Molecular signals controlling structural and functional integrity of synapses

The majority of excitatory synapses in the central nervous system (CNS) communicate through small membranous protrusions that arise from the dendritic shaft of the postsynaptic. These dendritic spines achieve their complex dynamic behaviour and morphological diversity by engaging thousands of proteins that instruct the filamentous (F) actin-rich network. Beyond providing the structural foundation of dendritic spines, F-actin networks also supply scaffolding for post-synaptic proteins and allow the trafficking of different receptors to ensure synaptic plasticity. Consequently, an intact actin cytoskeleton is essential for long-term changes associated with memory formation.

The actin binding protein Drebrin (DBN) regulates cytoskeletal functions during synapse development, and is thought to contribute to structural and functional synaptic changes associated with ageing and Alzheimer’s disease. We recently identified that DBN coordinates synaptic stress signalling with cytoskeletal dynamics, via a mechanism involving kinase ataxia-telangiectasia mutated (ATM). An excess of reactive oxygen species (ROS) stimulates ATM-dependent phosphorylation of DBN, which increased DBN stability and accounts for improved stress resilience in dendritic spines. Our combined data indicate an important regulatory function of ATM-DBN in integrating cytosolic ROS-induced signalling with the dynamics of actin remodelling to provide protection from synapse dysfunction. Currently, we investigate the cellular and molecular bases by which the actin cytoskeleton at the postsynapse – more generally – helps to provide protection from synapse dysfunction.

Key Publications

Kreis P, Gallrein C, Rojas-Puente E, Mack TGA, Kroon C, Dinkel V, Willmes C, Murk K, Tom-Dieck S, Schuman EM, Kirstein J, Eickholt BJ. ATM phosphorylation of the actin-binding protein drebrin controls oxidation stress-resistance in mammalian neurons and C. elegans. Nat Commun 2019;10(1):486. DOI:10.1038/s41467-019-08420-w

Willmes CG, Mack TG, Ledderose J, Schmitz D, Wozny C, Eickholt BJ. Investigation of hippocampal synaptic transmission and plasticity in mice deficient in the actin-binding protein Drebrin. Sci Rep 2017;7:42652. DOI:10.1038/srep42652

Patricia Kreis
Dimitra Ranti
Till Mack
Rafaela Pedro Silva
Janine Kirstein (Leibniz Institute of Ageing, Jena)