Vesicle Dynamics and Synaptic Plasticity
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 dysregulation 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, epilepsy, schizophrenia and autism to eventually be able to provide novel therapeutic targets.
Presynaptic mechanisms of synaptic plasticity
Both pre- and postsynaptic mechanisms contribute to changes in synaptic strength. We focus on presynaptic mechanisms by studying the function of key proteins of the synaptic vesicle fusion machinery, their interactors and downstream effectors in wildtype and disease model systems. One important goal is to understand the role of posttranslational modifications (phosphorylation, Ubi/SUMOylation) of presynaptic proteins in the dynamics of synaptic transmission.
Secretory vesicle dynamics and release
In addition to synaptic vesicles, neurons contain vesicles that store and release many different types of neuromodulatory cargo (neuropeptides and Neurotrophins o.a.). We study the molecular mechanisms that transport and recruit these vesicles to the plasma membrane, their calcium dependent fusion and the effect of secreted cargo on synaptic plasticity.
We use wide-field, 2-photon and TIRFM microscopy in combination with electrophysiology to monitor synapse activity and activity-dependent transport, capture and release of secretory vesicles in rodent and human iPSC-derived neurons in vitro and in vivo.
van Keimpema L, Kooistra R, Toonen RF#, and Verhage M#. CAPS-1 requires its C2, PH, MHD1 and DCV domains for dense core vesicle exocytosis in mammalian CNS neurons. (2017) Scientific Reports 7(1):10817
Arora S, Saarloos I, Kooistra R, van de Bospoort R, Verhage M, Toonen RF.
SNAP-25 gene family members differentially support secretory vesicle fusion. (2017) J. Cell Sci 130(11):1877-1889.
Emperador Melero J, Nadadhur AG, Schut D, Weering JV, Heine VM, Toonen RF#, Verhage M#. Differential Maturation of the Two Regulated Secretory Pathways in Human iPSC-Derived Neurons. (2017) Stem Cell Reports 8(3):659-672.
Schmitz SK, King C, Kortleven C, Huson V, Kroon T, Kevenaar JT, Schut D, Saarloos I, Hoetjes JP, de Wit H, Stiedl O, Spijker S, Li KW, Mansvelder HD, Smit AB, Cornelisse LN, Verhage M, Toonen RF. Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1. (2016) EMBO J. 35(11):1236-50
Farina M, van de Bospoort R, He E, Persoon CM, van Weering JR, Broeke JH, Verhage M, Toonen RF. CAPS-1 promotes fusion competence of stationary dense-core vesicles in presynaptic terminals of mammalian neurons. (2015) eLife doi: 10.7554/eLife.05438
Cijsouw T, Weber JP, Broeke JH, Broek JAC, Schut D, Kroon T, Saarloos I, Verhage M and Toonen RF. Munc18-1 redistributes in nerve terminals in an activity- and PKC-dependent manner. (2014) J Cell Biol. 204 (5);759–775
Spangler SA, Schmitz SK, Kevenaar JT, de Graaff E, de Wit H, Demmers J, Toonen RF#, and Hoogenraad CC#. Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission. (2013) J Cell Biol. 10;201(6):915-28
van de Bospoort R, Farina M, Schmitz SK, de Jong A, de Wit H, Verhage M, Toonen RF.
Munc13 controls the location and efficiency of dense-core vesicle release in neurons. (2012) J Cell Biol. 199(6):883-91.