Regulation of synaptic development by astrocyte signaling factors and their emerging roles in substance abuse

Astrocytes have critical functions throughout the central nervous system (CNS) and have emerged as regulators of synaptic development and function. With their highly complex morphologies, they are able to interact with thousands of synapses via peripheral astrocytic processes (PAPs), ensheathing neuronal axons and dendrites to form the tripartite synapse. In this way, astrocytes engage in crosstalk with neurons to mediate a variety of CNS processes including the regulation of extracellular matrix protein signaling, formation and maintenance of the blood-brain barrier (BBB), axon growth and guidance, homeostasis of the synaptic microenvironment, synaptogenesis, and the promotion of synaptic diversity. In this review, we discuss several key astrocyte signaling factors (thrombospondins, netrins, apolipoproteins, neuregulins, bone morphogenetic proteins, and neuroligins) in the maintenance and regulation of synapse formation. We also explore how these astrocyte signaling factors are impacted by and contribute to substance abuse, particularly alcohol and cocaine use

Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1

Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug target for epilepsy and neuropathic pain; thus the TSP–α2δ-1 interaction is implicated in both synaptic development and disease pathogenesis. However, the mechanism by which this interaction promotes synaptogenesis and the requirement for α2δ-1 for connectivity of the developing mammalian brain are unknown. In this study, we show that global or cell-specific loss of α2δ-1 yields profound deficits in excitatory synapse numbers, ultrastructure, and activity and severely stunts spinogenesis in the mouse cortex. Postsynaptic but not presynaptic α2δ-1 is required and sufficient for TSP-induced synaptogenesis in vitro and spine formation in vivo, but an α2δ-1 mutant linked to autism cannot rescue these synaptogenesis defects. Finally, we reveal that TSP–α2δ-1 interactions control synaptogenesis postsynaptically via Rac1, suggesting potential molecular mechanisms that underlie both synaptic development and pathology

Clinical and basic research investigations into the long‐term effects of prenatal opioid exposure on brain development

Coincident with the opioid epidemic in the United States has been a dramatic increase in the number of children born with neonatal abstinence syndrome (NAS), a form of withdrawal resulting from opioid exposure during pregnancy. Many research efforts on NAS have focused on short‐term care, including acute symptom treatment and weaning of the infants off their drug dependency prior to authorizing their release. However, investigations into the long‐term effects of prenatal opioid exposure (POE) on brain development, from the cellular to the behavioral level, have not been as frequent. Given the importance of the perinatal period for human brain development, opioid‐induced disturbances in the formation and function of nascent synaptic networks and glia have the potential to impact brain connectivity and cognition long after the drug supply is cutoff shortly after birth. In this review, we will summarize the current state of NAS research, bringing together findings from human studies and preclinical animal models to highlight what is known about how POE can induce significant, prolonged deficits in brain structure and function. With rates of NAS continuing to rise, particularly in regions that already face substantial socioeconomic challenges, we speculate as to the most promising avenues for future research to alleviate this growing multigenerational threat