Year: 2019
Type: dissertation
Abstract: Synaptic plasticity is the activity-dependent structural and functional modulation of the synapse, which is essential for learning and memory. These processes are regulated by signaling pathways involving cAMP and cGMP nucleotide messengers. cAMP signaling is associated with enhanced synaptic structure, function and memory at the hippocampus, but the exact role of cGMP remains elusive. Here, I use a novel optogenetic approach to study the role of cGMP in structural and functional plasticity in hippocampal neurons and memory in the dentate gyrus (DG). Strong synaptic activation induces synapse enlargement called structural long-term potentiation (sLTP), which is further enhanced by cAMP (cAMP-sLTP). By blocking the cGMP/PKG pathway, I demonstrated that postsynaptic cGMP signaling negatively regulates cAMP-sLTP. Using a two-photon optogenetic approach to activate a light-sensitive guanylyl cyclase at targeted dendritic spines, I revealed that an increase in postsynaptic cGMP was sufficient to suppress the cAMP effect on structural potentiation, but not induction of sLTP, suggesting a competitive bidirectional regulation of structural plasticity by cAMP and cGMP. To address the role of cGMP in synaptic plasticity and memory, I adapted the optogenetic technique to manipulate cGMP signaling in neurons of the DG, which is crucial for memory. I demonstrated that postsynaptic cGMP signaling at the perforant path synapses of the dentate gyrus (PP-DG) enhances functional synaptic potentiation. By utilizing a comprehensive battery of tests for mouse behavior, I also revealed that cGMP signaling is associated with enhanced anxiety and reference memory in mice. This project established a novel optogenetic technique for targeted cGMP manipulation and provided the first direct look at cGMP function from the level of the single synapse to the living mouse brain.
Source: TSpace (University of Toronto)
Author: Jelena Borovac
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2958478601