ABSTRACT

The Role of Spontaneous Activity in the Development of Retinal Direction Selectivity

By

Aaron Michael Hamby

Doctor of Philosophy in Molecular & Cell Biology

University of California, Berkeley

Professor Marla B. Feller, Chair

One of the most fascinating and distinctive features of the nervous system is that a vast number of neuronal cell-types arise from a limited number of precursors to assume a multitude of unique morphological and functional units throughout the brain. Furthermore, this mass of unique cell-types wire together with exquisite precision to form the neural circuits that do much of the work of the mature nervous system. How these highly specific and well-ordered assemblies of neurons achieve their ultimate structure and functional state is therefore one of the most important and challenging questions in modern neurobiology.

The direction selective circuit of the mammalian retina serves as a canonical example of how heterologous cell-types can be arranged in the nervous system to perform complex operations on sensory or synaptic input and transform noisy or mixed signals into specific channels that carry information about the outside world or internal states. How the specific synaptic connections underlying direction selectivity are specified, or how elements of the circuit acquire their unique identities is unclear. Both evoked and spontaneously generated neural activity have been well-documented to shape the assembly of neural circuits in diverse parts of the nervous system. Here, using a combination of multi-electrode array recordings, patch-clamp electrophysiology and anatomical and immunohistochemical techniques we test for a role of spontaneous activity in the development of retinal direction selectivity in mouse.

By developing transgenic mouse lines to identify direction selective ganglion cells for targeted investigation we identify a critical period of inhibitory synapse development crucial to the direction selective responses of these cells that occurs over the second post-natal week, a period dominated by glutamatergic retinal waves. Through the use of pharmacological and genetic manipulations to alter or block these retinal activity patterns we show that manipulations sufficient to disrupt the activity-dependent process of eye-specific segregation have no effect on the emergence of robust direction selective responses, indistinguishable from age-matched wild type controls. These results indicate that spontaneous activity does not play a critical role in the development of the direction selective circuit in retina.