Morphological alterations in astrocytes are characteristic for post mortem brains of patients affected by major depressive disorder (MDD). Recently, a significant reduction in the coverage of blood vessels (BVs) by aquaporin-4 (AQP-4)-positive astrocyte endfeet has been shown in the prefrontal cortex (PFC) of MDD patients, suggesting that either alterations in the morphology of endfeet or in AQP-4 distribution might be responsible for the disease phenotype or constitute a consequence of its progress. Antidepressant drugs (ADs) regulate the expression of several proteins, including astrocyte-specific ones. Thus, they may target AQP-4 to induce morphological changes in astrocytes and restore their proper shape or relocate AQP-4 to endfeet. Using an animal model of depression, rats selectively bred for high anxiety-like behavior (HAB), we confirmed a reduced coverage of BVs in the adult PFC by AQP-4-immunoreactive (AQP-4-IR) astrocyte processes with respect to non-selected Wistar rats (NAB), thereby validating it for our study. A further evaluation of the morphology of astrocyte in brain slices (ex vivo) and in vitro using an antibody against the astrocyte-specific cytoskeletal protein glial fibrillary acidic protein (GFAP) revealed that HAB astrocytes extended less processes than NAB cells. Furthermore, short-term drug treatment in vitro with the AD fluoxetine (FLX) was sufficient to increase the plasticity of astrocyte processes, enhancing their number in NAB-derived cells and recovering their basal number in HAB-derived cells. This enhanced FLX-dependent plasticity occurred, however, only in the presence of intact AQP-4, as demonstrated by the lack of effect after the downregulation of AQP-4 with RNAi in both NAB and HAB cells. Nonetheless, a similar short-term treatment did neither modulate the coverage of BVs with AQP-4-positive astrocyte endfeet in NAB nor in HAB rats, although dosage and time of treatment were sufficient to fully recover GFAP expression in HAB brains. Thus, we suggest that longer treatment regimes may be needed to properly restore the coverage of BVs or to relocate AQP-4 to astrocyte endfeet. In conclusion, FLX requires AQP-4 to modulate the plasticity of astrocyte processes and this effect might be essential to re-establish a functional glia-vasculature interface necessary for a physiological communication between bloodstream and brain parenchyma.

The enzyme acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and is thereby involved in several cellular processes such as differentiation, proliferation, and apoptosis in different cell types. However, the function of ASM in T cells is still not well characterized. Here, we used T cell-specific ASM overexpressing mice (t-ASM/CD4cre) to clarify the impact of cell-intrinsic ASM activity on T cell function in vitro and in vivo . We showed that t-ASM/CD4cre mice exhibit decreased frequencies of Foxp3 + T regulatory cells (Tregs) within the spleen. Enforced T cell-specific ASM expression resulted in less efficient induction of Tregs and promoted differentiation of CD4 + CD25 − naïve T cells into IFN-γ producing Th1 cells in vitro . Further analysis revealed that ASM-overexpressing T cells from t-ASM/CD4cre mice show elevated T cell receptor (TCR) signaling activity accompanied with increased proliferation upon stimulation in vitro . Plasmodium yoelii infection of t-ASM/CD4cre mice resulted in enhanced T cell activation and was associated with reduced parasitemia in comparison to infected control mice. Hence, our results provide evidence that ASM activity modulates T cell function in vitro and in vivo .

There is growing interest in the role of Social Prescribing (SP) to help promote mental wellbeing and support individuals with mental health difficulties. Yet, implementation of SP to children and young people (CYP) has proved slow and underdeveloped compared with adult populations. Understanding the barriers and facilitators will help key stakeholders to better embed SP for CYP into practice. Using the Theoretical Domains Framework (TDF), a comprehensive, theoretical-led framework, underpinned by 33 behaviour change theories and 128 constructs, perceived barriers and facilitators to SP were investigated. The sample comprised of 11 Link Workers and 9 individuals involved in facilitating SP with CYP, who took part in semi-structured interviews. Transcripts were analysed using a deductive thematic analysis, and themes were coded under each theoretical domain. Overall, 36 barriers and facilitators for SP were identified across 12 domains of the TDF. Under capability, barriers and facilitators were found for knowledge, skills, memory/attention/decision making processes, and behavioural regulation. For opportunity, barriers and facilitators were found for social/professional influences, as well as environmental context and resources. Finally, for motivation, domains covered included: beliefs about consequences, beliefs about capabilities, optimism, motivations/goals, reinforcement, and emotions. Findings suggest that a wide range of barriers and facilitators affect the implementation of CYP SP to improve mental health and wellbeing. Interventions which target different domains related to capability, opportunity and motivation should be developed to better facilitate CYP SP.