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Individual differences in the positive outcome from adolescent ketamine treatment in a female mouse model of anorexia nervosa involve drebrin A at excitatory synapses of the medial prefrontal cortex
SYNAPSE ( IF 1.6 ) Pub Date : 2022-09-19 , DOI: 10.1002/syn.22253 Rose Temizer 1 , Yi-Wen Chen 1 , Chiye Aoki 1
SYNAPSE ( IF 1.6 ) Pub Date : 2022-09-19 , DOI: 10.1002/syn.22253 Rose Temizer 1 , Yi-Wen Chen 1 , Chiye Aoki 1
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Anorexia nervosa (AN) is a mental illness with the highest rates of mortality and relapse, and no approved pharmacological treatment. Using an animal model of AN, called activity-based anorexia (ABA), we showed earlier that a single intraperitoneal injection of ketamine at a dose of 30 mg/kg (30mgKET), but not 3 mg/kg (3mgKET), has a long-lasting effect upon adolescent females of ameliorating anorexia-like symptoms through the following changes: enhanced food consumption and body weight; reduced running and anxiety-like behavior. However, there were also individual differences in the drug's efficacy. We hypothesized that individual differences in ketamine's ameliorative effects involve drebrin A, an F-actin-binding protein known to be required for the activity-dependent trafficking of NMDA receptors (NMDARs). We tested this hypothesis by electron microscopic quantifications of drebrin A immunoreactivity at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (GABA-IN) in deep layer 1 of prefrontal cortex (PFC) of these mice. Results reveal that (1) the areal density of excitatory synapses on GABA-IN is greater for the 30mgKET group than the 3mgKET group; (2) the proportion of drebrin A+ excitatory synapses is greater for both PN and GABA-IN of 30mgKET than 3mgKET group. Correlation analyses with behavioral measurements revealed that (3) 30mgKET's protection is associated with reduced levels of drebrin A in the cytoplasm of GABA-IN and higher levels at extrasynaptic membranous sites of PN and GABA-IN; (5) altogether pointing to 30mgKET-induced homeostatic plasticity that engages drebrin A at excitatory synapses of both PN and GABA-IN.
中文翻译：
雌性神经性厌食症小鼠模型青少年氯胺酮治疗的积极结果的个体差异涉及内侧前额叶皮层兴奋性突触的drebrin A
神经性厌食症（AN）是一种死亡率和复发率最高的精神疾病，目前尚无批准的药物治疗方法。使用称为活动性厌食症 (ABA) 的 AN 动物模型，我们之前表明单次腹腔注射氯胺酮剂量为 30 mg/kg (30mgKET)，但不是 3 mg/kg (3mgKET)，具有通过以下改变对青春期女性改善厌食症样症状产生长期影响：增加食物消耗和体重；减少跑步和类似焦虑的行为。然而，药物的功效也存在个体差异。我们假设氯胺酮改善作用的个体差异与drebrin A有关，drebrin A是一种F-肌动蛋白结合蛋白，已知是NMDA受体（NMDAR）的活性依赖性运输所必需的。我们通过电子显微镜定量这些小鼠前额皮质 (PFC) 深层 1 的锥体神经元 (PN) 和 GABA 能中间神经元 (GABA-IN) 的兴奋性突触中的 drebrin A 免疫反应性来测试这一假设。结果表明：（1）30mgKET组GABA-IN上兴奋性突触的面密度大于3mgKET组； (2)30mgKET组的PN和GABA-IN的drebrin A+兴奋性突触比例均大于3mgKET组。与行为测量的相关分析表明，（3）30mgKET的保护作用与GABA-IN细胞质中drebrin A水平降低以及PN和GABA-IN突触外膜位点drebrin A水平升高有关； (5) 共同指出 30mgKET 诱导的稳态可塑性使 PN 和 GABA-IN 的兴奋性突触处的 drebrin A 参与。
更新日期：2022-09-19
中文翻译：
雌性神经性厌食症小鼠模型青少年氯胺酮治疗的积极结果的个体差异涉及内侧前额叶皮层兴奋性突触的drebrin A
神经性厌食症（AN）是一种死亡率和复发率最高的精神疾病，目前尚无批准的药物治疗方法。使用称为活动性厌食症 (ABA) 的 AN 动物模型，我们之前表明单次腹腔注射氯胺酮剂量为 30 mg/kg (30mgKET)，但不是 3 mg/kg (3mgKET)，具有通过以下改变对青春期女性改善厌食症样症状产生长期影响：增加食物消耗和体重；减少跑步和类似焦虑的行为。然而，药物的功效也存在个体差异。我们假设氯胺酮改善作用的个体差异与drebrin A有关，drebrin A是一种F-肌动蛋白结合蛋白，已知是NMDA受体（NMDAR）的活性依赖性运输所必需的。我们通过电子显微镜定量这些小鼠前额皮质 (PFC) 深层 1 的锥体神经元 (PN) 和 GABA 能中间神经元 (GABA-IN) 的兴奋性突触中的 drebrin A 免疫反应性来测试这一假设。结果表明：（1）30mgKET组GABA-IN上兴奋性突触的面密度大于3mgKET组； (2)30mgKET组的PN和GABA-IN的drebrin A+兴奋性突触比例均大于3mgKET组。与行为测量的相关分析表明，（3）30mgKET的保护作用与GABA-IN细胞质中drebrin A水平降低以及PN和GABA-IN突触外膜位点drebrin A水平升高有关； (5) 共同指出 30mgKET 诱导的稳态可塑性使 PN 和 GABA-IN 的兴奋性突触处的 drebrin A 参与。
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