Acute FMR1 reduction alters cellular and circuit properties in human cortex

Acute FMR1 reduction in ex vivo human cortical slices increases intrinsic excitability of deep-layer pyramidal neurons and produces network-level population bursts measured by two-photon calcium imaging.

• Why it matters: Mechanistic links between FMR1 loss and cortical function in the human brain are missing, limiting understanding of Fragile X syndrome beyond the Fmr1-/y mouse model.
• What they did: The study acutely reduced FMR1 in human cortical slices, performed transcriptomic profiling, and compared the resulting gene-expression pattern with FXS patient cortex while testing neuronal and network activity using two-photon calcium imaging.
• The result: FMR1 reduction generated transcriptomic changes concordant with FXS patient cortex and identified many targets not altered in the Fmr1-/y mouse model, enabling a human-focused framework to find mechanisms and therapeutic targets.

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