. Behavioral selection relies on the nervous system's interpretation of sensory stimuli. The abrupt absence of a stimulus can be as striking as its sudden presence, yet these stimuli require distinction to guide behavior. Sensory circuits code stimulus onset and offset. These neural signals are split into parallel processing pathways via distinct synaptic structures and physiology. Alterations in synaptic structures are known to underlie sensory processing disorders. However, we lack a mechanistic understanding of how molecular cues establish synaptic configurations that split ON and OFF signals. To fully understand this critical feature of sensory processing and define therapeutic targets, we must identify and characterize the molecular cues that promote the development of synaptic structures that mediate the splitting of ON and OFF signals. We exploit the in vivo accessibility of retinal photoreceptor synaptic terminals. Here, signals coding light onset and offset are split into parallel pathways via structurally and functionally distinct synapses with ON and OFF bipolar cells (BCs), respectively.
We aim to define molecular cues that establish a photoreceptor's synaptic configurations that differentiate light onset from offset. Mutant analysis in zebrafish revealed a novel postsynaptic cue: pregnancy associated plasma protein aa (pappaa). pappaa mutants show impaired visual responses to light offset, but intact responses to light onset, and lack presynaptic structures at cone-OFF BC contacts. Pappaa, a secreted metalloprotease, is a local stimulator of insulin-like growth factor 1 (IGF1) signaling, yet its roles in synaptic development are unknown. We will test the hypothesis that Pappaa stimulates presynaptic IGF1 signaling, and governs the formation and function of cone-OFF BC synapses by regulating a cone terminal's calcium buffering capacity and driving formation of distinct OFF presynaptic glutamate release mechanisms.
In Aim 1, we will define the timing and cell type of Pappaa-IGF1 signaling that is critical for establishing cone-OFF BC synapses. Our results will define whether Pappaa stimulates pre- and/or postsynaptic IGF1 signaling to influence cone presynaptic architecture and whether this pathway supports the development, maintenance, and/or acute function of cone-OFF BC synapses.
In Aim 2, we will define if Pappaa regulates endoplasmic reticulum and mitochondrial-mediated calcium buffering. Our results will define whether Pappaa regulates this process in cones to influence cone-OFF BC synaptic structure and function.
In Aim 3, we will determine the Pappaa-dependent mechanism of glutamate release at cone-OFF BC synapses. Our results are expected to identify a presynaptic structure governed by Pappaa, which underlies a glutamate release mechanism required to convey light offset. Overall, our results will reveal mechanisms by which a single neuron organizes distinct presynaptic domains to split signals coding stimulus onset and offset.

Public Health Relevance

To appropriately guide behavior, an animal's nervous system must accurately interpret sensory information in the surrounding environment. Sensory processing deficits are a hallmark of prevalent behavioral disorders, including schizophrenia, autism, and substance abuse. Our research aims to define the molecular pathways that establish neural circuit structures and functions that underlie sensory processing with the long-term goal of identifying therapeutic approaches for disorders marked by sensory processing impairment.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Greenwell, Thomas
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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