Microglial dysregulation promotes aberrant synaptic engulfment and CXCL10-associated CD8⁺ T-cell accumulation in CMT2A mice
Abstract
Charcot–Marie–Tooth disease type 2A (CMT2A), caused by pathogenic variants in MFN2, is primarily recognized as a peripheral axonopathy. Depression and psychological distress have also been reported in patients with CMT, but it remains unclear whether MFN2 mutations are associated with central neuroimmune alterations that contribute to behavioral changes. We compared Mfn2 T105M and R94W mouse models and observed anxiety-, repetitive-, and depression-related behavioral abnormalities. To assess the contribution of basolateral amygdala (BLA) microglia, we used CX3CR1-directed, Cre-dependent designer receptors exclusively activated by designer drugs (DREADDs). Chemogenetic Gi activation, but not Gq activation, improved behavioral outcomes in R94W mice.
R94W microglia showed increased somatic volume and surface area, increased COX IV immunoreactivity, and more synaptophysin- and PSD95-positive cargo. Bulk BLA synaptophysin levels were unchanged, suggesting enhanced spatially restricted microglial phagocytosis without evidence of widespread synaptic protein loss. Bulk RNA sequencing of the BLA identified phagosome, innate immune, antigen-processing and presentation, chemokine-signaling, and T-cell-related programs, many of which were attenuated by microglial Gi-DREADD activation. The R94W BLA also showed increased MYD88, NF-κB p65, and CXCL10 signals, accompanied by marked CD8⁺ T-cell accumulation. Gi-DREADD activation reduced these inflammatory signals, microglial morphological changes, synaptic cargo, and CD8⁺ T-cell accumulation. AMG487 treatment reduced marble burying, BLA CD8⁺ T-cell accumulation, and microglial CXCL10 signal, and partially improved elevated-plus-maze measures.
These results suggest that BLA microglial dysregulation contributes to behavioral abnormalities associated with MFN2 R94W and is accompanied by abnormal synaptic engulfment, CXCL10-associated CD8⁺ T-cell accumulation, and inflammatory changes. They also extend the pathophysiological framework of CMT2A beyond peripheral axons and suggest a neuroimmune component to the neurobehavioral burden reported in CMT.
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