Current research

1. Molecular structure and function of central nerve terminals

Synaptic communication between neurons relies on the transfer of all-or-none signals: presynaptic action potentials are translated into graded synaptic currents on the postsynaptic side. Mainly two scaling factors define the efficacy of this translation: the magnitude of the response generated by a single action potential and the frequency-dependent modulation of this translation process. Most synapses respond to repeated action potentials by a transient and short-lasting reduction of synaptic scaling, known as short-term depression (STD). This synaptic filtering has a fundamental impact on neuronal computation. Current evidence suggests that the depletion of synaptic vesicles (SV) and the rate of recruitment of recycled or new SVs to the active zone (AZ) determines the extent of STD at an individual synapse. Therefore, the dynamics of membrane trafficking events control an important parameter of synaptic transmission and neuronal communication. To understand the molecular basis of this process it is crucial to know more about the reactions that translocate synaptic vesicles from the reserve pool to the AZ and prepare them for Ca2+-dependent release of neurotransmitter (NT) quanta. In fact, very little is known about the precise spatio-temporal organization and the identity of protein-protein interactions underlying these processes in neurons.

2. Neuronal chloride signaling imaged with a genetically encoded indicator

The polarity of GABAergic or glycinergic synaptic transmission is controled by the transmembrane gradient of Cl- and the resting membrane potential. At a typical membrane potential of -70 mV, GABA and glycine yield hyperpolarizing responses at low intracellular concentrations of Cl-, but depolarizing responses at high concentrations of Cl-. Hence, the control of intracellular Cl- can have a fundamental influence on GABAergic and glycinergic neurotransmission by defining the polarity of the postsynaptic response. Using Clomeleon, a genetically encoded indicator for Cl-, we study the spatial and temporal distribution of Cl- in hippocampal neurons and the impact of Cl- gradients and local accumulation on GABAergic synaptic transmission. Clomeleon is expressed in selected neuronal subtypes by transgenic or viral techniques. We use quantitative ratiometric confocal and two-photon imaging combined with electrophysiology to study intracellular Cl- dynamics in neurons.

3. From molecules to behavior: neuronal mechanisms of odor discrimination*

Lateral inhibition is a prominent mechanism generating contrast enhancement in sensory systems. In the olfactory system, lateral inhibition is thought to be mediated by a synaptic interaction between mitral cells (MC) and granule cells (GC) of the olfactory bulb. Dendrites of MCs and GCs are connected by the reciprocal synapse, a specialized bidirectional contact capable to act as a receiver and sender of synaptic signals. Thus, glutamate release from MC dendrites can translate into a graded response involving either GABA release from the same terminal (reciprocal inhibition), from nearby ones (local lateral inhibition), or even from all terminals of a GC (global lateral inhibition). The contribution of these mechanisms to odor discrimination in the mouse is only poorly understood. We study the effect of specific molecular manipulations at the reciprocal synapse of GCs on odor discrimination in mice. Acute targeted genetic perturbations (ATGp) will be used to specifically interfere with molecular targets in granule cells of the olfactory bulb. The behavioral consequences of perturbations will be assessed with an odor discrimination test (Abraham et al., 2004). After behavioral testing identified relevant perturbations, the physiological consequences will be examined with electrophysiological and imaging techniques on the level of individual GCs.

* This work is done in collaboration with the WIN-group of olfactory dynamics.