The serotonin 6 (5-HT6) receptor is almost exclusively localized in the CNS, predominantly in regions involved in the regulation of cognitive processes such as the cerebral cortex, the hippocampus and the striatum. Correspondingly, it has become an increasingly promising target for the treatment of cognitive deficits associated with various CNS disorders including Alzheimer’s disease and schizophrenia. 5-HT6 receptors also participate in neuro-developmental processes, controlling the migration and normal positioning of cortical interneurons. Although 5-HT6 receptors are known to signal through Gs-adenylyl cyclase, coupling pathways and mechanisms controlling their activity remain poorly explored. To address these issues, we have recently used proteomic approaches associating co-immunoprecipitation or affinity chromatography experiments and high-resolution mass spectrometry, to identify novel signalling proteins associated with the receptor. These studies revealed interaction of the receptor with several members of the mammalian target of rapamycin (mTOR) cascade, including mTOR itself and Neurofibromin (Nf1), which are known to control synaptic plasticity, learning and memory formation. They also demonstrated association of the receptor with a network of proteins, including Cdk5 (Cyclin-dependent kinase 5) and one of its substrates WAVE-1 (Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1), involved in the actin cytoskeleton dynamics, which is crucial for neurite growth, dendritic spine formation and neuronal migration. In preliminary studies, we demonstrated that stimulation of 5-HT6 receptor activated the mTOR pathway in various brain areas including the prefrontal cortex, the site of modulation of social recognition by 5-HT6 ligands. Correspondingly, blocking the mTOR pathway by peripheral administration of rapamycin, in rats, prevented the reduction of short-term memory evoked by injection of a 5-HT6 agonist in a social recognition test but did not blunt pro-cognitive effects of 5-HT6 receptor antagonists. Our preliminary data also showed that expression of 5-HT6 receptor in neuroblastoma cell lines (SH-SY5Y, NG108-15) induced drastic morphological changes that are usually associated with neuronal differentiation (neurite outgrowth, formation of spine-like structures). This project, which combines cell biology, behavioural and quantitative phosphoproteomics approaches, will pursue four objectives: 1) to characterize the mechanisms underlying activation of mTOR pathway by 5-HT6 receptor and its behavioural impact in various cognition paradigms and in a developmental model of schizophrenia; 2) to determine the role of Nf1 in 5-HT6 receptor-operated signalling (notably activation of mTOR pathway) and in regulation of cognitive functions by 5-HT6 ligands; 3) to demonstrate a role of 5-HT6 receptors and of the associated Cdk5/WAVE-1 signalling network in neuronal differentiation, focusing on neurite growth and dendritic spine formation; and 4) to identify mTOR- and Cdk5-dependent signalling mechanisms engaged by 5-HT6 receptor. This program should define whether activation of Nf1/mTOR signalling pathway by 5-HT6 receptors compromise cognition and whether manipulating this pathway would be a valuable strategy for the treatment of cognitive deficits in psychoses such as schizophrenia. It should also identify novel molecular substrates of neuro-developmental effects of serotonin.

The grant proposal CGOSD (Corporate Governance, Organization and Sustainable Development) is set on two types of premises: - first, the widely shared assumption that in the face of the recent failure of the Copenhagen summit and of the multiple crisis – social, economic, financial, ecological – signalling the limitations and risks of contemporary management systems, building more balanced forms of resource management from a social and ecological perspective is necessary; - second, a more original consideration and a core foundation of the CGOSD program, that combining social, economic and ecological objectives in sustainable development policies is far from trivial and actually raises significant paradoxes and difficulties. Accordingly, CGOSD is established with the aims of using the analytical frameworks and tools of management sciences to identify, characterize and theorize the forms of resolution of ‘sustainable development’ paradoxes that organizational actors might build through managerial practices in the context of organizations characterized by varied governance systems. Our field inquiries are indeed geared towards diverse forms of organizations including small enterprises (part 1), large multinational corporations (part 2) and alternative non-profits and NGOs (part 3), on the basis of the hypothesis that the goals and decision systems embedded in the governance of these three types of organizations are likely to influence the ways in which organizational actors solve the paradoxes of sustainable development policies. CGOSD is organized along a matrix structure: ten tasks are vertically distributed across the three main parts of the program and simultaneously interconnected by nine horizontal comparative themes. By adopting an approach based on paradoxes – from the Greek para (against) and doxa (opinion) – we follow a critical management study perspective running against the consensual view of sustainable development held by the current managerial wisdom, that tends to focus on ecological issues and thus, overlook the complexities of balancing economic, social and environmental considerations. Such approach is channelled through a neo-institutionalist perspective on managerial practices and contextualized with reference to the Global Value Chain framework. CGOSD draws on a broad set of competencies held by 31 researchers of varied status inside the Coordinator Lab ERFI (University of Montpellier 1), and in the Partner Labs LGI (Ecole Centrale de Paris) and ICI (University of Brest) respectively contributing 11 and 6 researchers. Such partnership provides the program with a strong knowledge base on small firms, large corporations and non-profits in relation to sustainable development policy issues and the expertise of AgroParisTech researchers affiliated to ERFI in Montpellier. The program will benefit from the international research networks built by the three laboratories. Part 1 on small firms is established on the basis of a partnership with the Management School of the University of Ottawa, and its extension is envisioned under a comparative European analysis with six partner universities in Europe. Part 2 on large firms builds on close relationships with the Cultural Political Economy Research Centre of the University of Lancaster and the Otto Suhr Institute - Center for Labor Relations of the Free University in Berlin. Part 3 on non-profits and NGOs will draw on a number of partnerships established through the AgroParisTech members of ERFI with the Brasilian research Institute INPA (Instituto Nacional de Pesquisas da Amazonia), the World Wide Fund for Nature, and the International Union for Conservation of Nature, among others.