Genes and Dynamics of Memory Systems, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris 75005, France.
Genes and Dynamics of Memory Systems, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris 75005, France
J Neurosci. 2020 May 20;40(21):4219-4229. doi: 10.1523/JNEUROSCI.2311-19.2020. Epub 2020 Apr 17.
In , the mushroom bodies (MB) constitute the central brain structure for olfactory associative memory. As in mammals, the cAMP/PKA pathway plays a key role in memory formation. In the MB, Rutabaga (Rut) adenylate cyclase acts as a coincidence detector during associative conditioning to integrate calcium influx resulting from acetylcholine stimulation and G-protein activation resulting from dopaminergic stimulation. encodes a secreted neuropeptide required in the MB for two phases of aversive olfactory memory. Previous sequence analysis has revealed strong homology with the mammalian pituitary adenylate cyclase-activating peptide (PACAP). Here, we examined whether is involved in cAMP/PKA dynamics in response to dopamine and acetylcholine co-stimulation in living flies. Experiments were conducted with both sexes, or with either sex. Our data show that is necessary for the PKA activation process that results from coincidence detection in the MB. Since PACAP peptide is cleaved by the human membrane neprilysin hNEP, we searched for an interaction between Amnesiac and Neprilysin 1 (Nep1), a fly neprilysin involved in memory. We show that when Nep1 expression is acutely knocked down in adult MB, memory deficits displayed by hypomorphic mutants are rescued. Consistently, Nep1 inhibition also restores normal PKA activation in mutant flies. Taken together, the results suggest that Nep1 targets Amnesiac degradation to terminate its signaling function. Our work thus highlights a key role for Amnesiac in establishing within the MB the PKA dynamics that sustain middle-term memory (MTM) formation, a function modulated by Nep1. The gene encodes a secreted neuropeptide whose expression is required for specific memory phases in the mushroom bodies (MB), the olfactory memory center. Here, we show that Amnesiac is required for PKA activation resulting from coincidence detection, a mechanism by which the MB integrate two spatially distinct stimuli to encode associative memory. Furthermore, our results uncover a functional relationship between Amnesiac and Neprilysin 1 (Nep1), a membrane peptidase involved in memory and expressed in the MB. These results suggest that Nep1 modulates Amnesiac levels. We propose that on conditioning, Amnesiac release from the MB allows, via an autocrine process, the sustaining of PKA activation-mediating memory, which subsequently is inactivated by Nep1 degradation.
在昆虫中，蘑菇体（MB）构成嗅觉联想记忆的中枢脑结构。与哺乳动物一样，cAMP/PKA 途径在记忆形成中起着关键作用。在 MB 中，Rut 腺苷酸环化酶在联想条件作用下充当协同检测，以整合由乙酰胆碱刺激引起的钙内流和由多巴胺能刺激引起的 G 蛋白激活。编码一种分泌神经肽，在 MB 中需要两个厌恶嗅觉记忆阶段。以前的序列分析显示与哺乳动物垂体腺苷酸环化酶激活肽（PACAP）有很强的同源性。在这里，我们检查了是否 参与多巴胺和乙酰胆碱共刺激在活体蝇中对 cAMP/PKA 动力学的影响。实验同时进行了雌雄两性，或仅进行了雄性或雌性。我们的数据表明， 在 MB 中的协同检测导致的 PKA 激活过程中是必需的。由于 PACAP 肽被人类膜神经肽酶 hNEP 切割，我们搜索了 Amnesiac 和 Neprilysin 1（Nep1）之间的相互作用，Nep1 是一种参与记忆的果蝇神经肽酶。我们表明，当 Nep1 在成年 MB 中急性敲低表达时， 突变体显示的记忆缺陷得到挽救。一致地，Nep1 抑制也恢复了 突变体果蝇中正常的 PKA 激活。总之，结果表明 Nep1 将 Amnesiac 靶向降解以终止其信号功能。我们的工作因此强调了 Amnesiac 在建立 MB 内维持中期记忆（MTM）形成的 PKA 动力学中的关键作用，该功能受 Nep1 调节。 基因编码一种分泌神经肽，其表达是蘑菇体（MB）中特定记忆阶段所必需的，MB 是嗅觉记忆中心。在这里，我们表明 Amnesiac 是协同检测引起的 PKA 激活所必需的，这是 MB 整合两个空间上不同的刺激以编码联想记忆的一种机制。此外，我们的结果揭示了 Amnesiac 和 Neprilysin 1（Nep1）之间的功能关系，Nep1 是一种参与记忆并在 MB 中表达的膜肽酶。这些结果表明 Nep1 调节 Amnesiac 的水平。我们提出，在条件作用下，Amnesiac 从 MB 释放出来，通过自分泌过程，维持 PKA 激活介导的记忆，随后被 Nep1 降解失活。
