The processing of light information by retinal circuits depends critically on the interplay between excitatory and inhibitory neurotransmission. The output of retinal ganglion cells (RGCs) to higher visual centers is shaped by a balance of excitation and inhibition provided by their presynaptic partners, bipolar cells and amacrine cells. Direct inhibition onto RGCs and feedback inhibition onto presynaptic bipolar cells contribute to the final output profile of the RGCs. Previously, we examined how excitatory synapses are established at appropriate densities across the dendritic arbor of RGCs during development and discovered that perturbation of excitatory transmission from bipolar cells results in a reduction in glutamatergic synapses on RGC dendrites. Here, we propose to test the hypothesis that neurotransmission during development regulates the development of inhibitory inputs onto RGCs, and coordinates the maturation of the balance of excitation and inhibition onto these cells. We will also test the hypothesis that transmission influences the development of feedback inhibition onto the axon terminals of the bipolar cells.
In Aim 1, we will determine the mature organization of inhibitory synapses onto RGC dendrites and examine how these patterns arise during development. This will be achieved using confocal and multiphoton imaging of RGCs with fluorescently tagged inhibitory postsynaptic sites. These experiments are needed to reveal the spatial and temporal relationships of the development of inhibitory and excitatory synapses on the dendrites of individual RGCs.
In Aim 2, we will directly test the hypothesis that neurotransmission regulates inhibitory synapse development on RGCs using transgenic mice in which either glutamatergic or GABAergic transmission is markedly suppressed.
In Aim 3, we will determine how feedback inhibition onto rod bipolar cells develop and ascertain the role of neurotransmission in the assembly of this synapse using the transmission-perturbed mice. Taken together, the results from these aims will advance our knowledge of how inhibitory circuits in the inner retina develop, and help define the role(s) of neurotransmission in attaining the proper wiring of retinal circuits or their miswiring in injury and disease.
Vision requires that nerve cells in the retina form the appropriate circuitry during development. Failure to do so leads to abnormal vision and often blindness. Our proposed studies will unravel the importance of neuronal activity during development in ensuring that retinal circuits develop the correct balance of excitation and inhibition. Such a balance is critical for shaping the output signals of the retina that are relayed to visual centers in the brain. Alterations in excitation and inhibition can also lead to disease. Collectively, findings from this project will provide important insights into how retinal circuits wire up normally and what cellular strategies may be required for rewiring after injury or disease.
|Bleckert, Adam; Zhang, Chi; Turner, Maxwell H et al. (2018) GABA release selectively regulates synapse development at distinct inputs on direction-selective retinal ganglion cells. Proc Natl Acad Sci U S A 115:E12083-E12090|
|Gamlin, Clare R; Yu, Wan-Qing; Wong, Rachel O L et al. (2018) Assembly and maintenance of GABAergic and Glycinergic circuits in the mammalian nervous system. Neural Dev 13:12|
|Ge, Yuan; Kang, Yunhee; Cassidy, Robert M et al. (2018) Clptm1 Limits Forward Trafficking of GABAA Receptors to Scale Inhibitory Synaptic Strength. Neuron 97:596-610.e8|
|Zhang, Chi; Kolodkin, Alex L; Wong, Rachel O et al. (2017) Establishing Wiring Specificity in Visual System Circuits: From the Retina to the Brain. Annu Rev Neurosci 40:395-424|
|Gore, Bryan B; Miller, Samara M; Jo, Yong Sang et al. (2017) Roundabout receptor 2 maintains inhibitory control of the adult midbrain. Elife 6:|
|Sinha, Raunak; Hoon, Mrinalini; Baudin, Jacob et al. (2017) Cellular and Circuit Mechanisms Shaping the Perceptual Properties of the Primate Fovea. Cell 168:413-426.e12|
|Vlasits, Anna L; Morrie, Ryan D; Tran-Van-Minh, Alexandra et al. (2016) A Role for Synaptic Input Distribution in a Dendritic Computation of Motion Direction in the Retina. Neuron 89:1317-1330|
|Chozinski, Tyler J; Halpern, Aaron R; Okawa, Haruhisa et al. (2016) Expansion microscopy with conventional antibodies and fluorescent proteins. Nat Methods 13:485-8|
|Moore-Dotson, Johnnie M; Beckman, Jamie J; Mazade, Reece E et al. (2016) Early Retinal Neuronal Dysfunction in Diabetic Mice: Reduced Light-Evoked Inhibition Increases Rod Pathway Signaling. Invest Ophthalmol Vis Sci 57:1418-30|
|Hoon, Mrinalini; Sinha, Raunak; Okawa, Haruhisa et al. (2015) Neurotransmission plays contrasting roles in the maturation of inhibitory synapses on axons and dendrites of retinal bipolar cells. Proc Natl Acad Sci U S A 112:12840-5|
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