Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis

Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multiple sclerosis (MS). Since astrocyte activation and metabolic function have important roles in regulating neuroinflammation and neuropathology, we examined the serine/threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encephalomyelitis mouse model of MS. To reduce LKB1, a heterozygous astrocyte-selective conditional knockout (het-cKO) model was used. While disease incidence was similar, disease severity was worsened in het-cKO mice. RNAseq analysis identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in het-cKO mice relating to mitochondrial function, confirmed by alterations in mitochondrial complex proteins and reductions in mRNAs related to astrocyte metabolism. Enriched pathways included major histocompatibility class II genes, confirmed by increases in MHCII protein in spinal cord and cerebellum of het-cKO mice. We observed increased numbers of CD4+ Th17 cells and increased neuronal damage in spinal cords of het-cKO mice, associated with reduced expression of choline acetyltransferase, accumulation of immunoglobulin-γ, and reduced expression of factors involved in motor neuron survival. In vitro, LKB1-deficient astrocytes showed reduced metabolic function and increased inflammatory activation. These data suggest that metabolic dysfunction in astrocytes, in this case due to LKB1 deficiency, can exacerbate demyelinating disease by loss of metabolic support and increase in the inflammatory environment.     

Schwann cells: Rescuers of central demyelination

The presence of peripheral myelinating cells in the central nervous system (CNS) has gained the neurobiologist attention over the years. Despite the confirmed presence of Schwann cells in the CNS in pathological conditions, and the long list of their beneficial effects on central remyelination, the cues that impede or allow Schwann cells to successfully conquer and remyelinate central axons remain partially undiscovered. A better knowledge of these factors stands out as crucial to foresee a rational therapeutic approach for the use of Schwann cells in CNS repair. Here, we review the diverse origins of Schwann cells into the CNS, both peripheral and central, as well as the CNS components that inhibit Schwann survival and migration into the central parenchyma. Namely, we analyze the astrocyte- and the myelin-derived components that restrict Schwann cells into the CNS. Finally, we highlight the unveiled mode of invasion of these peripheral cells through the central environment, using blood vessels as scaffolds to pave their ways toward demyelinated lesions. In short, this review presents the so far uncovered knowledge of this complex CNS-peripheral nervous system (PNS) relationship.     

The effect of gender on mental health service use: an examination of mediation through material,social and health-related pathways

Purpose

We aimed to understand how much of the gender difference in mental health service use could be due to the joint mediation of employment, behavioural and material factors, social support and mental health need.

Methods

We used data from employed individuals aged 18–65 years who participated in the 2015–2017 waves of the Household, Income and Labour Dynamics in Australia survey. The exposure (male, female) and confounders were measured in 2015, mediators in 2016 and the outcome—whether a person had seen a mental health professional in the previous year—was measured in 2017. We estimated natural mediation effects using weighted counterfactual predictions from a logistic regression model.

Results

Men were less likely to see a mental health care provider than women. The total causal effect on the risk difference scale was  − 0.045 (95% CI  − 0.056,  − 0,034). The counterfactual of men taking the mediator values of women explained 28% (95% CI 1.7%, 54%) of the total effect, with the natural direct effect estimated to represent an absolute risk difference of  − 0.033 (95% CI  − 0.048,  − 0.018) and the natural indirect effect  − 0.012 (95% CI  − 0.022,  − 0.0027).

Conclusion

Gendered differences in the use of mental health services could be reduced by addressing inequalities in health, employment, material and behavioural factors, and social support.