SAR405, a Highly Specific VPS34 Inhibitor, Disrupts Auditory Fear Memory Consolidation of Mice Via Facilitation of Inhibitory Neurotransmission in Basolateral Amygdala

Background: Autophagy has been demonstrated to play an important role in memory deficits as well as the degradation of neurotransmitter receptors. SAR405 is a newly discovered inhibitor that can specifically inhibit vacuolar sorting protein 34 and prevent autophagosome biogenesis. However, the effects of SAR405 on memory processes remain largely unknown.

Methods: Western blotting, immunofluorescence, and transmission electron microscopy were used to assess the level of autophagy after fear conditioning and SAR405 treatment. Behavioral tests, biotinylation assay, electrophysiology, and co-immunoprecipitation were used to unravel the mechanisms of SAR405 in memory consolidation.

Results: SAR405 infusion into the basolateral amygdala impaired long-term memory through autophagy inhibition. Furthermore, the trafficking of gamma-aminobutyric acid type A receptors (GABARs) following fear conditioning was disrupted by SAR405, and the decreased frequency and amplitude of miniature inhibitory postsynaptic currents induced by fear conditioning were also reversed by SAR405, suggesting that SAR405 disrupted memory consolidation through blockade of the downregulated inhibitory neurotransmission in basolateral amygdala. GABAR-associated protein (GABARAP) and its interaction with GABAR γ2 subunit were found to be upregulated after fear conditioning, and SAR405 could suppress this increased interaction. Moreover, disruption of the GABARAP-GABAR binding by a trans-activating transcriptional activator-GABARAP inhibitory peptide blocked the decrease in surface expression of GABARs and attenuated long-term memory.

Conclusions: The present study suggests that SAR405 can prevent the memory consolidation via intervening autophagy and GABAR trafficking and has a potential therapeutic value for disorders characterized by exaggerated fear memories, such as posttraumatic stress disorder.