Pi4KIIα Regulates Unconditioned Stimulus-Retrieval-Induced Fear Memory Reconsolidation through Endosomal Trafficking of AMPA Receptors

Abstract

Targeting memory reconsolidation is an effective intervention for treating posttraumatic stress disorder (PTSD). Disrupting unconditioned stimulus (US)-retrieval-induced fear memory reconsolidation has become an effective therapeutic approach to attenuate fear memory, but the underlying molecular mechanisms remain unknown. Here, we report that US-retrieval-dependent increase in phosphatidylinositol 4-kinase IIa (Pi4KIIa) promotes early endosomal trafficking of AMPA receptors, leading to the enhancement of synaptic efficacy in basolateral amygdala (BLA) neurons. The inhibition of Pi4KIIa by an inhibitor or short hairpin RNA impaired contextual fear memory reconsolidation. This disruptive effect persisted for at least 2 weeks, which was restored by Pi4KIIa overexpression with TAT-Pi4KIIa. Furthermore, the blockade of early endosomal trafficking following US retrieval reduced synaptosomal membrane GluA1 levels and decreased subsequent fear expression. These data demonstrate that Pi4KIIa in the BLA is crucial for US-retrieval-induced fear memory reconsolidation, the inhibition of which might be an effective therapeutic strategy for treating PTSD.

GSK‐3β regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα

“…In particular, it functions in endosomal sorting processes to direct cargo for lysosomal degradation or recycling to the plasma membrane. Interestingly, PI4KIIα was identified as a neuronal GSK‐3β effector regulating the surface expression of AMPA receptors (Robinson et al., 2014) and endosomal trafficking of AMPA receptors during the reconsolidation of fear memory (Guo et al., 2020). In the present study, therefore, we investigated whether PI4KIIα regulates synaptic AMPA receptors.…”

Dendritic spine dynamics in associative memory: A comprehensive review

“…112 Besides, a recent study reported that phosphatidylinositol 4-kinase IIa (Pi4KIIa) Knockdown disrupted US retrieval-induced contextual fear memory reconsolidation and abolished the USretrieval-induced increase in synaptic transmission in the BLA. 95 Consistently, depletion of Pi4KIIa inhibited chemical LTP and induced a mild decrease in AMPARmediated synaptic transmission in cultured hippocampal neurons. Silencing of Pi4KIIIa (a type III phosphatidylinositol 4-kinase) expression in the hippocampal CA1 region abolished chemical LTP and caused severe impairment of long-term contextual fear memory.…”

“…90,93,94 US retrieval significantly increased spine density and synaptic transmission in rat basolateral amygdala (BLA) (Figure 2). 95 Besides, US retrieval led to differential changes in spine morphology. Golgi staining revealed that US retrieval increased the density of mushroom and thin spines, whereas the density of stubby and branched spines remained unchanged.…”

“…76 All the studies above have revealed that learninginduced dendritic spine formation seems vital to the F I G U R E 2 Model of dendritic spine dynamics underlying the processing of associative memory (e.g., fear memory) in the brain. On the one hand, the acquisition of fear memory results in a remarkable increase in spine density in the hippocampus (red line), 74,78 basolateral amygdala (yellow line), 95 and auditory cortex (red line). [69][70][71][72] On the other hand, auditory-cued fear conditioning seems to induce spine elimination in the motor cortex (green line) 79 and frontal association cortex (green line).…”

“…Golgi staining revealed that US retrieval increased the density of mushroom and thin spines, whereas the density of stubby and branched spines remained unchanged. 95 Thus, dendritic spine changes may provide a structural basis for the highly dynamic destabilizationrestabilization process.…”