Activity-Dependent Suppression of Synaptic Strength in the Mouse Hippocampus

Abstract

This thesis focuses on understanding how synapses are weakened, which represents the cellular basis for information erasure within the brain. In Project 1, age-dependent changes in mechanisms supporting “depotentiation,” an activity-dependent weakening of recently strengthened synapses, was assessed in aged mice. Ageing is associated with exaggerated forgetting, which may be due to impaired memory consolidation or rapid degradation of recently generated memories.

Memory consolidation is regulated by neuromodulators, neurochemicals that modify the ability of synapses to undergo activity-dependent changes. Noradrenaline is a neuromodulator secreted during arousal and novelty detection which boosts long-term potentiation (LTP). Accordingly, I sought to determine if 1) depotentiation is altered in aged hippocampus synapses and 2) if noradrenaline provides immunity against depotentiation during ageing. I found that aging increases the temporal window for depotentiating synapses which was reversed by treating aged brain slices with noradrenaline. Mechanistically, noradrenaline prevented depotentiation through activation of beta-adrenergic receptors and recruitment of protein synthesis, suggesting that activating beta-adrenergic receptors reverses aged-related synaptic deficits through boosting translation.

In Project 2, I further explored how synapses are weakened through characterizing an alternative form of synaptic depression: the phenomenon of LTP decay. LTP is a leading cellular model for the synaptic changes that encode memories. However, not all forms of LTP last, and there is growing evidence that intrinsic neuronal mechanisms actively oppose synaptic potentiation. In this study, I probed how gains in synaptic strength during potentiation are actively reversed. My approach was to block select cellular signals after inducing LTP, when synaptic strength “decays” or returns back to baseline.

Using this strategy, I discovered that LTP decays in an activity-dependent manner, which requires extrasynaptic GluN2B-containing NMDA receptors and downstream recruitment of Rac1. Interestingly, inhibition of Rac1 facilitated the recruitment of ERK and converted decaying LTP into an enduring, translation-dependent form. These findings suggest that intrinsic mechanisms within the hippocampus may actively promote forgetting by recruiting Rac1-mediated signaling pathways that suppress parallel molecular pathways that normally promote memory consolidation. Taken together, this thesis revealed novel cellular processes that actively reduce synapse potentiation, providing new insights into the neural basis for forgetting.