| Abstract [eng] |
During synaptic pruning synapses are eliminated from neuronal network. This process needs to be strictly controlled, since under-pruning and over-pruning are associated with physiological and morphological impairments, leading to various neurodevelopmental diseases, such as autism spectrum disorder or schizophrenia. Nowadays the amount of validated experiments is increasingly showing that during brain development synaptic pruning is mediated by brain macrophages – microglia. One of the molecular cues in microglia-neuron interaction is an “eat-me” signal phosphatidylserine (PtdSer). In this study, we investigated the role of PtdSer scramblase XK-related protein 8 (Xkr8) in brain development. To understand how PtdSer exposure contributes to microglia-mediated synaptic pruning we investigated a transgenic Xkr8Flx/Flx; Emx1::Cre; Thy1::GFP mouse line (Xkr8-cKO) with impaired Xkr8 expression in Emx1 excitatory neurons. We were interested whether insufficient PtdSer exposure on Xkr8-lacking neurons will affect the elimination of the synapses of these neurons during brain development. For this reason, we investigated two sets of connections differing in PtdSer exposure: cortico-cortical and thalamo-cortical connections and vice versa. It is known that Emx1::Cre driver is expressed in Xkr8-cKO mice line and is active during postnatal cortical cell death. Therefore, we investigated whether ablation of Xkr8 scramblase in excitatory neocortical neurons affected their development. Finally, we used a well described corticospinal tract system to evaluate cortical axonal pruning under normal and impaired Xkr8 scramblase expression. Our data demonstrated that Xkr8 scramblase is expressed in the neocortex in Xkr8-WT mice and is eliminated from the pyramidal neurons in Xkr8-cKO mice. Moreover, presynaptic PtdSer exposure is required for normal synaptic pruning. Finally, disruption of PtdSer scrambling interferes with developmental elimination of corticospinal axons. |
