Rapid cAMP signaling regulates the postsynaptic modification underlying synaptic plasticity and memory
Year: 2018
Type: dissertation
Abstract: Understanding how synaptic structure and function is modulated by synaptic activity is essential for elucidating the mechanisms of learning/memory. Here I propose to elucidate a novel role for postsynaptic cyclic AMP (cAMP), a ubiquitous second messenger, in synaptic plasticity and learning by establishing novel cAMP optogenetic techniques. Strong synaptic activation such as LTP (long-term potentiation) or LTD (long-term depression), induce changes in postsynaptic structures (dendritic spines) in a process called structural potentiation. This process is crucial not only for activity-dependent synapse structural changes but also for functional plasticity such as LTP. We previously revealed that the major cytoskeletal protein actin interacts with the abundant postsynaptic enzyme CaMKIIβ (calcium/calmodulin-dependent protein kinase II β subunit), directly regulating dendritic spine structure during plasticity. Furthermore, we found that it also regulates LTP through the activity-dependent dissociation of the CaMKIIβ/actin complex. However, the detailed signalling pathway for regulating this mechanism during plasticity remains elusive. Pharmacological and genetic manipulation of the postsynaptic cAMP pathway revealed that cAMP signaling is essential for synaptic plasticity and memory. However the rapid spatial and temporal functions are not well known due to the lack of techniques to spatiotemporally control signaling activity. To address how postsynaptic cAMP regulates synaptic plasticity and memory, I established optogenetic approaches to spatiotemporally manipulate cAMP amounts by light from the single synapse to the brain region of freely moving mice. Utilizing this technique, combined with two-photon live imaging, electrophysiology, and mouse behavior assays, I demonstrated a novel role for postsynaptic cAMP modulating structural and functional synaptic plasticity and short-term learning. This proposed research, in particular, the non-invasive light-dependent manipulation of cAMP levels ex vivo, could also serve as valuable tools for elucidating the role of cAMP signalling in a broad variety of research fields.
Source: TSpace (University of Toronto)
Author: Thomas T. Luyben
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2885834939