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

Zeynep Okur, Nadia Schlauri, Vassilis Bitsikas, Myrto Panopoulou, Raul Ortiz, Michaela Schwaiger, Kajari Karmakar, Dietmar Schreiner and Peter Scheiffele ()
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Zeynep Okur: University of Basel
Nadia Schlauri: University of Basel
Vassilis Bitsikas: University of Basel
Myrto Panopoulou: University of Basel
Raul Ortiz: University of Basel
Michaela Schwaiger: Swiss Institute of Bioinformatics
Kajari Karmakar: University of Basel
Dietmar Schreiner: University of Basel
Peter Scheiffele: University of Basel

Nature, 2024, vol. 629, issue 8011, 402-409

Abstract: Abstract Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition, which is essential for neuronal computation1,2. Deviations from a balanced state have been linked to neurodevelopmental disorders, and severe disruptions result in epilepsy3–5. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07317-z

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