前额叶皮层锥体神经元固有兴奋性上依赖于活动的 BDNF 信号的性双态特征。

IF 4.2 3区 医学 Q2 NEUROSCIENCES
Frontiers in Cellular Neuroscience Pub Date : 2024-11-06 eCollection Date: 2024-01-01 DOI:10.3389/fncel.2024.1496930
Kaijie Ma, Daoqi Zhang, Kylee McDaniel, Maria Webb, Samuel S Newton, Francis S Lee, Luye Qin
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引用次数: 0

摘要

自闭症谱系障碍(ASD)是一组神经发育障碍,具有很强的遗传异质性,男性发病率高于女性。我们和其他人推测,依赖活动的神经信号传导减弱是自闭症谱系障碍中常见的分子通路,它是由不同的基因突变引起的。脑源性神经营养因子(BDNF)是介导大脑活动依赖性神经信号传导的关键生长因子。人类 BDNF 基因前域的常见单核苷酸多态性(SNP)会导致第 66 个密码子(Val66Met)上的蛋氨酸(Met)取代缬氨酸(Val),从而显著降低活动依赖性 BDNF 的释放,而不影响基础 BDNF 的分泌。通过使用基因敲入人类 BDNF 蛋氨酸(Met)等位基因的小鼠,我们之前的研究表明,雌雄 BDNF+/Met 小鼠的自闭症样社交障碍严重程度不同。锥体神经元是前额叶皮层(PFC)的主要神经元,而前额叶皮层是大脑中社交行为的关键区域。在这里,我们研究了活动依赖性 BDNF 信号减弱对前额叶皮质锥体神经元内在兴奋性的影响。令人惊讶的是,依赖于活动的 BDNF 信号减弱会显著提高雄性小鼠锥体神经元的固有兴奋性,而雌性小鼠则不会。值得注意的是,雄性 BDNF+/Met 小鼠的动作电位阈值明显下降,而雌性 BDNF+/Met 小鼠则没有。电压钳记录显示,雄性 BDNF+/Met 小鼠锥体神经元中的钠离子电流密度明显增加,这是由编码钠离子通道 NaV 1.2 的 Scn2a 的转录水平增加所介导的。超极化后介质(mAHP)是确定神经元内在兴奋性的另一个重要参数,它与神经元的发射频率密切相关。此外,只有雄性BDNF+/Met小鼠的mAHP振幅显著降低,而这是由编码小电导钙激活钾通道2(SK2)的Kcnn2下调介导的。这项研究揭示了活动依赖性BDNF信号对PFC锥体神经元固有神经元兴奋性降低的性别双态特征,为特发性ASD患者和携带BDNF Val66Met SNP的人类自闭症患者的性别差异提供了可能的细胞和分子机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A sexually dimorphic signature of activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the prefrontal cortex.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. We and others hypothesize that diminished activity-dependent neural signaling is a common molecular pathway dysregulated in ASD caused by diverse genetic mutations. Brain-derived neurotrophic factor (BDNF) is a key growth factor mediating activity-dependent neural signaling in the brain. A common single nucleotide polymorphism (SNP) in the pro-domain of the human BDNF gene that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) significantly decreases activity-dependent BDNF release without affecting basal BDNF secretion. By using mice with genetic knock-in of this human BDNF methionine (Met) allele, our previous studies have shown differential severity of autism-like social deficits in male and female BDNF+/Met mice. Pyramidal neurons are the principal neurons in the prefrontal cortex (PFC), a key brain region for social behaviors. Here, we investigated the impact of diminished activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the PFC. Surprisingly, diminished activity-dependent BDNF signaling significantly increased the intrinsic excitability of pyramidal neurons in male mice, but not in female mice. Notably, significantly decreased thresholds of action potentials were observed in male BDNF+/Met mice, but not in female BDNF+/Met mice. Voltage-clamp recordings revealed that the sodium current densities were significantly increased in the pyramidal neurons of male BDNF+/Met mice, which were mediated by increased transcriptional level of Scn2a encoding sodium channel NaV 1.2. Medium after hyperpolarization (mAHP), another important parameter to determine intrinsic neuronal excitability, is strongly associated with neuronal firing frequency. Further, the amplitudes of mAHP were significantly decreased in male BDNF+/Met mice only, which were mediated by the downregulation of Kcnn2 encoding small conductance calcium-activated potassium channel 2 (SK2). This study reveals a sexually dimorphic signature of diminished activity-dependent BDNF signaling on the intrinsic neuronal excitability of pyramidal neurons in the PFC, which provides possible cellular and molecular mechanisms underpinning the sex differences in idiopathic ASD patients and human autism victims who carry BDNF Val66Met SNP.

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来源期刊
CiteScore
7.90
自引率
3.80%
发文量
627
审稿时长
6-12 weeks
期刊介绍: Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
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