To process information the brain is constantly changing the strength of the individual contacts (synapses) between nerve cells. Strict control of synaptic plasticity is important, as deregulation of this process is often associated with neurological and psychiatric disorders. The main goal of the lab is to advance our understanding of the mechanisms that support synaptic plasticity and their dysfunction in disorders such as Alzheimer´s, schizophrenia and autism to eventually be able to provide novel therapeutic targets.
The two main research areas are:
1. Presynaptic mechanisms of synaptic plasticity
Both pre- and postsynaptic mechanisms can contribute to changes in synaptic strength. We focus on presynaptic mechanisms by studying the function of key proteins of the synaptic vesicle release machinery, their interactors and downstream effectors of second messenger systems like DAG and calcium both in wildtype and disease modelsystems. One important goal is to understand the role of posttranslational modifications of presynaptic proteins (via kinases and Ubi/SUMOylation) in the dynamics of synaptic transmission.
2. Secretory vesicle dynamics and release
In addition to synaptic vesicles, neurons contain large dense-core vesicles that store and release many different types of neuromodulatory cargo. We study the molecular mechanisms that transport and recruit these vesicles to the plasma membrane, their calcium dependent release and the effect of secreted cargo on synaptic plasticity.
We use optical techniques (wide-field, 2-photon and TIRFM) in combination with electrophysiology to monitor synapse activity and activity-dependent transport, capture and release of secretory vesicles in neurons both in vitro and in vivo.
Please see also: http://cncr.nl/people/staff_s-t/toonen_rfg
5 Selected Publications
Spangler SA., Schmitz SK., Kevenaar JT., de Graaff E., de Wit H., Demmers J., Toonen RF., Hoogenraad CC. (2013) Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission. J Cell Biol., 201 (6): 915-28.
van de Bospoort R., Farina M., Schmitz SK., de Jong A., de Wit H., Verhage M., and Toonen RF. (2012) Munc13 controls the location and efficiency of dense-core vesicle release in neurons. J Cell Biol., 199 (6): 883-91.
de Wit J., Toonen RF., and Verhage M. (2009) Matrix-dependent local retention of secretory vesicle cargo in cortical neurons. J Neurosci., 29 (1): 23-37.
Verhage M., and Toonen RF. (2007) Munc18-1 in secretion: lonely Munc joins SNARE team and takes control. Trends Neurosci., 30 (11): 564-72.
Toonen RF., Wierda K., de Wit H., Brussaard AB., Verhage M. (2007) Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity. Neuron., 54 (2): 275-90.