Excitotoxicity induced by enhanced excitatory neurotransmission in cultured hippocampal pyramidal neurons.

Cultures of rat hippocampal pyramidal neurons were used to examine the roles of excitatory synaptic transmission, NMDA receptors, and elevated [Ca2+]i in the production of excitotoxicity. In integral of 70% of the cells observed, perfusion with Mg2(+)-free, glycine-supplemented medium induced large spontaneous fluctuations or maintained plateaus of [Ca2+]i. [Ca2+]i fluctuations could be blocked by tetrodotoxin, NMDA receptor antagonists, dihydropyridines, or compounds that inhibit synaptic transmission in the hippocampus, but not by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. When cells were treated with Mg2(+)-free, glycine-supplemented medium and examined 24 hr later, integral of 30% of the neurons were found to have died. Cell death could be inhibited by the same agents that reduced [Ca2+]i fluctuations. These results support a role for direct excitatory synaptic transmission, as opposed to the general release of glutamate, in excitotoxicity. A major role for synaptically activated NMDA receptors, rather than kainate/quisqualate receptors, is also indicated. Neuronal death may be produced by abnormal changes in neuronal [Ca2+]i.

Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+ prevents neurotoxicity.

NMDA receptor activation leads to elevated Ca2+ in cultured rat cortical and retinal ganglion cell neurons. If excessive, this Ca2+ response is associated with delayed neurotoxicity. We used dantrolene and ionomycin to test if the Ca2+ response to NMDA was due to mobilization of intracellular Ca2+ stores rather than merely to Ca2+ influx. In the presence of EGTA, ionomycin resulted in release and subsequent depletion of intracellular Ca2+ stores. Henceforth, despite normal extracellular Ca2+, NMDA elicited only about half of its former Ca2+ response. Similarly, when dantrolene was used to block Ca2+ release from intracellular stores, we observed > 50% smaller NMDA-evoked Ca2+ responses. These results quite surprisingly indicate that at least half the Ca2+ response to NMDA is due to release of intracellular Ca2+, a process triggered by influx of extracellular Ca2+. Dantrolene also protected neurons from NMDA receptor-mediated neurotoxicity. Release of intracellular Ca2+ may therefore be a necessary step in the cascade leading to neuronal damage induced by excessive NMDA receptor stimulation and may be amenable to pharmacological intervention.

Potassium channel activators abolish excitotoxicity in cultured hippocampal pyramidal neurons.

When hippocampal pyramidal neurons are grown in culture they develop excitatory synaptic contacts. If these cultures are perfused with Mg2(+)-free, glycine supplemented medium the neurons exhibit fluctuations in [Ca2+]i and associated cell death ('excitotoxicity'). These phenomena involve the activation of NMDA receptors. When cultures are treated with the K(+)-channel activators cromakalim and diazoxide both the [Ca2+]i fluctuations and the neuronal death are abolished. These effects are reversed by the sulfonylurea glyburide. It thus appears that K(+)-channel activators may be a novel therapeutic intervention in epilepsy and associated disorders.

The informational impact of mood on effort mobilization: a study of cardiovascular and electrodermal responses.

The impact of mood on effort quantified as autonomic adjustments was investigated in an experiment. The authors induced positive versus negative moods with either 1 of 2 mood induction procedures (music vs. autobiographical recollection) that differed in the extent of required effort. Then participants performed an achievement task after demand appraisals were made. Results were as predicted. During the mood inductions, autonomic reactivity (systolic blood pressure [SBP], diastolic blood pressure, heart rate, skin conductance responses) was stronger in the relatively effortful recollection conditions than in the relatively effortless music conditions. Mood valence had no impact here. But in the context of task performance, the authors found (a) mood congruency effects on the demand appraisals that reflected subjectively higher demand in a negative than in a positive mood, and (b) stronger SBP reactivity in a negative mood compared with a positive mood. Furthermore, SBP reactivity during task performance was correlated with achievement.

[A scissors-effect in career development of female and male medical doctors]. / Der Schereneffekt bei der beruflichen Entwicklung von Arztinnen und Arzten1.

BACKGROUND AND OBJECTIVE: Women are equally interested in studying medicine as men, and there is an equal proportion of female and male graduates in medicine. Women's occupational careers in medicine, however, are on the average less successful than men's. Whereas there are already many cross-sectional studies on this issue the present paper reports data of a prospective longitudinal study. PARTICIPANTS AND METHODS: Participants were 139 female graduates and 172 male medical graduates. These were questioned three times, after their second "Staatsexamen", one and a half years later during their practical medical training time, and again one and a half years later within their specialized training. The questionnaires tapped performance data, occupational self-efficacy, attitudes, goals, work satisfaction, experience of work situation, occupational development and private development. RESULTS: There were no gender differences in grades, study duration, occupational self-efficacy and goals immediately after the exam. Experience of the work situation as well as work satisfaction did not differ, either. However, at time three female medical doctors were less often full-time employed than their male colleagues. This pertained not only to mothers but also to childless women. Full-time employed women often were singles without a partner. There were also gender differences in the expectations how occupation and family should be combined. Psychologically, women experienced a decrease in occupational self-efficacy, whereas men experienced an increase. Both equivocal female gender-role expectations and unfavorable organizational conditions of medical training are important for this development. CONCLUSION: The compatibility between work and family must be seen as a societal task. Otherwise many well-trained female medicine doctors will quit their jobs and as a consequence there will be a lack of doctors in the future.