Summary Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and weighted gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across 6 brain regions. We overlap our human profiles with those from a mouse model of chronic variable stress and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns, with male and female transcriptional profiles sharing very limited overlap, an effect seen in depressed humans and in stressed mice. We identify male and female hub genes and confirm their sex-specific impact as stress-susceptibility mediators. For example, downregulation of the female-specific hub gene DUSP6 in prefrontal cortex mimics stress susceptibility in females only by increasing ERK signaling and pyramidal neuron excitability. Such DUSP6 downregulation also recapitulates the transcriptional remodelling that occurs in PFC of depressed females. Together, our findings reveal dramatic sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.

Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival 1 . Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A 1 R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.

Chemical modifications of histones can mediate diverse DNA-templated processes including gene transcription 1 – 3 . Here, we provide evidence for a new class of histone posttranslational modification (PTM), serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in serotonin (5-hydroxytryptamine, 5-HT) producing organisms. We demonstrate that tissue Transglutaminase 2 (TGM2) can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3) marked nucleosomes resulting in the presence of combinatorial H3K4me3Q5ser in vivo . H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that the mark is enriched in euchromatin, is sensitive to cellular differentiation and correlates with permissive gene expression, phenomena that are linked to the mark’s potentiation of TFIID 4 – 6 interactions with H3K4me3. Cells ectopically expressing an H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser target loci leading to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signaling, in the mediation of permissive gene expression.