Early developmental changes in a rat model of malformations of cortical development: Abnormal neuronal migration and altered response to NMDA-induced excitotoxic injury
Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental...
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| Veröffentlicht in: | Experimental neurology 2024-06, Vol.376, p.114759-114759, Article 114759 |
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| description | Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental changes in the brain of the MCD rat model, which exhibits increased seizure susceptibility during infancy (P12–15), we analyzed the pathological changes in the brains of MCD model rats during the neonatal period and tested NMDA-induced seizure susceptibility.
Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8.
In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p |
| doi_str_mv | 10.1016/j.expneurol.2024.114759 |
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Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8.
In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p < 0.001). Golgi staining and immunofluorescence revealed abnormal neuronal migration, with a reduced number of neuronal cell populations and less dendritic arborization at P8. Furthermore, MCD rats exhibited a significant reduction in the expression of NMDA receptors and AMPAR4, along with an increase in AMPAR3 expression (p < 0.05). Although there was no difference in the latency to seizure onset between MCD rats and controls, the MCD rats survived significantly longer than the controls.
These results provide insights into the early developmental changes in the cortex of a MCD rat model and suggest that delayed and abnormal neuronal development in the immature brain is associated with a blunted response to NMDA-induced excitotoxic injury. These developmental changes may be involved in the sudden onset of epilepsy in patients with MCD or prenatal brain injury.
•In vivo MR imaging can detect abnormalities in cortical growth in neonatal rats.•Prenatal exposure to methylazoxymethanol disrupts rat cortical migration from day 1.•MCD rats exhibit delayed expression of synaptic proteins on day 8.•MCD rats exhibit reduced responses to NMDA-induced toxic injury on day 8.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2024.114759</identifier><identifier>PMID: 38519010</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animal model ; Animals ; Animals, Newborn ; Cell Movement - drug effects ; Cerebral Cortex - drug effects ; Cerebral Cortex - pathology ; Disease Models, Animal ; Female ; Magnetic Resonance Imaging ; Male ; Malformation of cortical development (MCD) ; Malformations of Cortical Development - chemically induced ; Malformations of Cortical Development - pathology ; Methylazoxymethanol acetate (MAM) ; Methylazoxymethanol Acetate - analogs & derivatives ; Methylazoxymethanol Acetate - toxicity ; N-methyl-D-aspartic acid (NMDA) ; N-Methylaspartate - toxicity ; Neurons - drug effects ; Neurons - pathology ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Spasms</subject><ispartof>Experimental neurology, 2024-06, Vol.376, p.114759-114759, Article 114759</ispartof><rights>2024 The Author(s)</rights><rights>Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c366t-3609ddc3346516971204160ab516d886a9b6945f0f28774d4abd75c70c0bee393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.expneurol.2024.114759$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38519010$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Minyoung</creatorcontrib><creatorcontrib>Kim, Eun-Jin</creatorcontrib><creatorcontrib>Yum, Mi-Sun</creatorcontrib><title>Early developmental changes in a rat model of malformations of cortical development: Abnormal neuronal migration and altered response to NMDA-induced excitotoxic injury</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental changes in the brain of the MCD rat model, which exhibits increased seizure susceptibility during infancy (P12–15), we analyzed the pathological changes in the brains of MCD model rats during the neonatal period and tested NMDA-induced seizure susceptibility.
Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8.
In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p < 0.001). Golgi staining and immunofluorescence revealed abnormal neuronal migration, with a reduced number of neuronal cell populations and less dendritic arborization at P8. Furthermore, MCD rats exhibited a significant reduction in the expression of NMDA receptors and AMPAR4, along with an increase in AMPAR3 expression (p < 0.05). Although there was no difference in the latency to seizure onset between MCD rats and controls, the MCD rats survived significantly longer than the controls.
These results provide insights into the early developmental changes in the cortex of a MCD rat model and suggest that delayed and abnormal neuronal development in the immature brain is associated with a blunted response to NMDA-induced excitotoxic injury. These developmental changes may be involved in the sudden onset of epilepsy in patients with MCD or prenatal brain injury.
•In vivo MR imaging can detect abnormalities in cortical growth in neonatal rats.•Prenatal exposure to methylazoxymethanol disrupts rat cortical migration from day 1.•MCD rats exhibit delayed expression of synaptic proteins on day 8.•MCD rats exhibit reduced responses to NMDA-induced toxic injury on day 8.</description><subject>Animal model</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Cell Movement - drug effects</subject><subject>Cerebral Cortex - drug effects</subject><subject>Cerebral Cortex - pathology</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Magnetic Resonance Imaging</subject><subject>Male</subject><subject>Malformation of cortical development (MCD)</subject><subject>Malformations of Cortical Development - chemically induced</subject><subject>Malformations of Cortical Development - pathology</subject><subject>Methylazoxymethanol acetate (MAM)</subject><subject>Methylazoxymethanol Acetate - analogs & derivatives</subject><subject>Methylazoxymethanol Acetate - toxicity</subject><subject>N-methyl-D-aspartic acid (NMDA)</subject><subject>N-Methylaspartate - toxicity</subject><subject>Neurons - drug effects</subject><subject>Neurons - pathology</subject><subject>Pregnancy</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Spasms</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAUhSMEotPCK4CXbDJcJ44zZjdqC0UqsIG15dg3xSPHDrZTzbwRj4mnUyp2rPz3nXOv76mqtxTWFCh_v1vjfva4xODWDTRsTSnrO_GsWlEQUDeshefVCoCymm02_Kw6T2kHAII1_cvqrN10VACFVfX7WkV3IAbv0YV5Qp-VI_qn8neYiPVEkagymYJBR8JIJuXGECeVbfDpeKFDzFYXzT8OH8h28EfKkYcWfdlM9i4-qIjyhiiXMaIhEdNcjJDkQL5-udrW1ptFlwfca5tDDnurSxe7JR5eVS9G5RK-flwvqh8fr79f3tS33z59vtze1rrlPNctB2GMblvGO8pFTxtglIMaysmUSSgxcMG6EcZm0_fMMDWYvtM9aBgQW9FeVO9OvnMMvxZMWU42aXROeQxLko3oGUBx4wXtT6iOIaWIo5yjnVQ8SAryGJPcyaeY5DEmeYqpKN88FlmGCc2T7m8uBdieACxfvbcYZdIWfRmNjaizNMH-t8gfL-arnA</recordid><startdate>202406</startdate><enddate>202406</enddate><creator>Lee, Minyoung</creator><creator>Kim, Eun-Jin</creator><creator>Yum, Mi-Sun</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202406</creationdate><title>Early developmental changes in a rat model of malformations of cortical development: Abnormal neuronal migration and altered response to NMDA-induced excitotoxic injury</title><author>Lee, Minyoung ; Kim, Eun-Jin ; Yum, Mi-Sun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c366t-3609ddc3346516971204160ab516d886a9b6945f0f28774d4abd75c70c0bee393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animal model</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Cell Movement - drug effects</topic><topic>Cerebral Cortex - drug effects</topic><topic>Cerebral Cortex - pathology</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Magnetic Resonance Imaging</topic><topic>Male</topic><topic>Malformation of cortical development (MCD)</topic><topic>Malformations of Cortical Development - chemically induced</topic><topic>Malformations of Cortical Development - pathology</topic><topic>Methylazoxymethanol acetate (MAM)</topic><topic>Methylazoxymethanol Acetate - analogs & derivatives</topic><topic>Methylazoxymethanol Acetate - toxicity</topic><topic>N-methyl-D-aspartic acid (NMDA)</topic><topic>N-Methylaspartate - toxicity</topic><topic>Neurons - drug effects</topic><topic>Neurons - pathology</topic><topic>Pregnancy</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Spasms</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Minyoung</creatorcontrib><creatorcontrib>Kim, Eun-Jin</creatorcontrib><creatorcontrib>Yum, Mi-Sun</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Minyoung</au><au>Kim, Eun-Jin</au><au>Yum, Mi-Sun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Early developmental changes in a rat model of malformations of cortical development: Abnormal neuronal migration and altered response to NMDA-induced excitotoxic injury</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2024-06</date><risdate>2024</risdate><volume>376</volume><spage>114759</spage><epage>114759</epage><pages>114759-114759</pages><artnum>114759</artnum><issn>0014-4886</issn><eissn>1090-2430</eissn><abstract>Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental changes in the brain of the MCD rat model, which exhibits increased seizure susceptibility during infancy (P12–15), we analyzed the pathological changes in the brains of MCD model rats during the neonatal period and tested NMDA-induced seizure susceptibility.
Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8.
In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p < 0.001). Golgi staining and immunofluorescence revealed abnormal neuronal migration, with a reduced number of neuronal cell populations and less dendritic arborization at P8. Furthermore, MCD rats exhibited a significant reduction in the expression of NMDA receptors and AMPAR4, along with an increase in AMPAR3 expression (p < 0.05). Although there was no difference in the latency to seizure onset between MCD rats and controls, the MCD rats survived significantly longer than the controls.
These results provide insights into the early developmental changes in the cortex of a MCD rat model and suggest that delayed and abnormal neuronal development in the immature brain is associated with a blunted response to NMDA-induced excitotoxic injury. These developmental changes may be involved in the sudden onset of epilepsy in patients with MCD or prenatal brain injury.
•In vivo MR imaging can detect abnormalities in cortical growth in neonatal rats.•Prenatal exposure to methylazoxymethanol disrupts rat cortical migration from day 1.•MCD rats exhibit delayed expression of synaptic proteins on day 8.•MCD rats exhibit reduced responses to NMDA-induced toxic injury on day 8.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>38519010</pmid><doi>10.1016/j.expneurol.2024.114759</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animal model Animals Animals, Newborn Cell Movement - drug effects Cerebral Cortex - drug effects Cerebral Cortex - pathology Disease Models, Animal Female Magnetic Resonance Imaging Male Malformation of cortical development (MCD) Malformations of Cortical Development - chemically induced Malformations of Cortical Development - pathology Methylazoxymethanol acetate (MAM) Methylazoxymethanol Acetate - analogs & derivatives Methylazoxymethanol Acetate - toxicity N-methyl-D-aspartic acid (NMDA) N-Methylaspartate - toxicity Neurons - drug effects Neurons - pathology Pregnancy Rats Rats, Sprague-Dawley Spasms |
| title | Early developmental changes in a rat model of malformations of cortical development: Abnormal neuronal migration and altered response to NMDA-induced excitotoxic injury |
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