Metaplastic Regulation of Bidirectional Hippocampal Synaptic Plasticity and Memory Disruption in Mice

Speaker: Quinn Brianna Pauli, PhD Candidate
Supervisor: Dr. Rob Bonin
Abstract
Learning and memory retention are foundational to our ability to navigate the world around us. Though often thought of as an unfortunate side effect of memory storage, forgetting serves an equally important role in decision making and behaviour. Inaccurate or irrelevant memories are degraded over time or with experience, while important and emotionally salient memories persist. Within the brain, synapses between neurons associated with a memory (engram synapses) undergo activity-dependent plasticity, rendering the memory accessible in response to relevant cues. This activity-dependent strengthening is referred to as long-term potentiation (LTP), which can be subsequently reversed by low-frequency activity. Depotentiation (DEP) at engram synapses may be a fundamental mechanism of forgetting and memory updating. This thesis aimed to assess the mechanisms of synaptic DEP in different models of learning.
Learning sessions spaced apart in time tend to create longer-lasting memories. Similarly, the temporal spacing of LTP-inducing theta-burst stimulations (TBS) can affect LTP modification including DEP. Mechanistically distinct forms of LTP are induced depending on TBS spacing, yet the overlap or divergence in mechanisms invoked during later plasticity events remains understudied. Using a combination of electrophysiological and immunodetection techniques, I tested whether spaced (s) and compressed (c) LTP induction with TBS administrations separated by 10 minutes or 10 seconds, respectively, affects the mechanisms recruited during subsequent
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plasticity events. I found that DEP of sLTP and cLTP require distinct ion flux-dependent and flux-independent N-methyl-D-aspartate receptor (NMDAR) signaling cascades and downstream mechanisms of plasticity expression. More specifically, DEP recruits additional plasticity signals following sLTP induction. sLTP is also more stable in the face of additional potentiating stimuli compared to cLTP. On a behavioural level, aversive foot shocks spaced apart by 10 minutes in a specific context produces an associative fear memory that is more resilient to later disruption compared to when foot shocks are spaced apart by only 10 seconds.
Taken together, I found that the temporal spacing of learning events or LTP induction affects both the susceptibility and mechanisms invoked during later disruption. This work illustrates the capacity of the synapse to store and integrate activity over time, with broad implications for physiological and pathological forgetting.