Abstract

The development of a complex nervous system is accompanied by a generation of superfluous neuronal connections that are removed when neural circuits mature. Why are so many synapses lost, what determines which synapses are eliminated, what are the molecular mechanisms involved, and what are the consequences of not getting it right? Synaptic pruning appears to be highly selective process that ensures selective elimination of some synapses and the maintenance of others. Structural and functional refinement of synaptic network is tightly related to the presence of brain immune cells microglia that actively contact and engulf unnecessary synapses. Aberrant or impaired microglial function leads to abnormal synaptic densities and dysfunctional connectivity that causes morphological, functional and behavioral deficits. For example, brain imaging and post-mortem studies suggest the role of deficient synaptic pruning in neurodevelopmental disorders, such as autism and schizophrenia. The reduction of brain volume and reduced density of dendritic spines in schizophrenia is suggestive of over-pruning, whereas increased brain volume and dendritic spine densities may indicate under-pruning in autism. Microglial phagocytic function has been implicated to have a central role in synaptic pruning; however, neuronal “eat-me” signal that discriminates weak and strong synapses remains to be identified. Using organotypic hippocampal slice cultures and in vivo mouse models we investigate the role of phosphatidylserine as a neuronal surface signal that labels synapses for elimination thus ensuring proper brain development and circuit maturation.