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Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma.
bioRxiv - Neuroscience Pub Date : 2020-10-25 , DOI: 10.1101/2020.10.23.352310
Matthew J. Van Hook , Corrine Monaco , Jennie C. Smith

Homeostatic plasticity plays important roles in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes relate to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma - the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, but not younger D2 mice or microbead-injected mice. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in both ages of D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner in older D2 mice. Among D2 mice, functional changes observed in younger mice without elevated IOP were distinct from those observed in older mice with elevated IOP and RGC degeneration, suggesting that glaucoma-associated changes to neurons in the dLGN might represent a combination of stabilizing/homeostatic plasticity at earlier stages and pathological dysfunction at later stages.

中文翻译:

青光眼小鼠模型中视觉丘脑的神经元和突触可塑性。

稳态可塑性在调节突触和内在神经元功能以稳定电路活动后的输出中起重要作用。青光眼是一种视觉系统的神经退行性疾病,通常与眼内压升高(IOP)有关,早期疾病与视网膜神经节细胞(RGC)的突触输入改变,RGC内在兴奋性改变以及视神经运输和能量缺乏有关代谢。这些早期的功能改变可以在RGC变性之前发生,并可能改变RGC输出到大脑中的目标结构,从而触发这些大脑区域的突触和神经元特性的稳态变化。在这项研究中,我们试图确定是否以及如何改变背外侧膝状核(dLGN)中的神经元和突触功能,丘脑中重要的RGC投影目标,以及功能变化与IOP的关系。我们在两个已建立的青光眼小鼠模型-DBA / 2J(D2)遗传小鼠模型和可诱导性青光眼模型中采用前房微珠注射以提高IOP的dLGN中的丘脑皮质(TC)中继神经元的膜片钳记录来实现这一目的。我们发现TC神经元的内在兴奋性在D2小鼠中得到增强,并且这些功能的变化反映在注射微珠小鼠的TC神经元的记录中。值得注意的是,许多D2小鼠的神经元特性与IOP相关,但与D2小鼠或注射微珠的小鼠无关。在D2小鼠的两个年龄段,微型兴奋性突触电流(mEPSC)的频率均降低,在老年D2小鼠中,RGC突触末端的vGlut2和vGlut2染色以IOP依赖性方式降低。在D2小鼠中,在没有IOP升高的年轻小鼠中观察到的功能变化与在IOP和RGC变性升高的年长小鼠中观察到的功能变化不同,这表明dLGN中与青光眼相关的神经元变化可能代表了稳定/稳态可塑性的组合。阶段和后期的病理功能障碍。
更新日期:2020-10-27
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