Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation.
Que Z, Olivero-Acosta M, Robinson M, Chen I, Zhang J, Wettschurack K, Wu J, Xiao T, Otterbacher C, Shankar V, Harlow H, Hong S, Zirkle B, Wang M, Cui N, Mandal P, Chen X, Deming B, Halurkar M, Zhao Y, Rochet J, Xu R, Brewster A, Wu L, Yuan C, Skarnes W, Yang Y. Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation. Journal Of Neuroscience 2024, e2027232024. PMID: 39557580, DOI: 10.1523/jneurosci.2027-23.2024.Peer-Reviewed Original ResearchNeuronal excitabilityHyperexcitable neuronsHuman microgliaCo-cultureVoltage-gated sodium channel Nav1.2Neuronal activityRepetitive action potential firingRodent models of seizuresBrain-resident immune cellsSodium channel expressionInfluence neuronal excitabilityAction potential firingHyperexcitability of cortical neuronsModulates neuronal excitabilityEpilepsy-causing mutationsSodium channel Nav1.2Resident immune cellsAbnormal neuronal activityPresence of microgliaSuppression of seizuresModulate neuronal activityDensity of sodium channelsModels of seizuresPresence of neuronsAxon initial segmentMicroglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids
Wu J, Zhang J, Chen X, Wettschurack K, Que Z, Deming B, Olivero-Acosta M, Cui N, Eaton M, Zhao Y, Li S, Suzuki M, Chen I, Xiao T, Halurkar M, Mandal P, Yuan C, Xu R, Koss W, Du D, Chen F, Wu L, Yang Y. Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids. Molecular Psychiatry 2024, 29: 2424-2437. PMID: 38499656, DOI: 10.1038/s41380-024-02518-4.Peer-Reviewed Original ResearchAutism spectrum disorderSpine densityAssociated with autism spectrum disorderLower spine densitySynaptic transmissionHuman cellsPost-synapseProtein-truncating mutationsNeurodevelopmental disorder affecting 1Phagocytosis of synapsesNeuro-immune responsesImpaired learningIntellectual disabilityNeuro-immune interactionsHuman genetic studiesRestoring synaptic transmissionReduced synaptic transmissionAblation of microgliaSpectrum disorderResident immune cellsHuman cerebral organoid modelCerebral organoidsBrain developmentCerebral organoid modelSCN2A mutations