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Abstract：
Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus.
摘要：
脆性X综合征(FXS)是一种智力发育障碍,除其他外,由于短期神经信息处理的缺陷，如感官处理和工作记忆。FXS的主要原因是脆性X信使核糖核蛋白（FMRP）的丢失，它与突触功能和可塑性密切相关。短期突触可塑性（STSP）可能在受FXS影响的功能中起重要作用。最近的证据表明，突触前钙传感器突触结合蛋白-7（Syt-7）在STSP中至关重要。然而,FMRP的丢失如何影响STSP和Syt-7尚未得到充分研究。此外，男性和女性受到FXS的影响不同，但是潜在的机制仍然难以捉摸。本研究的目的是研究Fmr1敲除（KO）大鼠模型中成年雄性和雌性的背侧（DH）和腹侧（VH）海马中STSP的可能变化以及Syt-7的表达。FXS。我们发现，成对脉冲比(PPR)和频率促进/抑制(FF/D)，STSP的两种形式，以及Syt-7的表达，在成年KO男性中是正常的，但是KO雌性腹侧海马的PPR增加（6.4±3.7vs.野生型(WT)和KO在25ms时18.3±4.2，分别)。此外，我们没有发现性别差异,但确实在STSP中发现了稳健的区域相关差异(例如，50ms时的PPR：50.0±5.5vs.WT雄性大鼠DH和VH的17.6±2.9；53.1±3.6vs.WT雌性大鼠的DH和VH为19.3±4.6；48.1±2.3vs.KO雄性大鼠的DH和VH为19.1±3.3；51.2±3.3与KO雌性大鼠的DH和VH为24.7±4.3)。AMPA受体在两种基因型的两个海马段和两种性别中相似地表达。此外，与女性相比，男性的基底兴奋性突触传递更高。有趣的是,在两种基因型的男性中，与腹侧海马相比，背侧的Syt-7水平高出两倍以上，而不是突触蛋白-1（0.43±0.1vs.WT雄性大鼠的DH和VH为0.16±0.02，和0.6±0.13vs.KO雄性大鼠的DH和VH为0.23±0.04）和WT雌性（0.97±0.23vs.DH和VH为0.31±0.09)。这些结果表明女性腹侧海马体对FMRP丢失的易感性。重要的是,Syt-7的不同水平，与背侧的较高得分平行突触促进的腹侧海马，提示Syt-7可能在定义STSP沿海马长轴的显着差异中起关键作用。
