Current projects

Our current projects involve several proteins and steps in the vesicle cycle:

In the process of neurotransmitter loading of vesicles, we are identifying and characterizing the function of the vesicular glutamate and GABA transporters in determining their role in regulating the neurotransmitter content as well as the release probability of synaptic vesicles.

In the process of vesicle priming and tethering, we have identified Munc13 isoforms essential vesicle priming factors. Surprisingly, these molecules play also a key role in modulating presynaptic plasticity, as different isoforms mediate drastically different short-term plasticity behavior. We are now studying how these two isoforms behave under dynamic release conditions and which parts of the molecules are responsible for activity dependent regulation of priming and release.

We currently study two proteins implicated in regulating calcium triggered release: the candidate calcium sensor of release, synaptotagmin I and the SNARE complex associated Complexins. Neurons lacking either of these proteins show a dramatic decrease in neurotransmitter release efficacy and a poorly timed release time course. We introduce specific mutations in these proteins with the goal to test for the I) Ca2+ sensor hypothesis, II) for the nature of protein and lipid interactions involved in their function, and III) their role in controlling efficiency and time course of neurotransmitter release.

At the postsynapse, we have worked over the years on several structure-function aspects of AMPA- and Kainate receptor, on the mechanism of AMPA receptor assembly, and the interaction of receptor subunits in gating. We are currently studying the molecular basis of heteromeric AMPA receptor assembly and gating. Furthermore, we use engineered AMPA receptors at the synapse to quantify the neurotransmitter concentration profile at the synapse, and how receptor desensitization affects the reliability of synapses.

Our current studies also include research on neurological disorders. Loss of function mutations in the X-linked gene encoding the transcriptional repressor, methyl-CpG binding protein 2 (MECP2) results in the development of Rett syndrome. We propose that MeCP2 dysfunction results in abnormal excitatory-inhibitory neuronal activity. We want to elucidate the physiological and pathophysiological role of MeCP2 expression on central synapse function and synapse formation. We are currently studying the impact of altered MeCP2 expression on synaptic function of glutamatergic and GABAergic central synapses.