Development of synaptic inputs in the rat lateral superior olive

Abstract

The developmental refinement of immature neural circuits into mature ones after initial establishment of synaptic connections is critical for nervous system function. During refinement, synapses undergo activity-dependent changes in location, number, as well as strength. The lateral superior olive (LSO), a nucleus in the brainstem, is specialized to compare sound level differences between the two ears. The LSO receives well organized excitatory inputs originating from the ipsilateral ear and inhibitory inputs originating from the contralateral ear and exhibits stereotypical characteristics of development refinement (i.e., elimination of some synapses and strengthening of remaining ones). In addition, the inhibitory input to the LSO undergoes several synaptic changes in neurotransmission, making the LSO a preferable model circuit for studying mechanisms by which immature neural circuits refine. This thesis aimed to tackle two open questions in our understanding of how inputs to the LSO are refined before hearing onset. First, we investigated how early GABA release, presumed to be important for circuit refinement, is regulated in the LSO by studying the expression and function of proteins involved in GABA synthesis and release. Second, we characterized the synaptic ultrastructure of immature inputs to the LSO and examined whether structural changes associated with functional refinement occur at the level of individual synapses. We found that immature inhibitory inputs to the LSO, which release predominantly GABA during the period of refinement, do not rely on canonical forms of GABA synthesis and transport. Furthermore, inputs to the LSO undergo significant growth reflected in the bouton size, mitochondrion number and size, and also vesicle number. Although refinement is typically generalized into elimination and strengthening of synapses, individual circuits may exhibit unique differences in protein expression and function, and changes in synapse ultrastructure, that all influence how the circuit is ultimately optimized for its function.