Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Sci Transl Med. 2017 Dec 20;9(421). doi: 10.1126/scitranslmed.aai8753.
Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.
抑郁症患者常伴有认知障碍，这增加了疾病负担。我们使用社交挫败诱导的持续性应激（SDPS）在大鼠中诱导出抑郁样状态，然后在这些动物中研究无急性应激源时的长期记忆缺陷。SDPS 大鼠模型表现出短期物体位置记忆减少和背侧海马 CA1 锥体神经元长时程增强（LTP）的维持受损。SDPS 动物的背侧海马中突触软骨素蛋白聚糖的表达增加。这些效应在最后一次挫败后 8 周开始用抗抑郁药丙咪嗪治疗 3 周后被消除。接下来，我们观察到在 SDPS 动物中，围绕表达 parvalbumin 的中间神经元的周围神经毡网络（PNNs）数量增加，而海马 CA1 区抑制性突触后电流（IPSCs）的频率降低。脑室内给予软骨素酶 ABC 分解海马 CA1 细胞外基质，可恢复 PNNs 的数量、LTP 的维持、海马抑制性张力以及物体位置识别测试中的记忆表现。我们的数据揭示了在经历 SDPS 的大鼠中，海马细胞外基质增加与与慢性抑郁样状态相关的认知缺陷之间存在因果关系。
