Neuro-glioma activity-dependent growth mechanisms: an actionable circuit from NLGN3-ADAM10 to AMPA synapses - PubMed
4 hours ago
- #glioma-growth-mechanisms
- #AMPA-synapses
- #neuro-glioma-circuit
- Neuronal activity drives growth, invasion, and epileptogenesis in high-grade gliomas (HGGs), particularly IDH-wild-type glioblastoma (GBM).
- Activity-dependent shedding of neuroligin-3 (NLGN3) by ADAM10 generates soluble NLGN3 (sNLGN3), reprogramming glioma cells toward a synapse-competent state through pathways like LYN, PI3K-mTOR, and CSPG4-PIEZO1 signaling.
- Reprogrammed tumor cells assemble calcium-permeable AMPA receptors, form neuron-glioma synapses, receive excitatory input, and propagate calcium waves, amplifying peritumoral hyperexcitability and seizures in a positive feedback loop.
- An 'actionable circuit' framework is proposed, linking neuronal activity, NLGN3-ADAM10 shedding, intracellular signaling, synaptic integration, and network remodeling, with potential circuit-breaking strategies including activity dampening, inhibition of NLGN3 shedding, and AMPA synapse blockade.
- Translational challenges include target selectivity, brain delivery, biomarker development, and adaptive trial design, with circuit-informed interventions potentially complementing standard therapies for activity-driven glioma.