Dynamic modulation of cerebral cortex synaptic function by nitric oxide

Our experiments demonstrate that NO exerts several actions in the cerebral cortex (see Fig. 4). Its production is mediated by neuronal activity through at least two pathways, NMDA receptors and AMPA receptors. By virtue of its diffusion in extracellular space, NO can interact with synapses that are near the production site but not necessarily anatomically connected to the NO source by a conventional synaptic linkage. NO's primary action is amplification of the release of the excitatory neurotransmitter, L-glutamate, thus effectively creating a positive feed-forward gain system. However, a number of effective brakes, presumably activated under physiological conditions, serve to limit the cascade. These include NO's ability to inhibit NMDA receptors, its negative feedback on the rate limiting enzyme, NOS (Rengasamy and Johns, 1993; Park et al., 1994; Ravichandran et al., 1995) and other inhibitory actions (Figs. 3H and L). Under conditions of extremely strong activation or curtailment of the inhibitory feedback mechanisms, as might occur with a change in the local redox milieu (see Lipton, this volume), the amplification cascade may proceed unchecked leading to neurotoxicity (see Dawson, this volume). NO's ability to modulate synaptic function is indicated by both its positive and negative modulatory role in a form of activity-dependent synaptic plasticity, covariance-induced synaptic potentiation. These opposing effects may be due to NO's ability to amplify glutamate release and inhibit NMDA receptors, respectively. The actions of endogenous NO in vivo are primarily facilitatory in visual cortex (Fig. 4). However, inhibitory actions also occur in vivo. The targets for NO in vivo, are potentially more diverse including the neurotransmitter release process, NMDA receptors, other receptors and ion channels and the cerebral vasculature. However, regardless of the signaling pathways, the net result of endogenous NO production in the intact visual cortex is a potent modulation of cells' responses to visual stimulation. Thus, it is likely that this signal plays an important role in ongoing information processing in the mature cerebral cortex, dynamically altering the effective strength of cortical networks.