Long-term effects of a double hit murine model for schizophrenia on parvalbumin expressing cells and plasticity-related molecules in the thalamic reticular nucleus and the habenula.

IF 5.8 1区 医学 Q1 PSYCHIATRY Translational Psychiatry Pub Date : 2024-10-24 DOI:10.1038/s41398-024-03166-6
Patrycja Klimczak, Julia Alcaide, Yaiza Gramuntell, Esther Castillo-Gómez, Emilio Varea, Marta Perez-Rando, Juan Nacher
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Abstract

The exposure to aversive experiences during early-life affects brain maturation and induces changes in behavior. Additionally, when these experiences coincide with subtle neurodevelopmental alterations, they may contribute to the emergence of psychiatric disorders, such as schizophrenia. Studies in patients and animal models have identified changes in parvalbumin (PV) expressing inhibitory neurons, highlighting their significance in the etiology of this disorder. Most studies have been focused on the cortex, but PV+ neurons also provide inhibitory input to diencephalic regions, particularly to the thalamus (through cells in the thalamic reticular nucleus, TRN) and the habenula. Remarkably, alterations in both nuclei have been described in schizophrenia. Some of these changes in PV+ cells may be mediated by perineuronal nets (PNN), specialized regions of the extracellular matrix that often surround them and regulate their synaptic input and activity. Interestingly, the physiological maturation and integration of PV+ neurons, which involves the assembly of PNN, occurs during early postnatal life. Plasticity molecules associated to inhibitory neurons, such as PSA-NCAM, or NMDA receptors (NMDAR) can also influence the structure and function of these cells. Growing evidence also indicates that glial cells regulate the physiology of PV+ neurons by influencing their maturation and modulating their synaptic connectivity. To explore the impact of early-life aversive experiences and concomitant subtle neurodevelopmental alterations on diencephalic PV+ cells, we analyzed adult male mice subjected to a double-hit model (DHM) of schizophrenia, combining a single injection of an NMDAR antagonist at P7 and post-weaning social isolation. We observed that exploratory behavior, PV+ neurons and their associated PNN, as well as PSA-NCAM and NMDAR expression and glial cells, in the TRN and the habenula were affected by the DHM or one of its factors. To our knowledge, this is the first report on such alterations in these diencephalic structures in an animal model combining neurodevelopmental alterations and early-life stress during adolescence. Our findings complement previous work on PV+ neurons in cortical regions and underscore the importance of studying diencephalic inhibitory networks and their intricate interactions with aversive experiences and neurodevelopmental alterations during early life in the context of schizophrenia.

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精神分裂症双击小鼠模型对丘脑网状核和脑叶中副发光体表达细胞和可塑性相关分子的长期影响。
幼年时期的厌恶经历会影响大脑的成熟,并诱发行为的改变。此外,当这些经历与微妙的神经发育改变同时发生时,可能会导致精神分裂症等精神疾病的出现。对患者和动物模型的研究发现,表达抑制性神经元的副发光素(PV)发生了变化,这凸显了它们在精神分裂症病因学中的重要性。大多数研究都集中在大脑皮层,但 PV+ 神经元也向间脑区域提供抑制性输入,尤其是丘脑(通过丘脑网状核中的细胞)和哈贝脑。值得注意的是,精神分裂症患者的这两个核团都发生了改变。PV+细胞的部分变化可能是由神经元周围网(PNN)介导的,PNN是细胞外基质的专门区域,通常围绕着PV+细胞,并调节其突触输入和活动。有趣的是,PV+神经元的生理性成熟和整合涉及 PNN 的组装,发生在出生后早期。与抑制性神经元相关的可塑性分子,如 PSA-NCAM 或 NMDA 受体(NMDAR),也会影响这些细胞的结构和功能。越来越多的证据还表明,神经胶质细胞通过影响PV+神经元的成熟和调节其突触连接来调节PV+神经元的生理学。为了探索早年的厌恶经历和伴随而来的细微神经发育改变对间脑 PV+ 细胞的影响,我们分析了接受精神分裂症双重打击模型(DHM)的成年雄性小鼠,该模型结合了在小鼠 7 岁时注射一次 NMDAR 拮抗剂和断奶后的社会隔离。我们观察到,探索行为、PV+神经元及其相关的PNN、PSA-NCAM和NMDAR的表达以及神经胶质细胞、TRN和哈氏神经节均受到DHM或其中一个因素的影响。据我们所知,这是首次报道在一个结合了神经发育改变和青春期早期生活压力的动物模型中这些间脑结构的这种改变。我们的研究结果补充了之前关于皮质区域 PV+ 神经元的研究,并强调了在精神分裂症的背景下研究双脑抑制网络及其与厌恶体验和生命早期神经发育改变之间错综复杂的相互作用的重要性。
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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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