The molecular mechanisms of clustered synaptic plasticity: focus on lysosomes

• Applicant: Professorin Dr. Marina Mikhaylova
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259979908

Neuronal synapses form the basis for neuronal communication and the storage of information in brain. The strength and persistence of chemical synapses are tightly regulated and the plastic properties of neighboring dendritic synapses are also determined by molecular and electrical signaling in dendritic segments. Potentiation of a dendritic spine favors the potentiation of its neighbor. In this regard, the dendritic branch forms a perfect compartment for confined signaling. Clustering of co-active synapses has been observed in developing neuronal networks and during acquisition of new memories in adult animals. In the ongoing Emmy Noether Project we want to understand what defines a dendritic segment as a ‘plasticity unit’ and what are the underlying molecular mechanisms of clustered synaptic plasticity. We are currently exploring the involvement of protein sharing in interactions between nearby synapses and the contribution of local dendritic secretory trafficking systems in dendritic compartmentalization. While working on these questions we discovered a specialization of the dendritic actin cytoskeleton, so-called F-actin ‘hot spots’, that surround excitatory shaft synapses or can be found at the base of dendritic spines. These structures turned out to be very critical for regulating organelle transport, including lysosomal trafficking in dendrites: lysosomes frequently stop and stall at these loci. There is increasing interest in lysosomal function in dendrites. Thus, several very recent findings demonstrated that i) dendritic lysosomes can fuse with the plasma membrane in a Ca2+-dependent manner and release cathepsin B that locally activates extracellular protease MMP9; ii) MMP9 proteolytically cleaves the extracellular matrix allowing for spine growth following synaptic potentiation and is also required for maturation of BDNF; iii) BDNF plays an essential role in clustering of active inputs in developing neurons and in synaptic cross talk in mature neurons. This let us to hypothesize that spatially and temporarily controlled lysosomal cathepsin B release could be another critical step required for synaptic clustering and this mechanism could be a common feature in both developing networks and synaptic cross-talk in adult neurons. In the 6th year extension of the Emmy Noether Programm we propose to test the following axis where F-actin stalled lysosomes could release cathepsins into extracellular space near active synapses, cathepsin B would lead to the activation of MMP9, which will cleave ProBDNF allowing for spatially and temporary confined BDNF signalling leading to clustering of synaptic inputs. The validity of this hypothesis could uncover novel mechanisms of synaptic clustering and be relevant for understanding neurological deficiencies in lysosomal storage diseases.

• DFG Programme: Independent Junior Research Groups