Canalization of genetic and pharmacological perturbations in developing primary neuronal activity patterns.
Canalization of genetic and pharmacological perturbations in developing primary neuronal activity patterns.
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DOI：
10.1016/j.neuropharm.2015.07.027
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发表时间：
2016-01
影响因子：
4.7
通讯作者：
Grant SG
中科院分区：
文献类型：
--
作者：
Charlesworth P;Morton A;Eglen SJ;Komiyama NH;Grant SG
神经系统的功能取决于突触的完整性和脑回路中电活动的模式。基因组测序的快速进展揭示了大量破坏突触蛋白的突变，这可能导致称为突触病变的疾病。然而，同样明显的是，每个正常个体都携带数百种潜在的破坏性突变。虽然对几种生物体的遗传研究表明，突变可以在发育过程中通过一种被称为“渠化”的过程被掩盖，但尚不清楚这是否发生在大脑电活动的发育过程中。使用纵向记录的原代培养的神经元上的多电极阵列从小鼠携带敲除突变，我们报告的证据渠道发展的自发活动模式。缺乏AMPA受体Gria 1亚基的小鼠的年轻培养物中的活动模式的表型随着培养物的成熟而改善。同样，慢性药物NMDA受体阻滞剂的作用随着培养物的成熟而减弱。此外，活动模式的干扰，同时中断Gria 1和NMDA受体也被渠化的三个星期的文化。其他突变和遗传变异似乎也在不同程度上被疏导。这些发现表明，神经元网络渠道化是神经系统可塑性的一种形式，为发育中断提供了弹性。本文是题为“突触病-从生物学到治疗”的特刊的一部分。记录了具有突触突变的培养物中网络活动的发展。随着培养物的成熟，观察到具有θ周期性的同步爆发发射。Gria 1缺失和慢性NMDA-R阻断破坏了网络活动模式。dlg 2基因敲除破坏了网络活动，其他突触基因的影响很小。随着培养物的成熟，发育早期的网络活动表型被渠道化。
The function of the nervous system depends on the integrity of synapses and the patterning of electrical activity in brain circuits. The rapid advances in genome sequencing reveal a large number of mutations disrupting synaptic proteins, which potentially result in diseases known as synaptopathies. However, it is also evident that every normal individual carries hundreds of potentially damaging mutations. Although genetic studies in several organisms show that mutations can be masked during development by a process known as canalization, it is unknown if this occurs in the development of the electrical activity in the brain. Using longitudinal recordings of primary cultured neurons on multi-electrode arrays from mice carrying knockout mutations we report evidence of canalization in development of spontaneous activity patterns. Phenotypes in the activity patterns in young cultures from mice lacking the Gria1 subunit of the AMPA receptor were ameliorated as cultures matured. Similarly, the effects of chronic pharmacological NMDA receptor blockade diminished as cultures matured. Moreover, disturbances in activity patterns by simultaneous disruption of Gria1 and NMDA receptors were also canalized by three weeks in culture. Additional mutations and genetic variations also appeared to be canalized to varying degrees. These findings indicate that neuronal network canalization is a form of nervous system plasticity that provides resilience to developmental disruption. This article is part of the Special Issue entitled ‘Synaptopathy – from Biology to Therapy’. Development of network activity in cultures with synaptic mutations was recorded. Synchronous burst firing with theta periodicity was observed as cultures matured. Gria1 deletion and chronic NMDA-R blockade disrupted network activity patterns. Dlg2 knockout disrupted network activity, other synaptic genes had minimal effects. Network activity phenotypes early in development were canalized as cultures matured.