Increased transient Na+ conductance and action potential output in layer 2/3 prefrontal cortex neurons of the fmr1-/y mouse.
Increased transient Na+ conductance and action potential output in layer 2/3 prefrontal cortex neurons of the fmr1-/y mouse.
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fmr1-/y 小鼠第 2/3 层前额皮质神经元的瞬态 Na 电导和动作电位输出增加。
DOI：
10.1113/jp274258
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Brager,DarrinH
中科院分区：
文献类型：
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作者：
Routh,BrandyN;Rathour,RahulK;Baumgardner,MichaelE;Kalmbach,BrianE;Johnston,Daniel;Brager,DarrinH
前额叶皮层的2/3层神经元表现出更高的躯体兴奋性增益，对给定的刺激（infmr1−/ymice）产生更高数量的动作电位。Infmr1−/yL2/3神经元，动作电位更高、更快、更窄。外膜片钳记录显示，mr1−/yL2/3神经元的最大Na+电导密度更高。对三种生物物理上不同的K+电流的测量显示，在快速失活（a型）K+电导的激活中存在去极化转移。生物物理观察的真实神经元模拟再现了升高的动作电位和重复放电表型。【摘要】脆性X染色体综合征是最常见的遗传性智力障碍和自闭症。前额叶皮层负责高阶认知处理，前额叶功能障碍被认为是许多与脆性X综合征相关的认知和行为表型的基础。我们最近证明，fmr1 - /ymouse前额叶皮层(L) 5层锥体神经元的躯体和树突兴奋性由于几个电压门控离子通道的变化而显著改变。除了L5锥体神经元外，L2/3锥体神经元在前额叶回路中发挥重要作用，整合来自大脑下部区域和对侧皮层的输入。利用全细胞电流钳记录，我们发现在给定的刺激下，与野生型神经元相比，offmr1 - /ymouse前额叶皮层的L2/3锥体神经元激发了更多的动作电位。此外，mr1−/ y神经元的动作电位明显变大、变快、变窄。L2/3神经元外部斑块的电压箝位显示，mr1−/ y神经元的瞬态Na+电流明显更大。此外，体细胞A型K+电流的激活曲线被去极化。基于实际电导的模拟表明，这些Na+和K+通道功能的生物物理变化可以可靠地再现所观察到的动作电位放电增加和动作电位波形的改变。这些结果，结合我们之前在L5神经元上的发现，表明fmr1 - /ymouse中内侧前额叶皮层回路中的主要神经元以不同的方式改变，并可能导致脆性X综合征中前额叶皮层处理功能失调。
Key pointsLayer 2/3 neurons of the prefrontal cortex display higher gain of somatic excitability, responding with a higher number of action potentials for a given stimulus, infmr1−/ymice.Infmr1−/yL2/3 neurons, action potentials are taller, faster and narrower.Outside‐out patch clamp recordings revealed that the maximum Na+conductance density is higher infmr1−/yL2/3 neurons.Measurements of three biophysically distinct K+currents revealed a depolarizing shift in the activation of a rapidly inactivating (A‐type) K+conductance.Realistic neuronal simulations of the biophysical observations recapitulated the elevated action potential and repetitive firing phenotype.AbstractFragile X syndrome is the most common form of inherited mental impairment and autism. The prefrontal cortex is responsible for higher order cognitive processing, and prefrontal dysfunction is believed to underlie many of the cognitive and behavioural phenotypes associated with fragile X syndrome. We recently demonstrated that somatic and dendritic excitability of layer (L) 5 pyramidal neurons in the prefrontal cortex of thefmr1−/ymouse is significantly altered due to changes in several voltage‐gated ion channels. In addition to L5 pyramidal neurons, L2/3 pyramidal neurons play an important role in prefrontal circuitry, integrating inputs from both lower brain regions and the contralateral cortex. Using whole‐cell current clamp recording, we found that L2/3 pyramidal neurons in prefrontal cortex offmr1−/ymouse fired more action potentials for a given stimulus compared with wild‐type neurons. In addition, action potentials infmr1−/yneurons were significantly larger, faster and narrower. Voltage clamp of outside‐out patches from L2/3 neurons revealed that the transient Na+current was significantly larger infmr1−/yneurons. Furthermore, the activation curve of somatic A‐type K+current was depolarized. Realistic conductance‐based simulations revealed that these biophysical changes in Na+and K+channel function could reliably reproduce the observed increase in action potential firing and altered action potential waveform. These results, in conjunction with our prior findings on L5 neurons, suggest that principal neurons in the circuitry of the medial prefrontal cortex are altered in distinct ways in thefmr1−/ymouse and may contribute to dysfunctional prefrontal cortex processing in fragile X syndrome.