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Glutamate AMPA receptors (AMPARs) are major excitatory receptors in the vertebrate CNS. In many biological systems there are changes in the properties of AMPARs during development that are essential for providing an increase in efficiency of information transfer between neurons and a refinement of motor co-ordination and sensory perception and cognition. It is not surprising that improper development or loss of function of AMPARs can lead to many neurological disorders such as epilepsy and amyotrophic lateral sclerosis. Thus, determining the mechanisms by which AMPARs mature is of particular importance. The objectives of my thesis were to characterize the developmental changes in AMPAR-mediated currents in zebrafish Mauthner cells and to determine the mechanisms underlying any changes. The major findings reported in this thesis are that (1) there are developmental changes in the properties of AMPAR-currents as the Mauthner cell matures; (2) the mechanism underlying these changes is a switch in the composition of AMPA receptor subtypes; and (3) PKC is necessary for the developmental switch in AMPAR subtypes from slow receptors to fast receptors. These findings provide valuable insights into the mechanism underlying the development of AMPARs. In addition, they provide the first instance of a signalling link (PKC) required for the developmental subunit switch and the developmental speeding of AMPAR kinetics. / Physiology, Cell Biology and Developmental Biology

<p>The lateral superior olive (LSO) is an auditory brainstem nucleus crucial in the determination of sound source. To accomplish sound localization, principal neurons of the LSO compare the intensity of sounds reaching the two ears by integrating an excitatory input from the ipsilateral anteroventral cochlear nucleus (AVCN), which is activated by sound reaching one ear, with an inhibitory input from the ipsilateral medial nucleus of the trapezoid body (MNTB), which is activated by sound reaching the opposite ear. In order for LSO principal neurons to properly integrate these excitatory and inhibitory inputs, the inputs must be matched in a frequency-dependent matter to LSO neurons. The mechanisms that direct the organization, selection, and maturation of both the excitatory and inhibitory pathway during development are not well understood. The experiments presented in this thesis were aimed at understanding the mechanisms that may underlie these processes in the developing LSO.</p> <p>The excitatory neurotransmitter glutamate is released in both the excitatory AVCN-LSO pathway and the inhibitory MNTB-LSO pathway during their period of functional circuit refinement, and may be important in the development of both of these pathways. Using the patch-clamp technique in acute brainstem slices of rats, we evaluated glutamatergic transmission in both the excitatory AVCN-LSO pathway and the inhibitory MNTB-LSO pathway during their period of functional refinement. Additionally, using the patch-clamp technique in acute brainstem slices of mice, we examined what functions vesicular glutamate transporter 3 (VGlut3), the protein that supports glutamate release from MNTB terminals, may have in the developing MNTB-LSO pathway. When taken together, the results from the three studies presented support a model in which circuit maturation in the LSO relies on mechanisms driven through a specific glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor.</p> / Doctor of Philosophy (PhD)

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