INTRODUCTION: Brg1 is an ATP-dependent catalytic subunit of the BAF chromatin remodeling complex. It impacts gene expression, stimulates DNA repair, facilitates RNA processing, and contributes to neuron development and synaptic activity. Through mass spectrometry analysis, we identified Brg1 as one of the nuclear interactors of the mTOR. mTOR plays a pivotal role in cellular metabolism and growth across diverse cell types. Dysregulation of mTOR has been implicated in mTORopathies, including TSC and epilepsy.

AIM(S): Our study aimed to investigate the nuclear mTOR–Brg1 interaction and its implications for neuronal development and disease.

METHOD(S): Primary neuronal culture, human-derived iPSCs, Western blots, immunofluorescence staining, calcium imaging, RNA-seq analysis

RESULTS: Using in vitro cultured rat neurons, our data confirmed an increased nuclear mTOR-Brg1 interaction following kainic acid (KA) treatment, highlighting mTOR-induced phosphorylation of Brg1. We observed that modulation of mTOR and the proteasome influenced the Brg1 nuclear presence, suggesting proteasome-mediated degradation of Brg1 in the nucleus upon KA treatment. Consistent with these findings, the downregulation of Brg1 expression was noted upon TSC2 loss, resulting in mTOR hyperactivation in neurons. Ca²⁺ imaging and network analysis revealed strong similarities between neurons lacking TSC2 and those deficient in Brg1. However, further investigation demonstrated that their synaptic parameters differed, and the RNA-seq analysis revealed involvement of different gene programs.

CONCLUSIONS: These observations suggest that although network activity is increased upon TSC2 and Brg1 loss, Brg1 and TSC2 largely regulate distinct transcriptional programs. Collectively, these findings provide new insights into the nuclear functions of mTOR in neurons, particularly in regulating Brg1 stability and activity.

FINANCIAL SUPPORT: The research was financed under the NCN MAESTRO grant 2020/38/A/NZ3/00447.