{"title":"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","authors":"M. Neus Fullana , Verónica Paz , Francesc Artigas , Analia Bortolozzi","doi":"10.1016/j.rpsm.2021.09.002","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><p>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.</p></div><div><h3>Material and methods</h3><p>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.</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusions</h3><p>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.</p></div>","PeriodicalId":21391,"journal":{"name":"Revista de psiquiatria y salud mental","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"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\",\"authors\":\"M. Neus Fullana , Verónica Paz , Francesc Artigas , Analia Bortolozzi\",\"doi\":\"10.1016/j.rpsm.2021.09.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><p>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.</p></div><div><h3>Material and methods</h3><p>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.</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusions</h3><p>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.</p></div>\",\"PeriodicalId\":21391,\"journal\":{\"name\":\"Revista de psiquiatria y salud mental\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2022-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Revista de psiquiatria y salud mental\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1888989121001014\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Revista de psiquiatria y salud mental","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1888989121001014","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
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.
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.