在一种基于边缘下皮层星形胶质细胞谷氨酸转运体GLT-1敲低的新抑郁样小鼠模型中,氯胺酮通过调节突触可塑性触发快速抗抑郁作用

IF 5.2 3区 医学 Q1 PSYCHIATRY
M. Neus Fullana , Verónica Paz , Francesc Artigas , Analia Bortolozzi
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引用次数: 1

摘要

最近,我们报道了一种新的MDD样小鼠模型,该模型基于边缘下皮层(IL)星形胶质谷氨酸转运体GLAST/GLT-1的区域选择性敲除,该模型引起了小鼠大脑中与MDD患者中发现的典型改变相关的广泛变化。为了进一步表征这种新的mdd样小鼠模型,我们研究了GLT-1敲除小鼠前脑区域谷氨酸能/ gaba能神经传递和神经可塑性的一些转录因子。此外,我们评估了氯胺酮对这些转录过程的急性影响。材料和方法采用靶向GLT-1 mRNA的小干扰RNA (siRNA)池破坏小鼠IL中GLT-1的转录。采用组织学方法检测突触后密度蛋白-95 (PSD95)、神经素(NRN)、谷氨酰胺脱羧酶-65 (GAD65)以及IL和海马中GLT-1 mRNA的表达。结果小鼠IL中GLT-1表达下调可导致IL和海马中PSD95和NRN神经可塑性mrna表达降低,急性剂量氯胺酮抗抑郁药可逆转这一趋势。同样,单剂量氯胺酮也使GLT-1敲低小鼠IL中GAD65和GLT-1 mRNA水平升高,达到对照小鼠的基础水平。结论sirna诱导IL中星形胶质细胞谷氨酸转运蛋白敲低导致的谷氨酸能神经元过度活跃和GABA系统缺陷可损害MDD中受影响的神经回路的完整性/可塑性。合适的抑郁样动物模型来解决重度抑郁症的神经生物学变化是一个未被满足的需求,GLAST/GLT-1敲低小鼠模型的开发可能是了解氯胺酮速效抗抑郁作用的更好选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ketamine triggers rapid antidepressant effects by modulating synaptic plasticity in a new depressive-like mouse model based on astrocyte glutamate transporter GLT-1 knockdown in infralimbic cortex

Objective

Recently, we reported on a new MDD-like mouse model based on a regionally selective knockdown of astroglial glutamate transporters, GLAST/GLT-1, in infralimbic cortex (IL) which evokes widespread changes in mouse brain associated with the typical alterations found in MDD patients. To further characterize this new MDD-like mouse model, here we examine some transcriptional elements of glutamatergic/GABAergic neurotransmission and neuroplasticity in forebrain regions in the GLT-1 knockdown mice. Furthermore, we assess the acute ketamine effects on these transcriptional processes.

Material and methods

We used a small interfering RNA (siRNA) pool targeting GLT-1 mRNA to disrupt the GLT-1 transcription in mouse IL. Histological assays were performed to examine postsynaptic density protein-95 (PSD95), neuritin (NRN), glutamine acid descarboxilase-65 (GAD65), and GLT-1 mRNA expression in IL and hippocampus.

Results

Knockdown of GLT-1 in mouse IL leads to decreased expression of PSD95 and NRN neuroplasticity mRNAs in IL and hippocampus, which was reversed by an acute dose of ketamine antidepressant. Likewise, a single dose of ketamine also increased the mRNA levels of GAD65 and GLT-1 in IL of GLT-1 knockdown mice, reaching the basal values of control mice.

Conclusions

The glutamatergic neuronal hyperactivity and deficits in the GABA system resulting from siRNA-induced astroglial glutamate transporter knockdown in IL can compromise the integrity/plasticity of neurocircuits affected in MDD. Suitable depressive-like animal models to address the neurobiological changes in MDD are an unmet need and the development of the GLAST/GLT-1 knockdown mouse model may represent a better option to understand the rapid-acting antidepressant effects of ketamine.

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来源期刊
自引率
3.30%
发文量
58
期刊介绍: The Spanish Journal of Psychiatry and Mental Health (SJPMH), incorporated into ISSN 1888-9891, is the official scientific publication of the Spanish Society of Psychiatry and Mental Health. The journal focuses on studying mental illnesses, their pathological processes, and their psychosocial consequences, and aims to disseminate scientific advances in all areas related to mental health and illness. SJPMH accepts unpublished works on psychiatry and mental health, including their medical and social implications. The journal provides space for research in the biological, clinical, and psychosocial fields. Manuscripts undergo peer-review by external reviewers before being accepted for publication. SJPMH is indexed in Index Medicus/Medline, IBECS, Social Sciences Citation Index Journal Citation Reports/Social Sciences Edition, and Current Contents/Social and Behavioral Sciences.
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