Phosphoprofile reorganization of the actin binding protein Drebrin during long term depression

Rafaela Pedro Silva¹Till G.A. Mack¹Marieluise Kirchner²Philipp Mertins²Britta Johanna Eickholt¹Patricia Kreis^1*

• ¹Molecular Biology and Biochemistry Institute at Charité - Universitätsmedizin Berlin, Berlin, Germany
• ²Core Unit Proteomics, Berlin Institute of Health (BIH) at Charité and MDC, Berlin, Germany

Drebrin (DBN), an actin-binding protein critical for the structural integrity and function of dendritic spines, is highly phosphorylated at steady state in neurons. Here, we investigate the phosphorylation dynamics of DBN in the context of chemically induced long-term depression (cLTD), a synaptic plasticity model mimicking activity-dependent weakening of synapses. Using biochemical analyses and mass spectrometry analyses, we show that DBN undergoes rapid and robust changes in phosphorylation following cLTD induction. Notably, cLTD triggers a marked decrease in many DBN phosphorylation sites, accompanied by proteolytic cleavage of the protein, suggesting a tightly regulated mechanism linking post-translational modification to structural remodelling of the synapse. Our findings highlight the dynamic regulation of DBN by phosphorylation during synaptic depression and support its potential role as a modulator of activity-dependent synaptic plasticity.