ORCID
https://orcid.org/0000-0002-9170-4403
Concentration/Secondary Program
Neurosciences
Language
English (en)
Date of Award
12-15-2026
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Chair and Committee
Martha Bagnall
Committee Members
Timothy Holy, Daniel Kerschensteiner, Takeshi Yoshimatsu, Philip Williams
Abstract
Vision depends on retinal circuits that transform light into parallel representations of distinct features in the visual environment. These representations are shaped both by the molecular mechanisms that establish pathway-specific synaptic connectivity and by local computations that regulate how signals are integrated within neuronal arbors. This thesis investigates how these mechanisms organize feature-selective signaling in the mouse retina and how they influence neural and behavioral responses to approaching visual threats.
We first reveal a molecular mechanism that establishes the retinal OFF pathway at the first synapse of vision. Parallel ON and OFF pathways originate at cone photoreceptor synapses, where cones form spatially and functionally distinct connections with ON and OFF bipolar cells. We identify LRFN2 as a cone-expressed cell-adhesion molecule that localizes to basal contacts with OFF bipolar-cell dendrites. We show that LRFN2 stabilizes these contacts and trans-synaptically organizes ionotropic glutamate receptor clusters, thereby establishing excitatory transmission in the OFF pathway. Loss of LRFN2 abolishes direct dendritic excitation of OFF bipolar cells while largely preserving ON-pathway connectivity. Despite this loss, OFF bipolar cells retain contrast-dependent glutamate output through ON-driven axonal inhibition, revealing complementary contributions of dendritic excitation and inhibitory interactions between parallel pathways. We further show that disrupting LRFN2 weakens retinal responses to looming stimuli and visually evoked defensive behavior, linking molecular organization at the cone synapse to downstream threat detection.
We then dissect how postsynaptic inhibition controls local dendritic processing and sensory gain in VGluT3-expressing amacrine cells (VG3 ACs). VG3 dendrites maintain distinct representations of contrast polarity across retinal depth and object position across their lateral extent. Using cell-specific CRISPR/Cas9 editing, conditional genetic manipulations, two-photon calcium imaging, electrophysiology, and computational modeling, we show that postsynaptic GABAergic inhibition restricts signal propagation within VG3 dendrites and maintains both vertical and lateral compartmentalization. Loss of this inhibition shifts dendritic processing from local toward more global integration and increases contrast sensitivity. Computational modeling further links these effects by showing that reducing dendritic inhibition broadens signal propagation within the arbor and increases response gain, connecting the spatial scale of dendritic integration to contrast sensitivity. We further show that altered VG3 dendritic processing reshapes downstream retinal signaling: W3 retinal ganglion cells develop enlarged receptive fields, whereas transient OFF alpha ganglion cells acquire abnormal ON input. Across VG3 ACs and their downstream ganglion-cell pathways, loss of postsynaptic GABAergic inhibition increases sensitivity to looming contrast. At the behavioral level, these mice show increased sensitivity to low-contrast looming stimuli, with greater escape probability, shorter response latency, and increased escape vigor. Preferentially retina-restricted recombination reproduces this phenotype, whereas optomotor response measurements show unchanged contrast sensitivity, indicating that VG3-dependent gain control selectively regulates looming-related defensive behavior rather than producing a general increase in visual sensitivity.
Together, these findings reveal how retinal computations are organized across multiple scales, from pathway-specific synapse formation to inhibitory control of dendritic integration. We discover that LRFN2 establishes the molecular architecture of the OFF pathway, while postsynaptic GABAergic inhibition sets the spatial scale and gain of local dendritic processing in VG3 ACs. Together, these mechanisms shape how feature-selective signals are constructed, transmitted through retinal circuits, and translated into visually guided behavior.
DOI
https://doi.org/10.48765/3721-n830
Recommended Citation
Lin, Chin-I, "Synaptic Organization and Dendritic Computation in Retinal Visual Processing" (2026). WUSM Theses and Dissertations – All Programs. 64.
https://digitalcommons.wustl.edu/all_etd/64
