Aversive memories associated with drug withdrawal may contribute to persistent drug seeking. Molecular mechanisms that are critical for aversive memory formation have yet to be elucidated. Recently, we showed in a rat conditioned place aversion (CPA) model that synaptic actin polymerization in the amygdala were required for aversive memory information. Here, we demonstrated that actin polymerization within the amygdala triggered transportation of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) into amygdalar synapses. Increased synaptic Arc/Arg3.1 expression contributed to aversive memory formation by regulating synaptic AMPA receptor (AMPAR) endocytosis, as in vivo knockdown of amygdalar Arc/Arg3.1 with Arc/Arg3.1-shRNA prevented both AMPAR endocytosis and CPA formation. We also demonstrated that conditioned morphine withdrawal led to induction of LTD in the amygdala through AMPAR endocytosis. We further demonstrated that Arc/Arg3.1-regulated AMPAR endocytosis was GluR2 dependent, as intraamygdala injection of Tat-GluR2 3Y , a GluR2-derived peptide that has been shown to specifically block regulated, but not constitutive, AMPAR endocytosis, prevented AMPAR endocytosis, LTD induction, and aversive memory formation. Therefore, this study extends previous studies on the role of actin polymerization in synaptic plasticity and memory formation by revealing the critical molecular events involved in aversive memory formation as well as LTD induction, and by showing that Arc/Arg3.1 is a crucial mediator for actin polymerization functions, and, thus, underscores the unknown details of how actin polymerization mediates synaptic plasticity and memory.
Vascular prostanoids, isomerized from an intermediate prostaglandin (PG), H2, produced by cyclooxygenase (COX), exert various effects on the vascular system, both protective and destructive. During endothelial dysfunction, vascular protector prostacyclin/prostaglandin I2 (PGI2) is decreased, while inflammatory PGE2 and thrombotic TXA2 are increased. Therefore, our research aim was to reverse the event by controlling PGH2 metabolism by generating an in vivo model via enzymatic engineering of COX-1 and prostacyclin synthase (PGIS). The COX-1 and PGIS genes were linked to a 10-residue amino acid linker to form a Single-chain Enzyme Complex (SCHEC), COX-1-10aa-PGIS. Transgenic (CP-Tg) mice in a FVB/N background were generated using the pronuclear microinjection method. We first confirmed mRNA and protein expression of COX-1-10aa-PGIS in various CP-Tg mouse tissues, as well as upregulation of circulating PGI2. We then examined the cardiovascular function of these mice. Our CP-Tg mice exhibited marked resistance to vascular assault through induced carotid arterial blockage, acute thrombotic stroke and arterial arrest, angiotensin-induced peripheral vasoconstriction, and hepatic lipid accumulation after receiving a high-fat diet. They also had a longer lifespan compared with wild-type mice. This study raises the possibility of fighting cardiovascular diseases by regulating cellular arachidonic acid-derived PGH2 metabolites using enzymatic engineering.
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