Brain stars take the lead during critical periods of early postnatal brain development: relevance of astrocytes in health and mental disorders

Abstract

In the brain, astrocytes regulate shape and functions of the synaptic and vascular compartments through a variety of released factors and membrane-bound proteins. An imbalanced astrocyte activity can therefore have drastic negative impacts on brain development, leading to the onset of severe pathologies. Clinical and pre-clinical studies show alterations in astrocyte cell number, morphology, molecular makeup and astrocyte-dependent processes in different affected brain regions in neurodevelopmental (ND) and neuropsychiatric (NP) disorders. Astrocytes proliferate, differentiate and mature during the critical period of early postnatal brain development, a time window of elevated glia-dependent regulation of a proper balance between synapse formation/elimination, which is pivotal in refining synaptic connectivity. Therefore, any intrinsic and/or extrinsic factors altering these processes during the critical period may result in an aberrant synaptic remodeling and onset of mental disorders. The peculiar bridging position of astrocytes between synaptic and vascular compartments further allows them to "compute" the brain state and consequently secrete factors in the bloodstream, which may serve as diagnostic biomarkers of distinct healthy or disease conditions. Here, we collect recent advancements regarding astrogenesis and astrocyte-mediated regulation of neuronal network remodeling during early postnatal critical periods of brain development, focusing on synapse elimination. We then propose alternative hypotheses for an involvement of aberrancies in these processes in the onset of ND and NP disorders. In light of the well-known differential prevalence of certain brain disorders between males and females, we also discuss putative sex-dependent influences on these neurodevelopmental events. From a translational perspective, understanding age- and sex-dependent astrocyte-specific molecular and functional changes may help to identify biomarkers of distinct cellular (dys)functions in health and disease, favouring the development of diagnostic tools or the selection of tailored treatment options for male/female patients.

Fig. 1. The critical period for astrogenesis and synaptic circuit formation during postnatal brain development in rodents and humans.

The timelimes show the major processes occurring from pre- and postnatal early stages through adulthood in rodents and humans to develop properly functional astrocyic and neuronal synaptic networks. A few examples of intracellular signaling molecules which determine the switch between neurogenic to gliogenic cell fates are depicted, as well as selected proteins relevant for astrocyte-specific differentiation/maturation processes (e.g. Cx30 and TGFβ/NLGN1/TLSP/DKK1/BMP4 ligands). We refer the reader to the text for details regarding experimental evidences supporting our current knowledge about each event displayed in the Figure. Cx30, connexin 30. Figure created with BioRender.com.

Fig. 2. The role of critical period for the onset of neurodevelopmental and neuropsychiatric disorders.

Intrinsic molecular programmes and environmental factors may interact with each other during the critical period of brain development to drive the proper formation of neuronal circuits. Any alterations in the sequences of events occurring during these time frames might lead to the onset of neurodevelopmental (ND) disorders such as Autism Spectrum Disorder (ASD) or neuropsychiatric (NP) disorders such as Schizophrenia (SCZ) or Major depressive disorder (MDD). Stressful triggers, such as early-life adversity (ELA), chronic social defeat stress or early social isolation, experienced during the critical period show a higher impact on the development of ND and NP disorders later in life. Molecules like Cx30 may play a role in the closure of the critical period of astrocyte development, which is necessary for the proper formation of brain circuits. Figure created with BioRender.com.

Fig. 3. Glia-mediated synaptic pruning.

Astrocytes and microglia cells both regulate the refinement of synaptic neuronal networks through the elimination of weak synapses during early postnatal developmental stages. Signaling molecules called “eat me” signals, such as C1q and phosphatidylserine (PS), recruited during these events have been identified, as well as binding partners located on the respective cells, like MEGF10 receptor on astrocytes and the receptors of the complement cascade on microglia cells. It remains unclear whether PS and C1q are directly implicated in the astrocyte-mediated synaptic elimination as well. Figure created with BioRender.com.

Fig. 4. Sex-dependent differences in astrogenesis and vulnerability to disease onset.

A sex-dependent predisposition to brain disorders has been long recognized for many brain pathologies. Differential time-shifted maturation trajectories observed in astrocytes and astrocyte-mediated processes between males and females may account for such sex-dependent biased windows of vulnerability to disease onset. Figure created with BioRender.com.