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The Role of Spontaneous Activity in the Development of Retinal Direction Selectivity
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, ChairOne 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
CaV3.2 KO mice have altered retinal waves but normal direction selectivity
Early in development, before the onset of vision, the retina establishes direction-selective responses. During this time period, the retina spontaneously generates bursts of action potentials that propagate across its extent. The precise spatial and temporal properties of these “retinal waves” have been implicated in the formation of retinal projections to the brain. However their role in the development of direction selective circuits within the retina has not yet been determined. We addressed this issue by combining multi-electrode array and cell-attached recordings to examine mice that lack the CaV3.2 subunit of T-type Ca(2+) channels (CaV3.2 KO) because these mice exhibit disrupted waves during the period that direction selective circuits are established. We found that the spontaneous activity of these mice displays wave-associated bursts of action potentials that are altered from control mice: the frequency of these bursts is significantly decreased and the firing rate within each burst is reduced. Moreover, the retina’s projection patterns demonstrate decreased eye-specific segregation in the dLGN. However, after eye-opening, the direction selective responses of CaV3.2 KO DSGCs are indistinguishable from those of wild-type DSGCs. Our data indicate that, although the temporal properties of the action potential bursts associated with retinal waves are important for activity-dependent refining of retinal projections to central targets, they are not critical for establishing direction selectivity in the retina
CaV3.2 KO mice have altered retinal waves but normal direction selectivity
Early in development, before the onset of vision, the retina establishes direction-selective responses. During this time period, the retina spontaneously generates bursts of action potentials that propagate across its extent. The precise spatial and temporal properties of these "retinal waves" have been implicated in the formation of retinal projections to the brain. However, their role in the development of direction selective circuits within the retina has not yet been determined. We addressed this issue by combining multielectrode array and cell-attached recordings to examine mice that lack the CaV3.2 subunit of T-type Ca2+ channels (CaV3.2 KO) because these mice exhibit disrupted waves during the period that direction selective circuits are established. We found that the spontaneous activity of these mice displays wave-associated bursts of action potentials that are altered from that of control mice: the frequency of these bursts is significantly decreased and the firing rate within each burst is reduced. Moreover, the projection patterns of the retina demonstrate decreased eye-specific segregation in the dorsal lateral geniculate nucleus (dLGN). However, after eye-opening, the direction selective responses of CaV3.2 KO direction selective ganglion cells (DSGCs) are indistinguishable from those of wild-type DSGCs. Our data indicate that although the temporal properties of the action potential bursts associated with retinal waves are important for activity-dependent refining of retinal projections to central targets, they are not critical for establishing direction selectivity in the retina