Control of neuronal excitation-inhibition balance by BMP-SMAD1 signalling

• 成果类型: Article
• 署名作者: Okur, Zeynep; Schlauri, Nadia; Bitsikas, Vassilis; Panopoulou, Myrto; Ortiz, Raul; Schwaiger, Michaela; Karmakar, Kajari; Schreiner, Dietmar; Scheiffele, Peter
• 署名单位: University of Basel; Swiss Institute of Bioinformatics; Friedrich Miescher Institute for Biomedical Research; University of Basel; Roche Holding
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5822
• DOI: 10.1038/s41586-024-07317-z
• 发表日期: 2024-05-16
• 页码: 402-409
• 关键词: homeostatic plasticity; neural circuits; roof plate; bmp; parvalbumin; proteins; expression; autism

摘要

Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition, which is essential for neuronal computation 1,2 . Deviations from a balanced state have been linked to neurodevelopmental disorders, and severe disruptions result in epilepsy 3-5 . To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here we identify a signalling pathway in the adult mouse neocortex that is activated in response to increased neuronal network activity. Overactivation of excitatory neurons is signalled to the network through an increase in the levels of BMP2, a growth factor that is well known for its role as a morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of perineuronal nets. PV-interneuron-specific disruption of BMP2-SMAD1 signalling is accompanied by a loss of glutamatergic innervation in PV cells, underdeveloped perineuronal nets and decreased excitability. Ultimately, this impairment of the functional recruitment of PV interneurons disrupts the cortical excitation-inhibition balance, with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signalling is repurposed to stabilize cortical networks in the adult mammalian brain. Signalling by the developmental morphogen BMP2 through the transcription factor SMAD1 has a key role in controlling the glutamatergic innervation of parvalbumin-expressing interneurons and maintaining the balance between excitation and inhibition in the mammalian cortex.