Role of hippocampal activity-induced transcription in memory consolidation

Abstract

Experience-dependent changes in the strength of connections between neurons in the hippocampus (HPC) are critical for normal learning and memory consolidation, and disruption of this process drives a variety of neurological and psychiatric diseases. Proper HPC function relies upon discrete changes in gene expression driven by transcription factors (TFs) induced by neuronal activity. Here, we describe the induction and function of many of the most well-studied HPC TFs, including cyclic-AMP response element binding protein, serum-response factor, AP-1, and others, and describe their role in the learning process. We also discuss the known target genes of many of these TFs and the purported mechanisms by which they regulate long-term changes in HPC synaptic strength. Moreover, we propose that future research in this field will depend upon unbiased identification of additional gene targets for these activity-dependent TFs and subsequent meta-analyses that identify common genes or pathways regulated by multiple TFs in the HPC during learning or disease.

Figure 1:. Hippocampal synaptic plasticity relies on activity-dependent transcription.

(A) Depiction of bilateral location of dorsal (dHPC) and ventral (vHPC) mouse HPC (top) and of a coronal slice of dHPC (bottom) showing the connections between the subregions and the general direction of glutamatergic projections (red arrows). (B) Graphical representation of LTP (left) and LTD (right) induced by HFS or LFS, respectively. Gray region indicates long-lasting change in synaptic strength requiring activity-dependent transcription. (C) Select molecular mechanisms of LTP and LTD at CA3–CA1 glutamatergic synapses involving products of genes regulated by activity-dependent TFs (see Table 1).

Figure 2:. Common signaling cascades leading to activity-dependent TF activation.

Extracellular signals and changes in membrane potential can lead to increases in second-messenger (cAMP and Ca²⁺) or ERK signaling that converge on kinase activity within the nucleus resulting in phosphorylation and activation of CREB and SRF complexes. These bind to specific elements in promoter regions to regulate transcription of a variety of genes, including IEGs that encode other activity-dependent TFs, like c-fos and FosB.

Figure 3:. Identifying novel genes and pathways regulated by activity-dependent HPC gene transcription.

(A) Hypothetical heat plots of RNAseq and proteomic experiments in which individual activity-dependent TFs are genetically or pharmacologically manipulated to reveal genes whose expression is directly or indirectly regulated by each TF. Comparing the unbiased output of such experiments will reveal common potential gene targets that may underlie learning or disease (orange boxes). (B) Similarly, ChIPseq experiments using antibodies against individual activity-dependent TFs to precipitate bound chromatin from HPC of mice undergoing learning or models of disease will reveal common gene targets for activity-dependent TF binding (orange box). Combining the data from such experiments will produce new molecular models of learning and disease.