Schaefer Tori L, Davenport Matthew H, Grainger Lindsay M, Robinson Chandler K, Earnheart Anthony T, Stegman Melinda S, Lang Anna L, Ashworth Amy A, Molinaro Gemma, Huber Kimberly M, Erickson Craig A
Division of Psychiatry, MLC 7004, Cincinnati Children's Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229-3039 USA.
Present address: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 USA.
J Neurodev Disord. 2017 Jun 12;9:6. doi: 10.1186/s11689-017-9184-y. eCollection 2017.
Fragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene () and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of acamprosate and the significance of the molecule's calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of acamprosate were assessed in the (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments.
mice and their wild-type (WT) littermates were utilized to assess acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic acamprosate treatment and any potential effects of the calcium moiety using CaCl treatment on behavior and nuclear ERK1/2 activation.
Acamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation.
These data indicate that acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in KO mice and that acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of acamprosate in these instances.
脆性X综合征（FXS）是由于脆性X智力低下1基因（FMR1）沉默以及随后脆性X智力低下蛋白（FMRP）表达缺失所致。FMRP的缺失改变了兴奋性/抑制性信号平衡，导致神经元兴奋性增加和行为改变。阿坎酸（N - 乙酰高牛磺酸钙盐）是一种经美国食品药品监督管理局（FDA）批准用于预防成人酒精依赖复发的药物，是一种具有多种机制的新型药物，可能对FXS患者有益。关于阿坎酸的神经活性作用以及该分子钙部分的意义存在一些问题。因此，在几个实验中，在控制钙盐的FXS基因敲除（KO）小鼠模型中评估了阿坎酸的电生理、细胞、分子和行为学效应。
使用Fmr1 KO小鼠及其野生型（WT）同窝仔鼠来评估阿坎酸治疗对皮质上行状态参数、树突棘密度和癫痫易感性的影响。利用脑细胞外信号调节激酶1/2（ERK1/2）激活来研究该信号分子作为治疗反应潜在生物标志物的情况。使用额外的成年小鼠来评估慢性阿坎酸治疗以及使用氯化钙（CaCl₂）治疗对行为和核ERK1/2激活的任何潜在钙部分效应。
阿坎酸可减轻皮质上行状态持续时间延长现象，降低KO小鼠脑组织中升高的ERK1/2激活水平，并减少齿状回中核ERK1/2激活。在Fmr1 KO小鼠的焦虑和运动测试中，阿坎酸治疗改变了行为，其中对照处理的KO小鼠表现出与对照处理的WT小鼠不同。用CaCl₂处理的小鼠在成年行为测试或核ERK1/2激活方面与用生理盐水处理的小鼠没有差异。
这些数据表明，在Fmr1 KO小鼠中，是阿坎酸而非钙改善了类似于焦虑样行为减少和多动减少的功能，并且阿坎酸减轻了可能在FXS病理生理学中起作用的特定电生理和分子失调。在识别记忆测试或听觉惊吓反应/前脉冲抑制检查中，对照处理的KO小鼠和WT小鼠之间的差异不明显，这妨碍了在这些情况下对阿坎酸治疗效果得出结论。
