to the cell nucleus, where it activates a CREB protein. The activated CREB protein then binds to a CRE region, and is then bound to by CBP (CREB-binding protein), which coactivates it, allowing it to switch certain genes on or off. The DNA binding of CREB is mediated via its basic leucine zipper domain (bZIP domain) as depicted in the image. Evidence suggests the β-adrenoceptor (a G-protein coupled receptor) stimulates CREB signalling. Function in the brain CREB has many functions in many different organs, and some of its functions have been studied in relation to the brain. CREB proteins in neurons are thought to be involved in the formation of long-term memories; this has been shown in the marine snail Aplysia, the fruit fly Drosophila melanogaster, in rats and in mice (see CREB in Molecular and Cellular Cognition). CREB is necessary for the late stage of long-term potentiation. CREB also has an important role in the development of drug addiction and even more so in psychological dependence. There are activator and repressor forms of CREB. Flies genetically engineered to overexpress the inactive form of CREB lose their ability to retain long-term memory. CREB is also important for the survival of neurons, as shown in genetically engineered mice, where CREB and CREM were deleted in the brain. If CREB is lost in the whole developing mouse embryo, the mice die immediately after birth, again highlighting the critical role of CREB in promoting neuronal survival. Disease linkage Disturbance of CREB function in the brain can contribute to the development and progression of Huntington's disease. Abnormalities of a protein that interacts with the KID domain of CREB, the CREB-binding protein, (CBP) is associated with Rubinstein-Taybi syndrome. There is some evidence to suggest that the under-functioning of CREB is associated with major depressive disorder. Depressed rats with an overexpression of CREB in the dentate gyrus behaved similarly to rats treated with antidepressants. From post-mortem examinations it has also been shown that the cortices of patients with untreated major depressive disorder contain reduced concentrations of CREB compared to both healthy controls and patients treated with antidepressants. The function of CREB can be modulated via a signalling pathway resulting from the binding of serotonin and noradrenaline to post-synaptic G-protein coupled receptors. Dysfunction of these neurotransmitters is also implicated in major depressive disorder. CREB is also thought to be involved in the growth of some types of