The vulnerability of thalamocortical circuitry to hypoxic-ischemic injury in a mouse model of periventricular leukomalacia.
The vulnerability of thalamocortical circuitry to hypoxic-ischemic injury in a mouse model of periventricular leukomalacia.
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DOI：
10.1186/s12868-015-0237-4
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发表时间：
2016-01-05
期刊：
影响因子：
2.4
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Liu XB;Shen Y;Pleasure DE;Deng W
脑室周围白质软化(PVL)是早产儿神经功能障碍的主要原因，包括运动和认知障碍。脑室周围白质软化症的特征是未成熟脑白质受损，但未成熟脑白质受损导致广泛的认知和运动功能障碍的机制尚不清楚。丘脑皮质系统对人类的意识和认知功能至关重要，新生儿期皮质-丘脑投射的发育受损可能是PVL儿童认知功能异常的重要原因。在这项研究中，使用PVL小鼠模型，我们试图验证PVL样损伤影响丘脑皮质回路的不同成分的假说，这两个成分可以由囊泡谷氨酸转运体1和2(vGluT1和vGluT2)来定义，这两个转运体都是中枢神经系统谷氨酸能突触传递所必需的。我们结合免疫细胞化学和免疫电子显微镜来研究vGluT1免疫标记特异性识别的皮质-丘脑突触的变化。我们发现PVL小鼠体感觉丘脑vGluT1标记谱密度显著降低，其中腹后核(VP)减少72-74%，丘脑网状核(RTN)减少42-82%。我们进一步在电子显微镜水平上检查了这些终末，发现vGluT1标记的皮质丘脑终末在VP和RTN中的大小减少了一倍至两倍。本研究为阐明PVL小鼠模型丘脑回路改变的细胞机制提供了解剖学和超微结构证据，并揭示了PVL样损伤对皮质丘脑投射系统的直接影响。我们的发现提供了第一组证据表明PVL小鼠的丘脑皮质回路受到影响且易受攻击，这支持了PVL小鼠中vGluT1定义的皮质丘脑突触发生改变的工作模型，以及vGluT2定义的丘脑皮质突触与这种变化相关，导致PVL小鼠丘脑皮质回路受损。我们的研究表明，在PVL模型中，丘脑皮质回路非常容易受到缺氧缺血的影响，从而确定了PVL病理中的一个新的靶点。
Periventricular leukomalacia (PVL) is the leading cause of neurological disabilities including motor and cognitive deficits in premature infants. Periventricular leukomalacia is characterized by damage to the white matter in the immature brain, but the mechanisms by which damage to immature white matter results in widespread deficits of cognitive and motor function are unclear. The thalamocortical system is crucial for human consciousness and cognitive functions, and impaired development of the cortico-thalamic projections in the neonatal period is implicated to contribute importantly to abnormalities of cognitive function in children with PVL. In this study, using a mouse model of PVL, we sought to test the hypothesis that PVL-like injury affects the different components of the thalamocortical circuitry that can be defined by vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2), both of which are required for glutamatergic synaptic transmission in the central nervous system. We combined immunocytochemistry and immuno-electron microscopy to investigate changes in cortico-thalamic synapses which were specifically identified by vGluT1 immunolabeling. We found that a drastic reduction in the density of vGluT1 labeled profiles in the somatosensory thalamus, with a reduction of 72–74 % in ventroposterior (VP) nucleus and a reduction of 42–82 % in thalamic reticular nucleus (RTN) in the ipsilateral side of PVL mice. We further examined these terminals at the electron microscopic level and revealed onefold–twofold decrease in the sizes of vGluT1 labeled corticothalamic terminals in VP and RTN. The present study provides anatomical and ultrastructural evidence to elucidate the cellular mechanisms underlying alteration of thalamic circuitry in a mouse model of PVL, and reveals that PVL-like injury has a direct impact on the corticothalamic projection system. Our findings provide the first set of evidence showing that the thalamocortical circuitry is affected and vulnerable in PVL mice, supporting a working model in which vGluT1 defined corticothalamic synapses are altered in PVL mice, and vGluT2 defined thalamocortical synapses are associated with such changes, leading to the compromised thalamocortical circuitry in the PVL mice. Our study demonstrates that the thalamocortical circuitry is highly vulnerable to hypoxia–ischemia in the PVL model, thus identifying a novel target site in PVL pathology.