Nitric oxide-related species inhibit evoked neurotransmission but enhance spontaneous miniature synaptic currents in central neuronal cultures

Abstract

Nitric oxide (NO ⅐ ) does not react significantly with thiol groups under physiological conditions, whereas a variety of endogenous NO donor molecules facilitate rapid transfer to thiol of nitrosonium ion (NO ؉ , with one less electron than NO ⅐ ). Here, nitrosonium donors are shown to decrease the efficacy of evoked neurotransmission while increasing the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs). In contrast, pure NO ⅐ donors have little effect (displaying at most only a slight increase) on the amplitude of evoked EPSCs and frequency of spontaneous mEPSCs in our preparations. These findings may help explain heretofore paradoxical observations that the NO moiety can either increase, decrease, or have no net effect on synaptic activity in various preparations.A number of experiments, most of which have used inhibitors of endogenous nitric oxide synthase, have suggested that nitric oxide (NO ⅐ ) acts presynaptically to enhance the amplitude of evoked synaptic potentials during long-term potentiation (LTP) (1-5). Yet, a variety of exogenous NO donors produce a reversible depression (and only rarely an enhancement) of synaptic transmission (1, 6-10). Apparent discrepancies between effects of various endogenous and exogenous NO donors on neurotoxicity or neuroprotection were attributed at least in part to different redox-related species of the NO group and their disparate chemical reactivities (11,12). With this in mind, the present study was undertaken to determine if different redox-related forms of NO could contribute to differential effects on neurotransmission.Under physiological conditions, free nitric oxide (NO ⅐ ) reacts only very slowly with thiolate anions [the negatively charged form of thiol or -SH (sulfhydryl) groups]. Instead, the NO group in an alternative redox state from NO ⅐ reacts with protein thiol, producing transfer of NO ϩ equivalents to the thiolate anion (RS Ϫ ), resulting in RS-NO formation (11,(13)(14)(15)(16). Under physiological conditions NO ϩ does not exist in a free state in the nervous system, but extensive evidence exists in vivo that the NO group exists in a form that can be donated as NO ϩ . For example, S-nitroso-glutathione, S-nitrosohemoglobin, iron-nitrosyl complexes, nitroso-albumen, and N-nitrosamines are all present in biologic tissue, including the nervous system, and each of these chemical species can donate NO ϩ (15, 17, 18). We report here that donors with NO ϩ character, but not NO ⅐ , decrease evoked neurotransmission, apparently via reaction with thiol groups. Concomitantly, the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs) is increased. MATERIALS AND METHODSNO Donors. Preparations of nitroglycerin (NTG), Snitrosocysteine (SNOC), diethylamine͞nitric oxide complex (DEA͞NO), N-ethylmaleimide (NEM), and their control solutions have been described (11,(19)(20)(21). These reagents were mixed in the extracellular solution, adjusted to pH 7.2, applied via bath superfusion for Ϸ2 min, and then washed ou...

Adaptive Depression in Synaptic Transmission in the Nucleus of the Solitary Tract afterIn VivoChronic Intermittent Hypoxia: Evidence for Homeostatic Plasticity

“…However, miniature and asynchronous release was greater in CIH rather than reduced. Directionally different results have been observed previously in which a decrease in evoked EPSP/EPSCs or endplate potentials is accompanied by increases or unaltered miniature events (Eliot et al, 1994;Zengel and Sosa, 1994;Cummings et al, 1996;Pan et al, 1996). We propose that the effects of CIH on the frequency of mEPSCs and aEPSCs versus the eEPSCs reflect differential regulation of release of two vesicular pools.…”

Photolytically released nitric oxide produces a delayed but persistent suppression of LTP in area CA1 of the rat hippocampal slice

“…Moreover, photolysis of our caged NO affected NMDA but not non-NMDA receptor-mediated responses (see, for example, Fig. 3A and B) as predicted for the free radical (NO·) but not the nitrosonium (NO¤) species (Pan et al 1996). The mechanism by which NO depresses NMDA receptor function is not known, though redox modification of thiol groups associated with the receptor has been strongly implicated (Moriyoshi et al 1991;Lei et al 1992;Manzoni et al 1992;Lipton et al 1993).…”

“…The multiplicity of actions reported for NO is likely to reflect the redox species involved. Compounds that evolve the free radical (NO·) have very little effect on non-NMDA receptor function, but compounds releasing nitrosonium ions (NO¤) reversibly depress synaptic transmission (Pan et al 1996). We are confident that our caged compound releases the free radical NO·, the form of NO produced by the enzymatic action of NOS (Garthwaite, 1991), on the basis of changes in the absorption spectrum of haemoglobin when exposed to photolytically released NO; these changes, reflecting the conversion of deoxyhaemoglobin to nitrosyl-haemoglobin, are stimulated by NO· but not by NO¤ (Bettache et al 1996).…”

Role of Spinal Nitric Oxide in the Inhibitory Effect of [d-Pen2,d-Pen5]-Enkephalin on Ascending Dorsal Horn Neurons in Normal and Diabetic Rats

“…Different NO species formed in the spinal cord may be involved in the opposing actions of NO mentioned in the above studies. For instance, nitrosonium donors, but not pure NO donors, can alter synaptic neurotransmission (Pan et al, 1996). We have found that spinal NO interacts with L-cysteine to produce an antiallodynic effect through formation of S-nitrosothiols in a rat model of neuropathic pain (Chen et al, 2000).…”