Impact of dendritic inhibition on neuronal excitation and plasticity

• Applicant: Dr. Stefan Passlick
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 313929909

Signal processing in the mammalian brain is based on the balance between excitation and inhibition. Pyramidal neurons, the principle cells of the neocortex and hippocampus, receive the majority of excitatory and inhibitory synaptic inputs on their branched projections, called dendrites. However, our knowledge on how these signals interact along the dendrites is sparse and mainly based on theoretical assumptions. Early studies proposed that inhibition is highly local and most effective when placed "on-path" between the excitatory input and the soma of the cell. In contrast, more recent theoretical work suggested that due to the electrotonic properties of neuronal dendrites, more distal "off-path" inhibition is more powerful. In addition, it was proposed that inhibitory synapses may act cooperatively inducing a larger inhibitory effect centrally than at the inhibitory sites themselves. This might enable a few well-positioned inhibitory synapses to decouple an entire dendritic subregion from the soma. Other observations indicated that inhibition might regulate spike-timing-dependent plasticity, a form of synaptic plasticity that depends on the exact timing of pre- and postsynaptic activity.However, experimental studies trying to test these assumptions yielded inconsistent results so far. This is mainly attributable to a lack of appropriate techniques allowing the necessary spatial and temporal manipulation of physiological excitatory and inhibitory signals. Also, inhibitory synapses are difficult to identify.Within the scope of this research program, we will employ a recently developed technique, called two-color two-photon uncaging of neurotransmitters, which enables the precise activation of excitatory and inhibitory synapses in any spatiotemporal configuration. To identify inhibitory synapses, we will apply novel techniques allowing the fluorescent labeling of their pre- or postsynaptic structures. By combining these new tools with electrophysiological recordings in acute brain slices, we will be able to experimentally test the following hypotheses:(i) "Off-path" inhibition is more effective at dampening excitation than "on-path" inhibition.(ii) Multiple inhibitory synapses on adjacent dendritic branches act cooperatively exerting a larger inhibitory effect centrally than locally.(iii) A few inhibitory synapses are able to regulate branch-specificity of spike-timing-dependent plasticity.By using state-of-the-art optical and electrophysiological techniques our results are expected to considerably advance our knowledge of the interplay between excitation and inhibition and its effect on synaptic plasticity. The significance of understanding these processes is emphasized by recent results demonstrating the importance of dendritic inhibition in sensation, learning and memory and its involvement in neurological diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Graham Ellis-Davies