Hyperactivity of Newborn Pten Knock-out Neurons Results from Increased Excitatory Synaptic Drive
Hyperactivity of Newborn Pten Knock-out Neurons Results from Increased Excitatory Synaptic Drive
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DOI：
10.1523/jneurosci.3144-14.2015
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发表时间：
2015-01-21
影响因子：
5.3
通讯作者：
Luikart, Bryan W.
中科院分区：
文献类型：
--
作者：
Williams, Michael R.;DeSpenza, Tyrone, Jr.;Luikart, Bryan W.
发育中的神经元必须调节形态、内在兴奋性和突触发生以形成神经回路。当这些过程出错时，可能会导致包括自闭症谱系障碍（ASD）或癫痫在内的疾病。磷酸酶Pten在一些患有ASD和癫痫发作的患者中发生突变，这表明其突变部分通过增加神经元活性来破坏神经功能。支持这一观点的是，在小鼠中敲除Pten的神经元可导致大头畸形、类似于ASD的行为变化和癫痫发作。然而，Pten耗竭后兴奋性增强的机制尚不清楚。先前的研究已经分别表明，Pten耗尽的神经元可以驱动癫痫发作，接受升高的兴奋性突触输入，并具有异常的树突。因此，我们测试了这一假设，即开发Pten耗尽的神经元是过度活跃，由于兴奋性突触发生增加，使用电生理学，钙成像，形态学分析和建模。这是通过共注射逆转录病毒的“出生日期”或出生日期和敲除Pten在小鼠新生儿齿状回的颗粒神经元。我们发现，Pten基因敲除的神经元，尽管迅速发病的肥大，在体内更活跃。Pten基因敲除的神经元发射更多的超极化膜电位，显示更大的峰值尖峰速率，更敏感的去极化突触输入。Pten基因敲除神经元的敏感性增加，部分原因是位于更接近索马的突触密度更高。我们确定增加的突触驱动足以驱动肥大的Pten敲除神经元超过其改变的动作电位阈值。因此，我们的工作有助于增加Pten耗尽神经元的活性的发育机制。
Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate"or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons.