RESUMO
GABAergic neurons and GABAA receptors (GABAARs) are critical elements of almost all neuronal circuits. Most GABAARs of the CNS are heteropentameric ion channels composed of two α, two ß and one γ subunit. These receptors serve as important drug targets for benzodiazepine (BDZ) site agonists, which potentiate the action of GABA at GABAARs. Most GABAAR classifications rely on the heterogeneity of the α subunit (α1 - α6) included in the receptor complex. Heterogeneity of the γ subunits (γ1 - γ3), which mediate synaptic clustering of GABAARs and contribute, together with α subunits, to the benzodiazepine (BDZ) binding site, has gained less attention, mainly because γ2 subunits greatly outnumber the other γ subunits in most brain regions. Here, we have investigated a potential role of non-γ2 GABAARs in neural circuits of the spinal dorsal horn, a key site of nociceptive processing. Female and male mice were studied. We demonstrate that besides γ2 subunits, γ1 subunits are significantly expressed in the spinal dorsal horn, especially in its superficial layers. Unlike global γ2 subunit deletion, which is lethal, spinal cord specific loss of γ2 subunits was well tolerated. GABAAR clustering in the superficial dorsal horn remained largely unaffected and antihyperalgesic actions of HZ-166, a non-sedative BDZ site agonist, were partially retained. Our results thus suggest that the superficial dorsal horn harbors functionally relevant amounts of γ1 subunits that support the synaptic clustering of GABAARs in this site. They further suggest that γ1 containing GABAARs contribute to the spinal control of nociceptive information flow.Significance statement Our results identify for the first time a CNS area (the spinal dorsal horn) in which atypical GABAA receptors containing the γ1 subunit serve a physiological role in the synaptic clustering of GABAA receptors. They also show that pharmacological modulation of γ1 GABAA receptors by a non-sedative GABAA receptor modulator alleviates chronic pain in neuropathic mice.
RESUMO
AIM OF THE STUDY: The aim of this study is to provide an analysis of the career trajectory of the recipients of a Swiss National MD-PhD grant thirty years after the creation of the Swiss interuniversity MD-PhD programme. METHODS: The study surveyed 277 recipients of a Swiss National MD-PhD grant using an online questionnaire in April 2022. There were twenty questions about participants' demographics, the duration of their MD-PhD training, their career trajectory, current position, research and clinical activity, the impact of the support on the recipients' careers, and their satisfaction with various aspects of the grant. RESULTS: The study showed that 141 out of the 277 grant recipients contacted returned the survey (51% response rate). The gender distribution of the participants was 33% women, 63% men, 4% unknown, which is almost the same as that of all grantees (35% women, 65% men). One hundred and fourteen (81%) respondents had completed their MD-PhD thesis and were graduates, while 27 (19%) were still MD-PhD students. The mean duration of the MD-PhD training was 4.27 years, with a slight upward trend over time. A large proportion of graduates, 81%, remained scientifically active after the grant, most of them in academic settings. Of the grantees who had completed their MD-PhD at least eight years before the survey, 55% had a paid research position with 40% combining research and clinical roles, and 15% doing research only. Seventy-six per cent remained clinically active, 54% occupied leadership positions, and 25% were professors. Most grantees believed that the grant had had a positive impact on their career trajectory. The main challenges included a delay in clinical training, a limited number of clinical positions with dedicated research time after the MD-PhD period, and sub-optimal recognition by hospital hierarchies. CONCLUSION: The data collected for this study confirm that the competitive Swiss National MD-PhD Grants Programme excels in supporting promising physician scientists who remain active in both research and clinical contexts in the long term. The individual grants are perceived as a distinction that acts as the basis for a successful career in academic medicine. Continued support and alternative funding sources, however, will be essential to ensure the programme's sustainability.