The Mechanism And Function Of Cyclindependent Kinase 7 In Learning And Memory

In the brain,de novo gene expression driven by learning-associated neuronal activities is critical for the formation of long-term memories.Transcription of immediate-early genes(IEGs)in neurons is known to be highly sensitive to neuronal activity and is critical for learning and memory.However,the signaling machinery mediating neuronal activity-induced gene expression,especially the rapid transcription of IEGs remains unclear.Cyclin-dependent kinases(Cdks)are a family of serine/threonine kinases that have been firmly established as key regulators of transcription processes underling coordinated cell cycle entry and sequential progression in nearly all types of proliferative cells.Cdk7 is a subunit of transcriptional initiation factorII-H(TFIIH)and the only known Cdk-activating kinase(CAK)in metazoans.Recent studies using a novel Cdk7 specific covalent inhibitor,THZ1,revealed important roles of Cdk7 in transcription regulation in cancer cells.However,whether Cdk7 plays a role in the regulation of transcription in neurons remains unknown,and whether Cdk7 participates in learning and memory is still unclear.In this study,we present evidence demonstrating that,in post-mitotic neurons,Cdk7 activity is positively correlated with neuronal activities in cultured primary neurons,acute hippocampal slices and in the brain.Cdk7 inhibition by THZ1 significantly suppressed mRNA levels of IEGs,selectively impaired long-lasting synaptic plasticity induced by 4 trains of high frequency stimulation(HFS)and prevented the formation of long-term memories.