ABSTRACT
The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, we examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent rtTA system to express a calcineurin inhibitor reversibly in the mouse brain, we find that the transient reduction of calcineurin activity facilitates LTP in vitro and in vivo. This facilitation is PKA dependent and persists over several days in vivo. It is accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements are reversed fully by suppression of transgene expression. These results demonstrate that endogenous calcineurin constrains LTP and memory.
Subject(s)
Calcineurin/genetics , Conditioning, Psychological/physiology , Long-Term Potentiation/physiology , Memory, Short-Term/physiology , Animals , Anti-Bacterial Agents/pharmacology , Calcineurin Inhibitors , Dentate Gyrus/physiology , Doxycycline/pharmacology , Electric Stimulation , Form Perception/physiology , Gene Expression Regulation/drug effects , In Vitro Techniques , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuronal Plasticity/physiology , Signal Transduction/physiology , Transgenes/physiologyABSTRACT
Basic leucine zipper (bZIP) transcription factors are dimers that recognize mainly palindromic DNA sites. It has been assumed that bZIP factors have to form a dimer in order to bind to their target DNA. We find that DNA binding of both monomeric and dimeric bZIP transcription factor GCN4 is diffusion-limited and that, therefore, the rate of dimerization of the bZIP domain does not affect the rate of DNA recognition and GCN4 need not dimerize in order to bind to its specific DNA site. The results have implications for the mechanism by which bZIP transcription factors find their target sites for transcriptional regulation.
