Plasticity mechanisms for the developmental acquisition of strong inhibitory synapses in the auditory brainstem

• Applicant: Professor Dr. Ralf Schneggenburger
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 218326203

We propose to investigate the plasticity mechanisms which lead to an activity-dependent refinement of inhibitory synapses in the lateral superior olive (LSO). The LSO is one of the first nuclei in the CNS auditory brainstem which integrates information from both ears. Excitation arising from bushy cells of the cochlear nucleus on the same brain side is integrated with inhibition from the ipsilateral medial nucleus of the trapezoid body (MNTB); the latter signal sounds from the opposite side of the head. It has been known that immature MNTB - LSO inhibitory synapses release the neurotransmitters glutamate and GABA before switching to glycine later in development. MNTB - LSO synapses undergo a marked process of synapse elimination, and strengthening of the remaining synapses during development; this synaptic refinement depends on spontaneous activity before hearing onset in rodents. Here, we propose to study the plasticity mechanisms which might induce developmental refinement of the MNTB - LSO inhibitory synapse. Our main hypothesis is that glutamate release from immature inhibitory synapses, together with activity at the excitatory VCN - LSO synapses, causes associative long-term potentiation of inhibitory synapses (iLTP). We will use electrophysiological measurements in an in-vitro approach (brain slices), coupled with state-of-the art conditional genetic inactivation of floxed alleles in mice, and with optogenetic techniques to stimulate selective sets of synapses, to investigate this hypothesis. Specifically, we will ask whether NMDA-receptors, which mediate classical associative long-term plasticity at cortical and hippocampal excitatory synapses, are necessary for the developmental refinement of MNTB - LSO inhibitory synapses. We will also test the role of phasic transmitter release driven by the presynaptic Ca2+ sensor protein Synaptotagmin-1 (Syt1) in this process. These experiments have the potential to show how use-dependent plasticity shapes the refinement of morphological and functional properties of synapses, to adapt these to their function in specific neuronal circuits.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1608: Ultrafast and Temporally Precise Information Processing: Normal and Dysfunctional Hearing
• International Connection: Switzerland