Dysregulated Microglial Synaptic Engulfment in Diffuse Midline Glioma

Mancusi, R.; Tatlock, E.; Shamardani, K.; Acosta-Alvarez, L.; Drexler, R.; Trivedi, V.; Gavish, A.; Niizuma, K.; Soni, N.; Woo, P. J.; Mulinyawe, S.; Jahan, S.; Logan, N.; Malacon, K.; Byun, Y. G.; Geraghty, A. C.; Barron, T.; Taylor, K. R.; Monje, M.

doi:10.64898/2025.12.22.696064

bioRxiv · 10.64898/2025.12.22.696064

Dysregulated Microglial Synaptic Engulfment in Diffuse Midline Glioma

Mancusi, R.·Tatlock, E.·Shamardani, K.·Acosta-Alvarez, L.·Drexler, R.·Trivedi, V.·Gavish, A.·Niizuma, K.·Soni, N.·Woo, P. J.·Mulinyawe, S.·Jahan, S.·Logan, N.·Malacon, K.·Byun, Y. G.·Geraghty, A. C.·Barron, T.·Taylor, K. R.·Monje, M.

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Abstract

Diffuse midline glioma (DMG) is a near-universally lethal form of pediatric high-grade glioma, driven by neuronal activity-regulated paracrine signaling and synaptic integration of malignant cells into neural circuits. In turn, DMG increases neuronal excitability, augmenting neuron-to-glioma signaling. In the healthy brain, microglia, the resident immune cells of the central nervous system (CNS), regulate neuronal excitability and synaptic connectivity. However, the role of microglia in promoting tumor-associated hyperexcitable neural networks in glioma remains unknown. Here, we investigate the activity-regulated engulfment of neuronal synapses by microglia in both healthy and glioma-bearing mice, and further explore how glioma cells alter microglia-mediated circuit refinement, contributing to pathogenic neuronal hyperexcitability. Microglia-mediated circuit refinement in the glioma microenvironment was characterized through synaptic engulfment analysis of both excitatory and inhibitory synapses by microglia in healthy mice and patient-derived DMG xenograft models, paired with optogenetic stimulation in the neocortex. We found that glutamatergic neuronal activity in the healthy brain increased excitatory synaptic engulfment by microglia in a previously unappreciated negative feedback mechanism that may guard against hyperexcitability. In contrast, this activity-regulated increase in excitatory synaptic engulfment was abrogated in DMG-infiltrated brains. Instead, inhibitory synaptic engulfment was significantly increased in DMG in response to glutamatergic neuronal activity. Together, these dysregulated synaptic engulfment mechanisms may create imbalance in the excitatory to inhibitory (E:I) synapse ratio predicted to increase neuronal excitability. Complementary single-nuclei sequencing studies revealed concordant tumor-specific, activity-regulated changes in microglia-neuron signaling showing reduced expression of excitatory synaptic refinement gene programs in microglia, potentially mediating the aberrant synaptic engulfment observed in DMG. These findings reveal novel cancer-neuron-immune interactions in DMG and provide an opportunity to potentially modulate tumor-associated neuronal hyperexcitability by targeting aberrant microglial synaptic engulfment. HIGHLIGHTSO_LIExcitatory synaptic engulfment by microglia increases in a glutamatergic neuronal activity-dependent manner in the healthy brain. C_LIO_LIIn the glioma-infiltrated brain, this feedback regulatory mechanism is inverted, with loss of activity-regulated excitatory synaptic engulfment and aberrant increased inhibitory synaptic engulfment. C_LIO_LITranscriptomic changes in glioma-associated microglia contribute to differential excitatory and inhibitory synaptic engulfment, with reduced excitatory synaptic refinement gene programs in tumor-associated microglia. C_LIO_LIActivity-regulated soluble factors drive this imbalanced excitatory-inhibitory postsynaptic engulfment by glioma-associated microglia. C_LI

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Mancusi, R., Tatlock, E., Shamardani, K., Acosta-Alvarez, L., Drexler, R., Trivedi, V., Gavish, A., Niizuma, K., Soni, N., Woo, P. J., Mulinyawe, S., Jahan, S., Logan, N., Malacon, K., Byun, Y. G., Geraghty, A. C., Barron, T., Taylor, K. R., Monje, M.. 2025-12-25. Dysregulated Microglial Synaptic Engulfment in Diffuse Midline Glioma. https://doi.org/10.64898/2025.12.22.696064

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