Molecular signals in the developing brain
The elimination of neuronal connections is known as synaptic pruning and this is fundamental for functional connectivity in the brain. Aberrant pruning may lead to neurodevelopmental and neuropsychiatric diseases such as autism spectrum disorders or schizophrenia. Recent mechanistic insight into the process of synaptic pruning indicates that the brain immune cells, called microglia are responsible for this synapse elimination. Microglia sense damage and through phagocytosis they maintain homeostasis by removing any unnecessary cells, their connections or debris. A number of attractant molecules and receptors have been identified to drive microglia attraction to the required site of the brain. To date, scientists were unable to identify any neuronal molecule that can discriminate between strong and weak synapses. The scope of the EU-funded SYNSIGNAL (Molecular signals for synaptic pruning by microglia) project was to evaluate how certain molecules control synaptic pruning in the developing brain. To facilitate their work, the consortium first developed an ex vivo system for culturing organotypic slices of the hippocampus. This system resembled the in vivo organ with respect to tissue and microglia morphology. Using this system, researchers examined the regulatory impact on synaptic pruning of phosphatidylserine, a molecule promoting phagocytosis, and sialic acid, a molecule prohibiting phagocytosis. Their observations indicated a role of sialic acid in the maintenance of synapses as well as in the molecular regulation of developmental synaptic pruning. To elucidate the role of phosphatidylserine, the consortium studied mice lacking the enzyme that exposes phosphatidylserine on the surface of the cells. They discovered that phosphatidylserine plays a role in synaptic turnover and may help eliminate unnecessary synapses. The identification of molecular communication between neurons and synapses through phagocytosis signals provides unprecedented insight into the synaptic pruning process. Given that impaired pruning is associated with neurodevelopmental pathologies, the SYNSIGNAL information will help understand these disorders and develop new approaches to their treatment.
Keywords
Synaptic pruning, microglia, synapse, phosphatidylserine, sialic acid
