Belliveau Claudia, Rahimian Reza, Fakhfouri Gohar, Hosdey Clémentine, Simard Sophie, Davoli Maria Antonietta, Mirault Dominique, Giros Bruno, Turecki Gustavo, Mechawar Naguib
McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Qc, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Qc, Canada.
McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Qc, Canada.
Brain Behav Immun. 2025 Feb;124:321-334. doi: 10.1016/j.bbi.2024.12.013. Epub 2024 Dec 11.
Microglia, known for their diverse roles in the central nervous system, have recently been recognized for their involvement in degrading the extracellular matrix. Perineuronal nets (PNNs), a specialized form of this matrix, are crucial for stabilizing neuronal connections and constraining plasticity. Our group recently reported increased PNN densities in the ventromedial prefrontal cortex (vmPFC) of depressed individuals that died by suicide in adulthood after experiencing childhood abuse (DS-CA) compared to matched controls. To explore potential underlying mechanisms, we employed a comprehensive approach in similar postmortem vmPFC samples, combining a human matrix metalloproteinase and chemokine array, isolation of CD11b-positive microglia and enzyme-linked immunosorbent assays (ELISA). Our findings indicate a significant downregulation of matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinases (TIMP)-2 in both whole vmPFC grey matter and isolated microglial cells from DS-CA samples. Furthermore, our experiments reveal that a history of child abuse is associated with diminished levels of microglial CX3CR1 and IL33R in both vmPFC whole lysate and CD11b isolated cells. However, levels of the CX3CR1 ligand, CX3CL1 (Fractalkine), did not differ between groups. While these data suggest potential long-lasting alterations in microglial markers in the vmPFC of individuals exposed to severe childhood adversity, direct functional assessments were not conducted. Nonetheless, these findings offer insight into how childhood abuse may contribute to PNN alterations via microglial-related mechanisms.
小胶质细胞以其在中枢神经系统中的多种作用而闻名，最近人们认识到它们参与了细胞外基质的降解。神经元周围网（PNNs）是这种基质的一种特殊形式，对于稳定神经元连接和限制可塑性至关重要。我们的研究小组最近报告称，与匹配的对照组相比，在童年期遭受虐待后成年自杀死亡的抑郁症患者（DS-CA）的腹内侧前额叶皮质（vmPFC）中，PNN密度增加。为了探索潜在的潜在机制，我们在类似的死后vmPFC样本中采用了一种综合方法，结合了人基质金属蛋白酶和趋化因子阵列、CD11b阳性小胶质细胞的分离以及酶联免疫吸附测定（ELISA）。我们的研究结果表明，在整个vmPFC灰质和来自DS-CA样本的分离小胶质细胞中，基质金属蛋白酶（MMP）-9和金属蛋白酶组织抑制剂（TIMP）-2均显著下调。此外，我们的实验表明，童年虐待史与vmPFC全裂解物和CD11b分离细胞中小胶质细胞CX3CR1和IL33R水平降低有关。然而，CX3CR1配体CX3CL1（趋化因子）的水平在两组之间没有差异。虽然这些数据表明，在经历严重童年逆境的个体的vmPFC中，小胶质细胞标志物可能存在潜在的长期改变，但未进行直接功能评估。尽管如此，这些发现为童年虐待如何通过小胶质细胞相关机制导致PNN改变提供了见解。
