GABABRs 对海马突触传递的调控在 5XFAD 小鼠中发生了改变,其改变与性别和年龄有关。

IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Molecular Neuroscience Pub Date : 2024-08-30 DOI:10.1007/s12031-024-02260-0
Joanne C. Damborsky, Jerrel L. Yakel
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引用次数: 0

摘要

海马(HS)神经元从海马向布罗卡内侧隔/对角带(MS/DBB)发出GABA能投射,这是一个对记忆至关重要的相互环路的一部分。HS 神经元被认为对淀粉样蛋白-β(Aβ)的病理暴露的有害影响特别敏感,阿尔茨海默病(AD)期间就会出现这种情况。然而,目前还不清楚在阿兹海默病发展过程中,MS/DBB中的HS GABA释放是如何改变的。为了在 AD 小鼠模型中靶向 HS 神经元,我们将 SST-Cre 小鼠与 5XFAD 小鼠杂交,并在小鼠 4、6、9 和 12 个月大时将含有 mCherry/channelrhodopsin-2 (ChR2) 的 Cre 依赖性 AAV 立体定向注射到后代的海马中。在对切片中的 MS/DBB 神经元进行全细胞膜片钳记录时,我们使用光遗传学方法选择性地刺激 HS 终末。雌性5XFAD小鼠在6个月大时,HS抑制性突触后电流(IPSC)的振幅会短暂降低,但雄性小鼠在任何年龄段都没有差异,而且任何年龄段的雌雄小鼠配对脉冲比率都没有差异。当浴用 GABABR 激动剂巴氯芬时,我们发现 9 个月大的 5XFAD 雌鼠和 12 个月大的 5XFAD 雄鼠的 HS-IPSC 振幅下降幅度更大。在 12 个月大的 5XFAD 雌性中,对巴氯芬的反应明显减弱。这些数据表明,5XFAD小鼠对GABABR激活的反应性有短暂的增加,雌性比雄性发生得早。HS 功能的这些性别特异性变化可能会影响海马和 MS/DBB 之间的信息传递。
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Regulation of Hippocamposeptal Synaptic Transmission by GABABRs Is Altered in 5XFAD Mice in a Sex- and Age-Dependent Manner

Hippocamposeptal (HS) neurons send GABAergic projections from the hippocampus to the medial septum/diagonal band of Broca (MS/DBB) as part of a reciprocal loop that is critical for memory. HS neurons are proposed to be particularly sensitive to the deleterious effects of pathological exposure to amyloid-β (Aβ), as would occur during Alzheimer’s disease (AD). However, it is not known how HS GABA release in the MS/DBB is altered during the progression of AD. To target HS neurons in a mouse model of AD, we crossed SST-Cre mice to 5XFAD mice and performed stereotaxic injections of Cre-dependent AAV containing mCherry/channelrhodopsin-2 (ChR2) into the hippocampus of offspring at 4, 6, 9, and 12 months. We used optogenetics to selectively stimulate HS terminals while performing whole-cell patch-clamp recordings from MS/DBB neurons in slices. There was a transient reduction in HS-inhibitory postsynaptic current (IPSC) amplitude in female 5XFAD mice at 6 months, but no difference in males at any age, and no difference in paired-pulse ratio in either sex at any age. When bath applying the GABABR agonist, baclofen, we found a larger decrease in HS-IPSC amplitude in 5XFAD females at 9 months and 5XFAD males at 12 months. In 12-month-old 5XFAD females, response to baclofen was significantly reduced. These data suggest that there is a transient increase in responsiveness to GABABR activation in 5XFAD mice that occurs earlier in females than in males. These sex-specific changes to HS function are likely to impact the relay of information between the hippocampus and MS/DBB.

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来源期刊
Journal of Molecular Neuroscience
Journal of Molecular Neuroscience 医学-神经科学
CiteScore
6.60
自引率
3.20%
发文量
142
审稿时长
1 months
期刊介绍: The Journal of Molecular Neuroscience is committed to the rapid publication of original findings that increase our understanding of the molecular structure, function, and development of the nervous system. The criteria for acceptance of manuscripts will be scientific excellence, originality, and relevance to the field of molecular neuroscience. Manuscripts with clinical relevance are especially encouraged since the journal seeks to provide a means for accelerating the progression of basic research findings toward clinical utilization. All experiments described in the Journal of Molecular Neuroscience that involve the use of animal or human subjects must have been approved by the appropriate institutional review committee and conform to accepted ethical standards.
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