Epigenetic programming is subserved by the overall process of gene expression. Synaptic stimulation triggers signaling cascades that feed back to RNA polymerase activity and its ability to increase or decrease the generation of mRNA transcripts of specific genes. Thus in response to experience-induced activation of neural circuitry, profiles of gene expression are altered. Cognition involves synaptic activity-dependent initiation of transcription of immediate early genes (IEGs) that direct de novo
protein synthesis that is essential for long-term memory formation. Transcription factors are key to this aspect of cognition (Alberini, 2009
). The cAMP response element binding protein, CREB, is the prototypical example of these regulatory transcription factors (RTFs). CREB is activated when synaptic activity induces its phosphorylation at Ser133 by protein kinases such as cAMP-activated PKA or Ca2+
-actviated members of the CaM kinase family. CREB then regulates the rate by which target genes are transcribed. Among these target genes, there are other transcription factors such as CCAAT enhancer binding proteins (C/EBPs) that amplify the gene cascade. Phosphorylation of Ser133 promotes the binding of CREB to a CREB-binding protein (CBP) allowing CREB to interact with the RNA polymerase II complex to initiate, or not initiate, gene transcription. Phospho-CREB serves as one well recognized marker of neuronal gene cascade activation. AP1 is another transcriptional factor composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families that regulate gene expression. AP1-like factors respond to a variety of stimuli and neuronal signaling pathways that invoke MAP kinase cascades. Hormones, growth factors, cytokines, and stress regulate CREB, C/EBP and AP1 activities, providing an example of how external factors affect cognitive mechanisms. NFκB is another transcriptional factor activated in response to neuronal activity that affects the expression of synaptic proteins such as CaMKII (Alberini, 2009
As prototypical mechanisms, these pathways provide insight into this targetable aspect of cognition. However, the number of genes containing these sequences may be in the thousands. Furthermore CREB activation has been reported for many forms of physiological and environmental stimuli and many pathways feed into its activation or inactivation. Thus it will be important to delineate presently unknown transcriptional regulation pathways in order to better understand which mechanisms present the most drugable targets for therapeutic development.
Once activity-dependent gene expression has been initiated, a plethora of immediate early (IEG) and target gene transcripts are generated and translated to proteins. The de novo
synthesized proteins encoded by IEGs frequently have short half-lives and mediate synaptic remodeling by controlling a variety of processes. Some factors feed back to mediate further gene expression. An example is Zif 268 (or Early Growth Response Protein 1, Egr1), which marks neuronal activation and contributes to learning and plasticity. The invocation of transient Zif 268 expression in response to synaptic activity is dependent upon activation of the NMDA class of excitatory ionotropic glutamate receptors (see below). ARC (activity-regulated cytoskeleton-associated protein) represents another important IEG, which appears to play a number of roles in synaptic remodeling and is required for memory consolidation (Miyashita et al., 2008
). Other IEGs and target genes affect structural components of synapses and cytoskeletal dynamics, protein trafficking, protein degradation, protein phosphorylation/dephosphorylation, and mRNA stability. The list of important IEGs continues to grow. One previously uncharacterized regulated transcript that appears to mediate cognition and shows promise as a target for memory enhancement is insulin-like growth factor II (IGFII) (C. Alberini et al, 2010, manuscript in preparation).