (ZIP) is shown in yellow, with black vertical lines indicating the leucine residues, and the basic region is colored red. The position of the activation domains (AD) and negative regulatory domains (RD) are shown in green and blue respectively. ? indicates that the N-terminus of C/EBPζ contains an activation domain, although its exact position remains to be determined. [From Ramji and Foka (201)].

Figure 5. Schematic representation of the CREB-C/EBP pathway activated during memory formation

Stress, neurotransmitter release, growth factors and membrane depolarization are among the stimuli that activate intracellular signal transduction pathways that can lead to the activation of the CREB-dependent cascade. An important step of this activation is the phosphorylation of CREB (pCREB), particularly in its Ser133 residue. The functional activation of CREB leads to the expression of target genes, among which there are immediate early genes (IEGs), such as the transcription factor C/EBP, which, in turn, presumably regulates the expression of late response genes [From Alberini et al. (13)].

Figure 6. Schematic representation of AP-1 activation pathways

A multitude of stimuli and environmental insults including cytokines, stress and growth factors can regulate a considerable number of intracellular processes that critically involve AP-1. The appropriate composition of subunits in the AP-1 dimer is determined by the nature of the extracellular stimulus and by the MAPK signaling pathway that is consequently activated [From Panomics © 2007 (189)].

Figure 7. Modular interactions between zinc fingers and DNA

a) The Zif268–DNA complex showing the three zinc fingers bound in the major groove of DNA. The DNA is blue and fingers 1, 2, and 3 are red, yellow, and violet respectively. Zinc ions are shown as grey spheres. (b) A diagram showing the sequence-specific protein–DNA interactions between Zif268 and its DNA-binding site. The recognition helices of the three fingers are represented in the centre of the panel and the bases on the two strands of the DNA site are shown on either side. The identity of key residues on the recognition helices (positions -1, 2, 3 and 6 with respect to the start of the helix) are also shown using the single-letter code. Contacts observed in the crystal structure are represented as dashed lines. The fingers and bases that they contact are color-coded using the same scheme as in (a). The fingers are spaced at three-base-pair intervals and tend to contact three adjacent bases on one strand of DNA and one base on the other strand. [From Jamieson et al. (103)].

Figure 8. Structure of the NFkB subunits

Domain motifs are indicated. Protein size is given on the right as amino acids. RHD: Rel homologous domain. NLS: nuclear localization signal; IPT: Ig-like, plexin, transcription factors; ANK: ankyrin repeats; DEATH: DEATH domain, found in proteins involved in cell death. [From Kaltschmidt et al. (113)]

Figure 9. Epigenetic marks on histone tails and DNA

A, left) View of the nucleosome down the DNA superhelix axis showing one half of the nucleosome structure. (Right) Schematic representation of the four-nucleosome core histones, H2A, H2B, H3 and H4. (B) Schematic representation of the N- and C-termini of the core histones and their residue-specific epigenetic modifications. (C) Crosstalk between epigenetic modifications on the H3 N-terminus tail. The relationship between the different residues is based on recent literature. C, C-terminus; N, N-terminus. [From Gräff and Mansuy (82)].

Figure 10. Differential states of chromatin

Chromatin can either be open (i.e. active, allowing gene expression) or condensed (i.e. inactive, repressing gene expression). This change in state is mediated by the modifications to core histone proteins. Histone acetylation (A) is associated with chromatin relaxation and the binding of transcription factors and co-activators, such as HATs (histone acetyl transferases) and SWI-SNF proteins that mediate the movement of nucleosomes along a strand of DNA. Histone methylation (M) results in condensed chromatin and transcriptional repression. [From McClung and Nestler (152)].