Molecular and cytobiological study on regulation of synapse

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The elucidation of molecular mechanisms of learning and memory is one of the most important and attractive projects in the field of neuroscience in the 21st century. High frequency stimulation of Schaffer collateral/commissural pathway in the slices of the hippocampus can cause long-lasting potentiation of synaptic transmission efficacy in the pyramidal cells of the CA1 area. This effect is called long-term potentiation (LTP), which is a possible model for a molecular mechanism for learning and memory.The present study elucidated the following findings. 1) LTP induction was associated with a significant decrease in protein phosphatase (PP) 2A activity. 2) A 55-kDa protein was phosphorylated during LTP induction. 3) Analysis with the specific antibody to the regulatory subunits of PP2A demonstrated that the 55-kDa protein is the B'α regulatory subunit of PP2A.4) CaM kinase IV and mitogen-activated protein kinase (MAPK) were transiently activated during LTP induction and returned to the original level within 30 min. Especially CaM kinase IV was activated in neuronal nuclei. 5) Activation of both kinases was associated with cyclic AMP-responsive elementbinding protein (CREB) phosphorylation. The use of inhibitors for CaM kinases and MAPK such as KN93 and U0126, respectively, indicated that CaM kinase IV and MAPK are each involved in CREB phosphorylation. Furthermore, c-Fos expression was stimulated 60 min after high frequency-stimulated LTP.The increase in c-Fos expression was inhibited by addition of calmidazolium and U0126.These results suggest that LTP induction is primarily performed by activation of CaM kinase II and its related reactions through Ca^<2+> influx into postsynaptic neurons by activation of NMDA glutamate receptors. Furthermore, LTP maintenance is associated with stimulation of gene expression and protein synthesis which may be necessary for synthesis of synaptic components and formation of new circuits.