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Role of NMDA receptors in Long‐Term Potentiation‐induced modulation of transcription factor binding

Long‐term potentiation (LTP), a lasting increase in the efficacy of connections between neurons, is thought to require the synthesis of mRNA for its consolidation. Several activity regulated genes can be up‐regulated within two minutes of stimulation, though the mechanism through which the signal rapidly reaches the nucleus from synapses hundreds of microns away is unknown. We propose that action potentials, not synapse‐to‐nucleus signals, regulate such rapid gene transcription. Transcription factors (TFs) controlling these genes can be studied using electrophoretic mobility shift assays to test for the role of the NMDA–type glutamate receptor. Previous work in our lab has shown that NMDAR antagonists block action potentials generation, which can be restored with a blockade of synaptic inhibition. We tested whether or not LTP‐inducing stimulation could continue to activate TFs in the presence of an NMDAR antagonist when synaptic inhibition was blocked. We show that when action potentials are preserved, NMDARs are not required for TF binding to consensus sequences for AP‐1, CBF, SRE, CREB, and Ets at 5 minutes post‐stimulation. Therefore, independent of NMDARs, action potentials can induce rapid modulation of transcription factor binding, which may contribute to the maintenance and stability of LTP.