Microglial GPR56 in synaptic pruning: mechanisms, comparative receptor biology, and context-dependent roles in brain...

Microglia regulate synaptic remodelling, eliminating weakened and dysfunctional synapses to maintain circuit development and homeostasis. Adhesion G protein-coupled receptor G1 (ADGRG1/GPR56) has emerged as a distinctive regulator integrating phosphatidylserine recognition, mechano-transduction, and G-protein signalling. This review synthesises the molecular, cellular and disease-level evidence, distinguishing throughout between direct experimental findings, associations, and proposed mechanisms. We discuss its structural organisation, the microglia-enriched splice variant 4 (S4), and how phosphatidylserine-exposing synapses are recognised and engulfed. The Gα12/13-RhoA cascade placed downstream of microglial GPR56 was defined in neural progenitor cells and has not been perturbed in microglia; it is presented as proposed rather than established. Comparison with CR3, CX3CR1, TREM2, MERTK, MEGF10 and BAI1, identifies microglia-enriched alternative splicing, direct coupling of phosphatidylserine recognition to G-protein signalling, and mechanosensitivity as distinguishing features. We then evaluate evidence linking GPR56 to traumatic brain injury, major depressive disorder, maternal immune activation models, and Alzheimer's disease. In every context the causal evidence is loss-of-function: removing the receptor worsens the phenotype, including in Alzheimer's disease, where microglial ADGRG1 is increased yet deletion aggravates amyloid pathology and cognitive decline. The evidence supports a protective receptor that, when lost, produces different outputs in different settings, not one that switches between protective and pathological roles. The four disease outcomes are different from each other and from developmental pruning. The idea that they all involve a single S4-dependent mechanism remains a hypothesis, not a confirmed fact. We conclude by discussing therapeutic and biomarker opportunities and translational challenges.