A role for autophagy in long‐term spatial memory formation in male rodents

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The formation of memory is initiated by learning‐related increases in neural activity. Enhanced activity causes the release of neurotransmitters, which engage post‐synaptic receptors to alter intracellular second messenger signaling (Atkins, Selcher, Petraitis, & Trzaskos, & Sweatt, 1998; Bibb, Mayford, Tsien, & Alberini, 2010; Chen et al., 2011; Kandel, Dudai, & Mayford, 2014; Park et al., 2014; Zhang et al., 2013). A large body of evidence indicates that these second messenger signaling molecules elicit covalent modifications of existing proteins that underlie short‐term memory (memories lasting minutes to hours; Giese & Mizuno, 2013; Roberson & Sweatt, 2001; Sweatt, 2016). Long‐term memory (memories lasting for days‐to‐weeks and longer), by comparison, is dependent on gene expression and protein synthesis that enhance the efficacy of specific neuronal circuit(s) by causing enhanced neurotransmitter release and morphological changes (e.g., formation of new synaptic connections; Abel & Klann, 2013; Alberini, 1999; Alberini & Kandel, 2015; Bailey, Kandel, & Harris, 2015; Knierim, 2015; Runyan & Dash, 2004; Sacktor, 2012; Sekeres, Neve, Frankland, & Josselyn, 2010). Available amino acids, lipids, and other molecules are used as building blocks for these changes. These materials exist in readily accessible pools or can be derived from existing proteins (and/or organelles). Existing proteins are primarily degraded by two intracellular catabolic systems, proteasomal degradation, and autophagy. The proteasome system degrades cellular proteins that have been tagged by ubiquitin. Previous studies have demonstrated the role of proteasome activity in memory formation in Aplysia and in rodents (Chain, Schwartz, & Hegde, 1999; Hegde et al., 1997; Lopez‐Salon et al., 2001). Autophagy is a lysosome‐dependent degradation process that helps to maintain cellular homeostasis by degrading damaged or improperly folded proteins and protein aggregates. In addition, dysfunctional organelles such as mitochondria are also degraded and the proteins, lipids, and nucleotides recycled. However, the role of autophagy in memory formation has not been examined.
It has been demonstrated that impaired autophagic machinery can lead to the accumulation/aggregation of intracellular proteins and damaged organelles causing neurodegeneration (Lionaki, Markaki, Palikaras, & Tavernarakis, 2015; Menzies, Fleming, & Rubinsztein, 2015; Rubinsztein, 2006). Three types of autophagy have been identified: chaperone‐mediated autophagy, microautophagy, and macroautophagy (Todde, Veenhuis, & van der Klei, 2009). Chaperone‐mediated autophagy targets specific proteins (e.g., proteins containing KFERQ motifs) directly into the lysosome for degradation. It is thought that this process is activated during starvation and degrades proteins not critical for survival. Microautophagy involves the direct engulfment of cellular components by the lysosomes for degradation and is thought to play a role in recycling amino acids and other molecules. Macroautophagy (referred to hereafter as simply autophagy) is a regulated process that involves the formation of autophagosome, a double membrane vesicle that grows around and encapsulates cytoplasmic contents, including protein aggregates and damaged organelles. Autophagosome then fuse with endosomes and lysosomes, leading to degradation of the captured material.
Autophagy is initiated by dephosphorylation of Unc‐51‐like autophagy activating kinase 1 (Ulk‐1), and is suppressed by the phosphorylation of Ulk‐1 by the target of rapamycin complex 1 (TORC1). Dephosphorylated Ulk‐1 leads to the nucleation and assembly of the initial phagophore membrane by the Beclin 1‐class III phosphatidylinositol 3‐kinase (class III PI3K) complex (Hara et al., 2008; Nazarko & Zhong, 2013). The expansion and closure of the autophagosome is dependent on multiple proteins, including phosphatidylethanolamine‐conjugated LC3 (LC3‐II), which is generated from the cytosolic precursor LC3‐I. The number of autophagosomes has been shown to correlate with the generation of LC3‐II, and its levels have been widely used as a surrogate marker of autophagosome formation (Kabeya et al., 2000).
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