Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation.

Astrocytes are intimately linked with brain blood vessels, an essential relationship for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as an important player in postnatal gliovascular maturation.

Sex differences in developmental patterns of neocortical astroglia: A mouse translatome database.

Astroglial cells are key players in the development and maintenance of neurons and neuronal networks. Astroglia express steroid hormone receptors and show rapid responses to hormonal manipulations. However, despite important sex differences in the cortex and hippocampus, few studies have examined sex differences in astroglial cells in telencephalic development. To characterize the cortical astroglial translatome in male and female mice across postnatal development, we use translating ribosome affinity purification together with RNA sequencing and immunohistochemistry to phenotype astroglia at six developmental time points. Overall, we find two distinct astroglial phenotypes between early (P1-P7) and late development (P14-adult), independent of sex. We also find sex differences in gene expression patterns across development that peak at P7 and appear to result from males reaching a mature astroglial phenotype earlier than females. These developmental sex differences could have an impact on the construction of neuronal networks and windows of vulnerability to perturbations and disease.

Antidepressant actions of ketamine engage cell-specific translation via eIF4E.

Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4-6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.

Astroglial cells as neuroendocrine targets in forebrain development: Implications for sex differences in psychiatric disease.

Astroglial cells are the most abundant cell type in the mammalian brain. They are implicated in almost every aspect of brain physiology, including maintaining homeostasis, building and maintaining the blood brain barrier, and the development and maturation of neuronal networks. Critically, astroglia also express receptors for gonadal sex hormones, respond rapidly to gonadal hormones, and are able to synthesize hormones. Thus, they are positioned to guide and mediate sexual differentiation of the brain, particularly neuronal networks in typical and pathological conditions. In this review, we describe astroglial involvement in the organization and development of the brain, and consider known sex differences in astroglial responses to understand how astroglial cell-mediated organization may play a role in forebrain sexual dimorphisms in human populations. Finally, we consider how sexually dimorphic astroglial responses and functions in development may lead to sex differences in vulnerability for neuropsychiatric disorders.

A Further Analysis and Commentary on: Profiling Changes in Cortical Astroglial Cells Following Chronic Stress.

The neuroplasticity hypothesis of depression proposes that major depressive disorders are related to decreased hippocampal and cortical neural plasticity, which is reversed by antidepressant treatment. Astroglial cells have emerged as key mediators of neural plasticity and are involved in the cause and treatment of depression and anxiety-like behaviors. One of the ways that astroglia modulate neuroplasticity is through the formation and maintenance of perineuronal nets (PNNs). Perineuronal nets are important extracellular matrix components that respond to stress and are implicated in anxiety-like behaviors. Normally, astroglial cells continuously turnover PNNs by degrading and donating PNN proteins; however, chronic stress slows PNN protein degradation and increases cortical PNN expression overall. In this report, we used weighted gene co-expression network analysis and eigengene analysis to further delineate the pathways and key regulators involved in the astroglial-PNN relationship following chronic stress. Our analyses indicate that chronic variable stress induces the expression of PNNs through inhibition of trophic pathways and key transcription factors in astroglial cells. These data further support the integral role of astroglial cells in the neuroplasticity hypothesis of depression through their modulation of anxiety-like behaviors and PNNs.