{"title":"Srrm4突变的布朗克斯华尔兹小鼠GABA能突触后传递异常与焦虑有关","authors":"Yuka Shirakawa , Heng Li , Yuki Inoue , Hitomi Izumi , Yoshimi Kaga , Yu-ichi Goto , Ken Inoue , Masumi Inagaki","doi":"10.1016/j.ibneur.2023.12.005","DOIUrl":null,"url":null,"abstract":"<div><p>The homozygous <em>Bronx waltzer</em> (<em>bv</em>) mouse, which shows hearing impairment, also exhibits anxiety accompanied by a reduction in cortical parvalbumin (PV)-positive GABAergic interneurons. Recently, a mutation in splicing factor Ser/Arg repetitive matrix 4 (Srrm4) was found in <em>bv</em> mice. However, the cellular consequences of the <em>Srrm4</em> mutation for anxiety remain unknown. Here, we tested our hypothesis that <em>bv</em> mutant primarily affects interneurons through a cell-intrinsic pathology that leads to a reduction of interneurons and consequently causes anxiety. We found that the anxiety becomes apparent at 6 weeks of age in <em>bv/bv</em> mice. However, in situ hybridization revealed that <em>Srrm4</em> is not expressed in interneurons, but rather dominates in pyramidal neurons. In addition, the PV-positive GABAergic interneurons were not reduced in number in the <em>bv/bv</em> cortex when anxiety became evident. However, electrophysiological abnormality of GABAergic transmission from interneurons was concomitantly present. Pharmacological blockage of GABA<sub>A</sub> receptors revealed increased excitability in <em>bv/bv</em> mice, although no gross change occurred in the expression of an <em>Srrm4</em>-downstream gene, <em>Kcc2</em>, which regulates chloride flux upon GABAergic transmission. These findings suggest that the <em>bv</em>-associated <em>Srrm4</em> mutation mainly involves post-synaptic GABAergic transmission in the central nervous system, which may be associated with the anxiety phenotype in <em>bv/bv</em> mice.</p></div>","PeriodicalId":13195,"journal":{"name":"IBRO Neuroscience Reports","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2023-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667242123022911/pdfft?md5=50b70548445f3fd37f8ded459a484f85&pid=1-s2.0-S2667242123022911-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Abnormality in GABAergic postsynaptic transmission associated with anxiety in Bronx waltzer mice with an Srrm4 mutation\",\"authors\":\"Yuka Shirakawa , Heng Li , Yuki Inoue , Hitomi Izumi , Yoshimi Kaga , Yu-ichi Goto , Ken Inoue , Masumi Inagaki\",\"doi\":\"10.1016/j.ibneur.2023.12.005\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The homozygous <em>Bronx waltzer</em> (<em>bv</em>) mouse, which shows hearing impairment, also exhibits anxiety accompanied by a reduction in cortical parvalbumin (PV)-positive GABAergic interneurons. Recently, a mutation in splicing factor Ser/Arg repetitive matrix 4 (Srrm4) was found in <em>bv</em> mice. However, the cellular consequences of the <em>Srrm4</em> mutation for anxiety remain unknown. Here, we tested our hypothesis that <em>bv</em> mutant primarily affects interneurons through a cell-intrinsic pathology that leads to a reduction of interneurons and consequently causes anxiety. We found that the anxiety becomes apparent at 6 weeks of age in <em>bv/bv</em> mice. However, in situ hybridization revealed that <em>Srrm4</em> is not expressed in interneurons, but rather dominates in pyramidal neurons. In addition, the PV-positive GABAergic interneurons were not reduced in number in the <em>bv/bv</em> cortex when anxiety became evident. However, electrophysiological abnormality of GABAergic transmission from interneurons was concomitantly present. Pharmacological blockage of GABA<sub>A</sub> receptors revealed increased excitability in <em>bv/bv</em> mice, although no gross change occurred in the expression of an <em>Srrm4</em>-downstream gene, <em>Kcc2</em>, which regulates chloride flux upon GABAergic transmission. These findings suggest that the <em>bv</em>-associated <em>Srrm4</em> mutation mainly involves post-synaptic GABAergic transmission in the central nervous system, which may be associated with the anxiety phenotype in <em>bv/bv</em> mice.</p></div>\",\"PeriodicalId\":13195,\"journal\":{\"name\":\"IBRO Neuroscience Reports\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2023-12-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2667242123022911/pdfft?md5=50b70548445f3fd37f8ded459a484f85&pid=1-s2.0-S2667242123022911-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"IBRO Neuroscience Reports\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2667242123022911\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"IBRO Neuroscience Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2667242123022911","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Abnormality in GABAergic postsynaptic transmission associated with anxiety in Bronx waltzer mice with an Srrm4 mutation
The homozygous Bronx waltzer (bv) mouse, which shows hearing impairment, also exhibits anxiety accompanied by a reduction in cortical parvalbumin (PV)-positive GABAergic interneurons. Recently, a mutation in splicing factor Ser/Arg repetitive matrix 4 (Srrm4) was found in bv mice. However, the cellular consequences of the Srrm4 mutation for anxiety remain unknown. Here, we tested our hypothesis that bv mutant primarily affects interneurons through a cell-intrinsic pathology that leads to a reduction of interneurons and consequently causes anxiety. We found that the anxiety becomes apparent at 6 weeks of age in bv/bv mice. However, in situ hybridization revealed that Srrm4 is not expressed in interneurons, but rather dominates in pyramidal neurons. In addition, the PV-positive GABAergic interneurons were not reduced in number in the bv/bv cortex when anxiety became evident. However, electrophysiological abnormality of GABAergic transmission from interneurons was concomitantly present. Pharmacological blockage of GABAA receptors revealed increased excitability in bv/bv mice, although no gross change occurred in the expression of an Srrm4-downstream gene, Kcc2, which regulates chloride flux upon GABAergic transmission. These findings suggest that the bv-associated Srrm4 mutation mainly involves post-synaptic GABAergic transmission in the central nervous system, which may be associated with the anxiety phenotype in bv/bv mice.