Role of spontaneous activity for the development of the giant synapse formed by the calyx of Held and principal neurons of the MNTB

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The calyx of Held is a giant presynaptic terminal in the auditory brainstem. Its specialized structure ensures fast, reliable and secure neurotransmission between globular bushy cells (GBCs) of the cochlear nucleus (CN) and principal neurons of the medial nucleus of the trapezoid body (MNTB). The precise mechanisms which lead to the formation of the calyx and the monoinnervation of MNTB neurons prior hearing-onset are largely unknown. Here, we will investigate the role of spontaneous activity for the development of this synapse. To this end, the tetanus neurotoxin will be expressed in GBCs to block neurotransmission by using the Cre-LoxP and a tetracycline-dependent expression system in a transgenic mouse line. This genetic system will also be used to silence only a subpopulation of GBCs in order to study the role of competitive neuronal activity. To analyse the consequences of neuronal silencing on the formation of the calyx of Held and the postsynaptic structure, immunohistochemistry will be performed with selected marker proteins. In addition, monoinnervation and tonopotic organisation of the projection will be studied by axonal tracing. Taken together, our results will identify the role of (competitive) spontaneous activity for the formation of this giant synapse in the auditory brainstem. This will deepen our knowledge concerning mechanisms of targeted innervation in neuronal systems. In addition, a versatile genetic system will be generated which allows functional analysis of individual genes in GBCs as well as investigations into the role of spontaneous and acoustically driven activity in the auditory brainstem.