Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories.DOI: http://dx.doi.org/10.7554/eLife.22564.001
Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO 2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO 2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca 2+ -impermeable to Ca 2+ -permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories.
Transient receptor potential melastatin 3 channel (TRPM3) is a calcium-permeable nonselective cation channel that plays an important role in modulating glucose homeostasis in the pancreatic beta cells. However, how TRPM3 is regulated under physiological and pathological conditions is poorly understood. In this study, we found that both intracellular and extracellular protons block TRPM3 through its binding sites in the pore region. We demonstrated that external protons block TRPM3 with an inhibitory pH50 of 5.5. whereas internal protons inhibit TRPM3 with an inhibitory pH50 of 6.9. We identified three titratable residues, D1059, D1062, and D1073, at the vestibule of the channel pore that contributes to pH sensitivity. The mutation of D1073Q reduced TRPM3 current by low external pH 5.5 from 62 ± 3% in wildtype to 25 ± 6.0% in D1073Q mutant. These results indicate that D1073 is essential for pH sensitivity. In addition, we found that a single mutation of D1059 or D1062 enhanced pH sensitivity. In summary, our findings identify molecular determinants respionsible for the pH regulation of TRPM3. The inhibition of TRPM3 by protons may indicate an endogenous mechanism governing TRPM3 gating and its physiological/pathological functions.
Primary cilia are mechanosensory organelles that are projected into the lumen of blood vessels. It has been demonstrated that vascular endothelia require primary cilia to sense and transmit external mechanical stimuli into internal biochemical reactions. One of these reactions includes the biosynthesis and release of nitric oxide, which is one of the most potent endogenous vasodilators. This idea has only been investigated in cultured endothelial cells in vitro . Based on this finding, however, a very bold hypothesis is formed to test that abnormal cilia function results in vascular hypertension. Our laboratory has recently generated and obtained several conditional mouse models to specifically study the function and structure of primary cilia in vascular endothelia. These models include 1) mice without cilia function ( Pkd1 or Pkd2 ); 2) mice without cilia structure ( Tg737 or Kif3a ). Our data indicate that mice with abnormal cilia function ( Pkd1 ) or structure ( Tg737 ) show significantly higher systolic (150±19 for Pdgfbcre:Pkd1 flox/flox and 147±10 for Tie2Cre:Tg737 flox/flox vs. 128±9 for wild-type) and diastolic (120±21 for Pdgfbcre:Pkd1 flox/flox and 120±11 for Tie2Cre:Tg737 flox/flox vs. 102±7 for wild-type) blood pressure than the corresponding wild-type mice. Because there is a positive and continuous correlation between blood pressure and cardiovascular diseases, satellite hypotheses are developed to look at the pathophysiological roles of endothelial cilia in cardiac functions and focal vascular diseases in vivo . Our data clearly point towards deteriorating phenotypes in the cardiac muscle, including cardiac fibrosis due to an increased cardiac workload. As a result, a heart-to-body weight ratio was significantly increased by 17 weeks old (0.008 PdgfbCre;Pkd1 f/f vs. 0.006 Pkd1 f/f ).The present study will very likely provide new insights for hypertension and offer advanced scientific understanding of vascular endothelial cilia in other cardiovascular diseases.
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