Weak synapticz activity induces ongoing signaling to the nucleus that is enhanced by B-DNF and suppressed by low-levels of nicotine

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 NMIDA 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. (C) 2004 Elsevier Inc. All rights reserved.