title: A PARP1-Erk2 synergism is required for stimulation-induced expression of immediate early genes.
abstract: A PARP1-Erk2 synergism was required to generate synaptic long-term potentiation in the CA3-CA1 hippocampal connections. This molecular mechanism was associated with the recently identified pivotal role of polyADP-ribosylation in learning. High frequency electrical stimulation of cortical and hippocampal neurons induced binding of phosphorylated Erk2 (transported into the nucleus) to the nuclear protein PARP1. PARP1-Erk2 binding induced PARP1 activation and polyADP-ribosylation of its prominent substrate, linker histone H1. A facilitated access of PARP1-bound phosphorylated Erk2 to its substrates, transcription factors Elk1 and CREB was attributed to the release of polyADP-ribosylated H1 from the DNA, causing local DNA relaxation. Erk-induced phosphorylation of transcription factors activating the HAT activity of CBP (CREB binding protein), recruited acetylated histone H4 to the promoters of immediate early genes (IEG)cfos, zif268andarc, which are implicated in synaptic plasticity. In accordance, their induced expression was suppressed after PARP1 genetic deletion in PARP1-KO mice, or after PARP1 inhibition or silencing. Moreover, under these conditions, long-term synaptic potentiation (LTP) (indicating synaptic plasticity) was not generation in the hippocampal CA3-CA1 connections, and learning abilities were impaired. Furthermore, both IEG expression and LTP generation failed when cerebral neurons accumulated single strand DNA breaks, due to a predominant binding of PARP1 to nicked DNA, occluding its Erk binding sites. Thus, a declined synaptic plasticity is anticipated when aged cerebral neurons accumulate DNA single-strand breaks during life span.
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, and the Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, 69978, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Cohen-Armon
keywords: Immediate early genes; LTP generation; PARP1-Erk2 synergism