Autophagy Enhances Memory Erasure through Synaptic Destabilization

Abstract

There is substantial interest in memory reconsolidation as a target for the treatment of anxiety disorders, such as post-traumatic stress disorder. However, its applicability is restricted by reconsolidation-resistant boundary conditions that constrain the initial memory destabilization. In this study, we investigated whether the induction of synaptic protein degradation through autophagy modulation, a major protein degradation pathway, can enhance memory destabilization upon retrieval and whether it can be used to overcome these conditions. Here, using male mice in an auditory fear reconsolidation model, we showed that autophagy contributes to memory destabilization and its induction can be used to enhance erasure of a reconsolidation-resistant auditory fear memory that depended on AMPAR endocytosis. Using male mice in a contextual fear reconsolidation model, autophagy induction in the amygdala or in the hippocampus enhanced fear or contextual memory destabilization, respectively. The latter correlated with AMPAR degradation in the spines of the contextual memory-ensemble cells. Using male rats in an LTP reconsolidation model, autophagy induction enhanced synaptic destabilization in an NMDAR-dependent manner. These data indicate that induction of synaptic protein degradation can enhance both synaptic and memory destabilization upon reactivation and that autophagy inducers have the potential to be used as a therapeutic tool in the treatment of anxiety disorders. It has been reported that inhibiting synaptic protein degradation prevents memory destabilization. However, whether the reverse relation is true and whether it can be used to enhance memory destabilization are still unknown. Here we addressed this question on the behavioral, molecular, and synaptic levels, and showed that induction of autophagy, a major protein degradation pathway, can enhance memory and synaptic destabilization upon reactivation. We also show that autophagy induction can be used to overcome a reconsolidation-resistant memory, suggesting autophagy inducers as a potential therapeutic tool in the treatment of anxiety disorders.

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

“…Importantly, autophagy is implicated in neurotransmitter release as well as the internalization and endolysosomal turnover of neurotransmitter receptors beyond GABAergic ones ( Figure 1). For instance, autophagy induction following inhibition of either GSK3β or mTOR regulates dopamine and glutamate release as well as the internalization of glutamate receptors [24,[52][53][54][55]. The latter is associated with a decrease in the amount of intracellular Ca 2+ and reduced excitotoxicity [55][56][57][58], which are key events implicated in seizure-induced neuronal damage ( Figure 1).…”

Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

“…As recently reviewed, dysfunctional autophagy at both pre-and post-synaptic sites leads to aging and neurodegeneration (Nikoletopoulou et al, 2015;Vijayan and Verstreken, 2017;Azarnia Tehran et al, 2018;Liang and Sigrist, 2018). Degradation of postsynaptic neurotransmitter receptors involves trafficking in autophagosomal structures (Rowland, 2006;Shehata et al, 2012Shehata et al, , 2018Hui et al, 2019). At dopaminergic presynaptic sites, autophagy shapes synapse ultrastructure and modulates neurotransmitter release, while at glutamatergic synapses mTOR-regulated autophagy promotes spine pruning during development (Hernandez et al, 2012;Tang et al, 2014).…”

“…In a recent article, selective induction of autophagy at the presynaptic site has been shown to specifically target damaged proteins, thus maintaining synapse integrity and function (Hoffmann et al, 2019). The discovery that neuronal autophagy and formation of APs at synapses are activity dependent (Shehata et al, 2018) suggests that synaptic autophagy may be regulated by long-term synaptic plasticity underlying learning and memory formation. However, whether autophagy stimulates or suppresses memory processes and its relationship with nutrient signaling pathways is still controversial.…”

Neuronal Activity at Synapse Resolution: Reporters and Effectors for Synaptic Neuroscience

“…Therefore, SEP-GluA1 containing spines likely represent the pool of synapses that underwent E-LTP-or received an equivalent physiological stimulation-a subset of those of course may also present L-LTP. Even if GluA2/3 containing synapses have been linked to a later stage of memory, such as consolidation and reconsolidation (Diering and Huganir, 2018;Shehata et al, 2018), it would be unclear then what a SEP-GluA2 (or SEP-GluA3) reporter could represent in terms of synaptic population, since SEP-GluA2 + synapses do not show analogous clustering to SEP-GluA1 + after whisker stimulation (Makino and Malinow, 2011).…”