TY - JOUR
T1 - CREB serine 133 is necessary for spatial cognitive flexibility and long-term potentiation
AU - Morè, Lorenzo
AU - Privitera, Lucia
AU - Perrett, Philippa
AU - Cooper, Daniel D.
AU - Bonnello, Manuel Van Gijsel
AU - Arthur, J. Simon C.
AU - Frenguelli, Bruno G.
N1 - Funding Information:
BBSRC (BB/L00139X/1 to BGF, and Doctoral Support BB/M01116X/1 to DDC. and PP), WPH Charitable Trust, the Sylvia Waddilove Foundation and the School of Life Sciences pump-priming fund for financial support.
Copyright Information:
© 2022 The Authors. Published by Elsevier Ltd.
PY - 2022/11/15
Y1 - 2022/11/15
N2 - 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. A more elegant recent approach targeting S133 in the endogenous CREB gene has yielded a mouse with constitutive replacement of this residue with alanine (S133A), but has generated results (no behavioural phenotype and no effect on gene transcription) at odds with contemporary views as to the role of CREB S133, and which may reflect compensatory changes associated with the constitutive mutation. To avoid this potential complication, we generated a post-natal and forebrain-specific CREB S133A mutant in which the expression of the mutation was under the control of CaMKIIα promoter. Using male and female mice we show that CREB S133 is necessary for spatial cognitive flexibility, the regulation of basal synaptic transmission, and for the expression of long-term potentiation (LTP) in hippocampal area CA1. These data point to the importance of CREB S133 in neuronal function, synaptic plasticity and cognition in the mammalian brain.
AB - 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. A more elegant recent approach targeting S133 in the endogenous CREB gene has yielded a mouse with constitutive replacement of this residue with alanine (S133A), but has generated results (no behavioural phenotype and no effect on gene transcription) at odds with contemporary views as to the role of CREB S133, and which may reflect compensatory changes associated with the constitutive mutation. To avoid this potential complication, we generated a post-natal and forebrain-specific CREB S133A mutant in which the expression of the mutation was under the control of CaMKIIα promoter. Using male and female mice we show that CREB S133 is necessary for spatial cognitive flexibility, the regulation of basal synaptic transmission, and for the expression of long-term potentiation (LTP) in hippocampal area CA1. These data point to the importance of CREB S133 in neuronal function, synaptic plasticity and cognition in the mammalian brain.
KW - CREB
KW - Cyclic AMP response element-binding protein
KW - LTP
KW - Learning and memory
KW - Plasticity
UR - http://www.scopus.com/inward/record.url?scp=85138113643&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2022.109237
DO - 10.1016/j.neuropharm.2022.109237
M3 - Article
C2 - 36049536
SN - 0028-3908
VL - 219
JO - Neuropharmacology
JF - Neuropharmacology
M1 - 109237
ER -