CREB serine 133 is necessary for spatial cognitive flexibility and long-term potentiation.

The transcription factor cAMP response element-binding protein (CREB) is widely regarded as orchestrating the genomic response that underpins a range of physiological functions in the central nervous system, including learning and memory. Of the means by which CREB can be regulated, emphasis has been placed on the phosphorylation of a key serine residue, S133, in the CREB protein, which is required for CREB-mediated transcriptional activation in response to a variety of activity-dependent stimuli. Understanding the role of CREB S133 has been complicated by molecular genetic techniques relying on over-expression of either dominant negative or activating transgenes that may distort the physiological role of endogenous CREB.