CDC50A dependent phosphatidylserine exposure induces inhibitory post-synapse elimination by microglia

Abstract

Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite important roles during development and neurological disorders, the "eat-me" signal that initiates glia-mediated phagocytosis of synapses remains largely elusive. Here, by generating inducible conditional knockout mice of Cdc50a, we induced stable exposure of phosphatidylserine in the neuronal outer membrane. Surprisingly, acute Cdc50a deletion in neurons causes specific loss of inhibitory post-synapses without affecting other synapses, thereby generating excessive excitability with appearance of seizure. Ablating microglia or deleting microglial Mertk rescues the loss of inhibitory post-synapses, indicating that microglial phagocytosis is responsible for inhibitory post-synapse elimination. Moreover, inhibitory post-synapses in normal juvenile brains also use phosphatidylserine for synapse pruning by microglia, suggesting that phosphatidylserine may serve as a general "eat-me" signal for inhibitory post-synapse elimination. One Sentence SummaryCdc50a dependent phosphatidylserine exposure functions as an "eat-me" signal for microgliadependent inhibitory post-synapse elimination

Glial Cells Promote Myelin Formation and Elimination

“…This may imply selective expression of a cue. Intriguingly, a recent preprint identified phosphatidylserine (PS), a known eat-me cue at synapses (Li et al, 2020;Park et al, 2020;Scott-Hewitt et al, 2020), as a likely cue for developmental myelin phagocytosis (Djannatian et al, 2021). Similar to synapse elimination, the cues that direct myelin phagocytosis may vary between brain regions (Gunner et al, 2019).…”

Fibrinogen and complement factor H: The two crucial markers of Parkinson’s disease with cognitive impairment

“…Reduced expression of complement component 3 (C3) is implicated in several bowel diseases viz. the Crohn’s disease, inflammatory bowel disease, and ulcerative colitis, as studied using knock-out modality (Park et al, 2020 preprint). CFAH being an active member of the complement system; a valid correlation may be speculated between enhanced levels of CFAH and constriction of lumen in the CFAH injected mice.…”

Please eat (only part) of me: synaptic phosphatidylserine cues microglia to feast

“…An insight into the upstream mechanism regulating PS exposure is found in a recent preprint (preprint: Park et al , ). CDC50a functions as part of the flippase required to maintain PS cytoplasmically (Segawa et al , ).…”

“…CDC50a functions as part of the flippase required to maintain PS cytoplasmically (Segawa et al , ). Its loss by Thy1‐Cre‐mediated deletion results in constitutive external leaflet expression of PS by Thy1‐expressing neurons (preprint: Park et al , ). Interestingly, the authors found that constant PS exposure leads to increased loss of post‐synapses selectively on inhibitory neurons.…”