CREB, Synapses and Memory Disorders: Past Progress and Future Challenges

Abstract

In neurons, appropriate long-term adaptive responses to changes in the environment require the conversion of extracellular stimuli into discrete intracellular signals. Many of these signals involve the regulation of gene expression. The cAMP responsive element binding protein (CREB) is a nuclear transcription factor that modulates transcription of genes containing cAMP responsive elements (CRE sites) in their promoters. CREB is a key part of many intracellular signaling events that critically regulate many neural functions. Numerous studies on invertebrates and vertebrates demonstrate that CREB is critical for long-term memory. Here, we review the key features of CREB-dependent transcription and critically evaluate the data examining the roles of CREB in different forms of plasticity, including long-term memory in mammals. Because learning and memory have been linked to specific types of synaptic plasticity in several species, we also review studies on the role of CREB in long-term facilitation in Aplysia and in hippocampal long-term potentiation (LTP). Several human cognitive disorders have been linked to alterations of CREB-regulated gene expression. Therefore, we explore the possibility of targeting CREB function in developing novel treatment strategies. Finally, we highlight areas of research on CREB that are ripe for further advancement.

Synaptic plasticity in early aging

“…The factor plays an essential role in Aplysia long-term facilitation (Dash et al, 1990) and is reported to be important for the maintenance of LTP (Barco et al, 2002). As expected from these physiological results, several studies have documented a role for CREB in long-term memory in Drosophila and mice (Josselyn and Nguyen, 2005). These results suggest that increasing CREB activity would both facilitate LTP and the memory arising from it.…”

“…Efforts to promote consolidation have largely dealt with the late, protein synthesisdependent period (rather than the cytoskeletal assembly phase) and, in particular, on the cAMP responsive element binding protein (CREB) family of transcription factors (Lynch, 2002;Josselyn and Nguyen, 2005). CREB, after having been phosphorylated (and activated) binds to the cyclic AMP response element of target genes.…”

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

“…It is unknown if the increase in p38 MAPK observed in our studies played a role in the CCL2-induced increase in synaptic network activity. Both p38 MAPK and CREB have been shown to play a key regulatory role in synaptic transmission, synaptic plasticity and memory mechanisms (Alonso et al, 2003;Brust et al, 2006;Butler et al, 2004;Josselyn and Nguyen, 2005;Rossato et al, 2006;Wang et al, 2007). Thus, these hippocampal synaptic functions may be an important target of CCL2 in the normal brain or during conditions associated with neuroinflammation and p38 MAPK may play a central role in the effects of CCL2 on these functions.…”

“…CCL2 and its primary receptor CCR2 are also widely expressed within the central nervous system (CNS), implicating roles for CCL2 in the CNS as well as in the immune system (Ambrosini and Aloisi, 2004;Bajetto et al, 2002). Sources of CCL2 within the CNS include microglia and astrocytes, although some neurons can also produce CCL2 (Babcock et al, 2003;Banisadr et al, 2005a;Farina et al, 2007;Josselyn and Nguyen, 2005;Kielian et al., 2002;Weiss and Berman, 1998) Emerging evidence supports both physiological and pathological roles for CCL2 in the CNS. CCL2 expression in the normal CNS starts at an early stage of development, suggesting a physiological role for CCL2 in CNS development (Geppert, 2003;Meng et al, 1999).…”

Stressor-Specific Regulation of Distinct Brain-Derived Neurotrophic Factor Transcripts and Cyclic AMP Response Element-Binding Protein Expression in the Postnatal and Adult Rat Hippocampus

“…In addition, specific stressors in adult life have been reported to regulate hippocampal CREB expression (Alfonso et al, 2006;Song et al, 2006) and a decline in CREB expression has been observed in depressed patients (Blendy, 2006;Lai et al, 2003;Yamada et al, 2003). Besides its role in the regulation of BDNF, CREB has been shown to influence both structural and synaptic plasticity in the hippocampus (Josselyn and Nguyen, 2005;Nakagawa et al, 2002). Given the crucial role that BDNF and its upstream transcriptional activator CREB have been suggested to play in stress-related hippocampal damage (Blendy, 2006;Duman, 2004), understanding their regulation by distinct stressors in postnatal and adult life is critical.…”