title: Weak synaptic activity induces ongoing signaling to the nucleus that is enhanced by BDNF and suppressed by low-levels of nicotine.
abstract: The developing nervous system adapts to a wide array of stimuli, in part, by evoking activity-dependent mechanisms that signal to the nucleus and induce long-term modifications in neuronal function. It is well established that one such stimulus is strong synaptic activity. Our interest, however, is whether weak activity generated at developing synapses also signals to the nucleus and if so, can these signals be modulated by extrinsic factors. Using cultured hippocampal neurons and a highly sensitive readout of CRE-mediated gene expression, we demonstrate that weak synaptic transmission, including non-evoked, spontaneous transmitter release, induces ongoing gene expression. These weak synaptic stimuli, acting through NMDA receptors, signal to the nucleus through a MAPK pathway, without a significant contribution of L-type Ca2+ channels. In addition, we show that BDNF, a molecule that has clear effects on synaptic plasticity, enhances this CRE-dependent gene expression by acting upstream of NMDA receptors. On the other hand, low levels of nicotine, which also effects synaptic plasticity, suppress ongoing CRE-mediated gene expression indirectly by acting on GABAergic neurons; this indirect action on gene expression suggests an alternative mechanism for how nicotine produces long-lasting changes.
authors.affiliation: Department of Physiology, McGill University, Montréal, Québec, Canada H3G 1Y6.
authors.forename: Damian G
authors.initials: DG
authors.lastname: Wheeler
authors.forename: Ellis
authors.initials: E
authors.lastname: Cooper
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D019426:Integrases / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; D019208:Brain-Derived Neurotrophic Factor; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D014764:Viral Proteins; D005680:gamma-Aminobutyric Acid; D009538:Nicotine; C045073:Cre recombinase; D019426:Integrases