Abstract
Reconsolidation has been considered a process in which a consolidated memory is turned into a labile stage. Within the reconsolidation window, the labile memory can be either erased or strengthened. Manipulating acid-sensing ion channels (ASICs) in the amygdala via carbon dioxide (CO2) inhalation enhances memory retrieval and its lability within the reconsolidation window. Moreover, pairing CO2 inhalation with retrieval bears the reactivation of the memory trace and enhances the synaptic exchange of the calcium-impermeable AMPA receptors to calcium-permeable AMPA receptors. Our patch-clamp data suggest that the exchange of the AMPA receptors depends on the ubiquitin-proteasome system (UPS), via protein degradation. Ziram (50 µM), a ubiquitination inhibitor, reduces the turnover of the AMPA receptors. CO2 inhalation with retrieval boosts the ubiquitination without altering the proteasome activity. Several calcium-dependent kinases potentially involved in the CO2-inhalation regulated memory liability were identified using the Kinome assay. These results suggest that the UPS plays a key role in regulating the turnover of AMPA receptors during CO2 inhalation.
Highlights
Being able to predict threats by recollecting fear stimuli is crucial for most animals such that one can behave adaptively to the dangerous environmental situation [1]
Inhibition of ubiquitination prevents Carbon dioxide (CO2) and retrieval‐induced α-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor (AMPAR)‐Excitatory postsynaptic current (EPSC) rectification Protein degradation and synthesis are critically involved in the process of reconsolidation [4, 9]
To further test if the ubiquitinproteasome system (UPS) involves in the CO2 inhalation-induced protein turnover, we measured the rectification of AMPARs after C O2 inhalation and retrieval with Ziram, a ubiquitin E1 ligase inhibitor [22]
Summary
Being able to predict threats by recollecting fear stimuli is crucial for most animals such that one can behave adaptively to the dangerous environmental situation [1]. Our earlier studies demonstrated that transient acidification by exposing animals to CO2 in conjunction with the retrieval cue significantly enhanced labilization of the target memory and more effectively weakened the aversive memory after memory extinction [6]. This regulatory effect was mediated by acid-sensing ion channels (ASICs), non-voltage gated Na+- and Ca2+-permeable. During retrieval, increased rectification suggested that AMPA receptors (AMPARs) switched from Ca2+-impermeable (CI) to Ca2+-permeable (CP) to promote neuroplasticity, and C O2 inhalation during retrieval augmented the exchange of AMPA receptors and further energized Ca2+ influx [7]. Adding CO2 to retrieval in ASIC1a−/− mice failed to increase rectification [6]
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