Medina Adriana, Watson Stanley J, Bunney William, Myers Richard M, Schatzberg Alan, Barchas Jack, Akil Huda, Thompson Robert C
Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
J Psychiatr Res. 2016 Jan;72:15-21. doi: 10.1016/j.jpsychires.2015.10.010. Epub 2015 Oct 23.
Glial cells are essential in maintaining synaptic function. In glutamatergic synapses astrocytes remove the products of neural activity, (i.e. potassium, glutamate and excess water) from the synaptic cleft and redistribute them across the glial network; these products of neural activity can then be recycled for neuronal use or released into the vascular compartment. This type of highly coupled cell network -or syncytium-maintains the balance of synaptic activity by restoring the basal levels of such molecules in the synaptic cleft. Previous studies have reported alterations of glia related genes in Major Depressive Disorder, including some genes related to syncytial function.
We used RNA isolated from hippocampal tissues of 13 MDD subjects and 10 healthy controls to broadly examine gene expression using microarrays. Hippocampal RNA samples were isolated by laser capture microdissection from human tissue sections carefully avoiding contamination from neighboring structures. Once RNA quality was validated RNA was labeled and hybridized to microarrays.
Analysis of microarray data identified mRNA transcripts involved in glial syncytial function that were downregulated in MDD subjects compared to controls, including potassium and water channels (KCNJ10, AQP4), gap junction proteins (GJA1) and glutamate transporters (SLC1A2, SLC1A3). These gene expression differences were confirmed by qPCR.
The downregulation of these genes related to the syncytial network activity of glial cells is consistent with the hypothesis that synaptic homeostasis is disrupted thereby disrupting hippocampal synaptic function in MDD patients. Such glial gene expression changes could contribute either to the onset or perpetuation of depressive symptoms and hence, represent targets for novel therapeutics.
神经胶质细胞对于维持突触功能至关重要。在谷氨酸能突触中，星形胶质细胞从突触间隙清除神经活动的产物（即钾离子、谷氨酸和多余的水分），并将它们重新分布到胶质网络中；这些神经活动的产物随后可以被循环利用以供神经元使用，或者释放到血管腔中。这种高度耦合的细胞网络——或合胞体——通过恢复突触间隙中此类分子的基础水平来维持突触活动的平衡。先前的研究报道了重度抑郁症中与胶质细胞相关基因的改变，包括一些与合胞体功能相关的基因。
我们使用从13名重度抑郁症患者和10名健康对照者的海马组织中分离出的RNA，通过微阵列广泛检测基因表达。通过激光捕获显微切割从人体组织切片中分离出海马RNA样本，小心避免邻近结构的污染。一旦RNA质量得到验证，就对RNA进行标记并与微阵列杂交。
微阵列数据分析确定了与胶质细胞合胞体功能相关的mRNA转录本，与对照组相比，这些转录本在重度抑郁症患者中下调，包括钾离子和水通道（KCNJ10、AQP4）、缝隙连接蛋白（GJA1）和谷氨酸转运体（SLC1A2、SLC1A3）。这些基因表达差异通过qPCR得到证实。
这些与胶质细胞合胞体网络活动相关基因的下调与以下假设一致，即突触稳态被破坏，从而扰乱了重度抑郁症患者的海马突触功能。这种胶质基因表达变化可能导致抑郁症状的发作或持续，因此，代表了新型治疗方法的靶点。
