Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice

BACKGROUND:Experimental evidence shows postnatal exposure to anesthesia negatively affects brain development. The PDZ2 domain, mediating protein–protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that ea...

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Veröffentlicht in:Anesthesiology (Philadelphia) 2020-10, Vol.133 (4), p.812-823
Hauptverfasser: Schaefer, Michele L., Perez, Patric J., Wang, Meina, Gray, Christy, Krall, Caroline, Sun, Xiaoning, Hunter, Elizabeth, Skinner, John, Johns, Roger A.
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container_end_page 823
container_issue 4
container_start_page 812
container_title Anesthesiology (Philadelphia)
container_volume 133
creator Schaefer, Michele L.
Perez, Patric J.
Wang, Meina
Gray, Christy
Krall, Caroline
Sun, Xiaoning
Hunter, Elizabeth
Skinner, John
Johns, Roger A.
description BACKGROUND:Experimental evidence shows postnatal exposure to anesthesia negatively affects brain development. The PDZ2 domain, mediating protein–protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that early postnatal disruption of postsynaptic density-95 PDZ2 domain interactions has persistent effects on dendritic spines and cognitive function. METHODS:One-week-old mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active postsynaptic density-95 wild-type PDZ2 peptide along with their respective controls. A subset of these mice also received 4 mg/kg of the nitric oxide donor molsidomine. Hippocampal spine density, long-term potentiation, novel object recognition memory, and fear learning and memory were evaluated in mice. RESULTS:Exposure of 7-day-old mice to isoflurane or postsynaptic density-95 wild-type PDZ2 peptide relative to controls causes(1) a long-term decrease in mushroom spines at 7 weeks (mean ± SD [spines per micrometer])control (0.8 ± 0.2) versus isoflurane (0.4 ± 0.2), P < 0.0001, and PDZ2MUT (0.7 ± 0.2) versus PDZ2WT (0.4 ± 0.2), P < 0.001; (2) deficits in object recognition at 6 weeks (mean ± SD [recognition index])naïve (70 ± 8) versus isoflurane (55 ± 14), P = 0.010, and control (65 ± 13) versus isoflurane (55 ± 14), P = 0.045, and PDZ2MUT (64 ±11) versus PDZ2WT (53 ± 18), P = 0.045; and (3) deficits in fear learning at 7 weeks and memory at 8 weeks (mean ± SD [% freezing duration])Learning, control (69 ± 12) versus isoflurane (52 ± 13), P < 0.0001, and PDZ2MUT (65 ± 14) versus PDZ2WT (55 ± 14) P = 0.011, and Memory, control (80 ± 17) versus isoflurane (56 ± 23), P < 0.0001 and PDZ2MUT (73 ± 18) versus PDZ2WT (44 ± 19) P < 0.0001. Impairment in long-term potentiation has fully recovered here at 7 weeks (mean ± SD [% baseline])control (140 ± 3) versus isoflurane (137 ± 8), P = 0.560, and PDZ2MUT (136 ± 17) versus PDZ2WT (128 ± 11), P = 0.512. The isoflurane induced decrease in mushroom spines was preventable by introduction of a nitric oxide donor. CONCLUSIONS:Early disruption of PDZ2 domain-mediated protein–protein interactions mimics isoflurane in decreasing mushroom spine density and causing learning and memory deficits in mice. Prevention of the decrease in mushroom spine density with a nitric oxide donor supports a role for neuronal nitric oxide synthase pathway in mediating this cellular change associated with cognitiv
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The PDZ2 domain, mediating protein–protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that early postnatal disruption of postsynaptic density-95 PDZ2 domain interactions has persistent effects on dendritic spines and cognitive function. METHODS:One-week-old mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active postsynaptic density-95 wild-type PDZ2 peptide along with their respective controls. A subset of these mice also received 4 mg/kg of the nitric oxide donor molsidomine. Hippocampal spine density, long-term potentiation, novel object recognition memory, and fear learning and memory were evaluated in mice. RESULTS:Exposure of 7-day-old mice to isoflurane or postsynaptic density-95 wild-type PDZ2 peptide relative to controls causes(1) a long-term decrease in mushroom spines at 7 weeks (mean ± SD [spines per micrometer])control (0.8 ± 0.2) versus isoflurane (0.4 ± 0.2), P &lt; 0.0001, and PDZ2MUT (0.7 ± 0.2) versus PDZ2WT (0.4 ± 0.2), P &lt; 0.001; (2) deficits in object recognition at 6 weeks (mean ± SD [recognition index])naïve (70 ± 8) versus isoflurane (55 ± 14), P = 0.010, and control (65 ± 13) versus isoflurane (55 ± 14), P = 0.045, and PDZ2MUT (64 ±11) versus PDZ2WT (53 ± 18), P = 0.045; and (3) deficits in fear learning at 7 weeks and memory at 8 weeks (mean ± SD [% freezing duration])Learning, control (69 ± 12) versus isoflurane (52 ± 13), P &lt; 0.0001, and PDZ2MUT (65 ± 14) versus PDZ2WT (55 ± 14) P = 0.011, and Memory, control (80 ± 17) versus isoflurane (56 ± 23), P &lt; 0.0001 and PDZ2MUT (73 ± 18) versus PDZ2WT (44 ± 19) P &lt; 0.0001. Impairment in long-term potentiation has fully recovered here at 7 weeks (mean ± SD [% baseline])control (140 ± 3) versus isoflurane (137 ± 8), P = 0.560, and PDZ2MUT (136 ± 17) versus PDZ2WT (128 ± 11), P = 0.512. The isoflurane induced decrease in mushroom spines was preventable by introduction of a nitric oxide donor. CONCLUSIONS:Early disruption of PDZ2 domain-mediated protein–protein interactions mimics isoflurane in decreasing mushroom spine density and causing learning and memory deficits in mice. Prevention of the decrease in mushroom spine density with a nitric oxide donor supports a role for neuronal nitric oxide synthase pathway in mediating this cellular change associated with cognitive impairment.</description><identifier>ISSN: 0003-3022</identifier><identifier>EISSN: 1528-1175</identifier><identifier>DOI: 10.1097/ALN.0000000000003482</identifier><identifier>PMID: 32773681</identifier><language>eng</language><publisher>United States: the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc</publisher><subject>Anesthetics, Inhalation - toxicity ; Animals ; Animals, Newborn ; Cognition - drug effects ; Cognition - physiology ; Dendritic Spines - drug effects ; Dendritic Spines - pathology ; Dendritic Spines - physiology ; Disks Large Homolog 4 Protein - antagonists &amp; inhibitors ; Disks Large Homolog 4 Protein - physiology ; Female ; Isoflurane - toxicity ; Male ; Mice ; Mice, Inbred C57BL ; Organ Culture Techniques ; Peptides - pharmacology ; Post-Synaptic Density - drug effects ; Post-Synaptic Density - pathology ; Post-Synaptic Density - physiology</subject><ispartof>Anesthesiology (Philadelphia), 2020-10, Vol.133 (4), p.812-823</ispartof><rights>the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.</rights><rights>Copyright © by 2020, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.</rights><rights>Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5532-c8fe22a3585aaaf4018357bfa3b5ebbaf4d03582849fcf96f3c291866abc29603</citedby><cites>FETCH-LOGICAL-c5532-c8fe22a3585aaaf4018357bfa3b5ebbaf4d03582849fcf96f3c291866abc29603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32773681$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schaefer, Michele L.</creatorcontrib><creatorcontrib>Perez, Patric J.</creatorcontrib><creatorcontrib>Wang, Meina</creatorcontrib><creatorcontrib>Gray, Christy</creatorcontrib><creatorcontrib>Krall, Caroline</creatorcontrib><creatorcontrib>Sun, Xiaoning</creatorcontrib><creatorcontrib>Hunter, Elizabeth</creatorcontrib><creatorcontrib>Skinner, John</creatorcontrib><creatorcontrib>Johns, Roger A.</creatorcontrib><title>Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice</title><title>Anesthesiology (Philadelphia)</title><addtitle>Anesthesiology</addtitle><description>BACKGROUND:Experimental evidence shows postnatal exposure to anesthesia negatively affects brain development. The PDZ2 domain, mediating protein–protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that early postnatal disruption of postsynaptic density-95 PDZ2 domain interactions has persistent effects on dendritic spines and cognitive function. METHODS:One-week-old mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active postsynaptic density-95 wild-type PDZ2 peptide along with their respective controls. A subset of these mice also received 4 mg/kg of the nitric oxide donor molsidomine. Hippocampal spine density, long-term potentiation, novel object recognition memory, and fear learning and memory were evaluated in mice. RESULTS:Exposure of 7-day-old mice to isoflurane or postsynaptic density-95 wild-type PDZ2 peptide relative to controls causes(1) a long-term decrease in mushroom spines at 7 weeks (mean ± SD [spines per micrometer])control (0.8 ± 0.2) versus isoflurane (0.4 ± 0.2), P &lt; 0.0001, and PDZ2MUT (0.7 ± 0.2) versus PDZ2WT (0.4 ± 0.2), P &lt; 0.001; (2) deficits in object recognition at 6 weeks (mean ± SD [recognition index])naïve (70 ± 8) versus isoflurane (55 ± 14), P = 0.010, and control (65 ± 13) versus isoflurane (55 ± 14), P = 0.045, and PDZ2MUT (64 ±11) versus PDZ2WT (53 ± 18), P = 0.045; and (3) deficits in fear learning at 7 weeks and memory at 8 weeks (mean ± SD [% freezing duration])Learning, control (69 ± 12) versus isoflurane (52 ± 13), P &lt; 0.0001, and PDZ2MUT (65 ± 14) versus PDZ2WT (55 ± 14) P = 0.011, and Memory, control (80 ± 17) versus isoflurane (56 ± 23), P &lt; 0.0001 and PDZ2MUT (73 ± 18) versus PDZ2WT (44 ± 19) P &lt; 0.0001. Impairment in long-term potentiation has fully recovered here at 7 weeks (mean ± SD [% baseline])control (140 ± 3) versus isoflurane (137 ± 8), P = 0.560, and PDZ2MUT (136 ± 17) versus PDZ2WT (128 ± 11), P = 0.512. The isoflurane induced decrease in mushroom spines was preventable by introduction of a nitric oxide donor. CONCLUSIONS:Early disruption of PDZ2 domain-mediated protein–protein interactions mimics isoflurane in decreasing mushroom spine density and causing learning and memory deficits in mice. Prevention of the decrease in mushroom spine density with a nitric oxide donor supports a role for neuronal nitric oxide synthase pathway in mediating this cellular change associated with cognitive impairment.</description><subject>Anesthetics, Inhalation - toxicity</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Cognition - drug effects</subject><subject>Cognition - physiology</subject><subject>Dendritic Spines - drug effects</subject><subject>Dendritic Spines - pathology</subject><subject>Dendritic Spines - physiology</subject><subject>Disks Large Homolog 4 Protein - antagonists &amp; inhibitors</subject><subject>Disks Large Homolog 4 Protein - physiology</subject><subject>Female</subject><subject>Isoflurane - toxicity</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Organ Culture Techniques</subject><subject>Peptides - pharmacology</subject><subject>Post-Synaptic Density - drug effects</subject><subject>Post-Synaptic Density - pathology</subject><subject>Post-Synaptic Density - physiology</subject><issn>0003-3022</issn><issn>1528-1175</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkd9u0zAUxi0EYmXsDRDyC2T4T5w4N0hVt0FRGZNg19FJetwYMruyk059IN4TZx3T2AWzZNnnnO_3WfJHyDvOTjmryg_z1eUpe7RkrsULMuNK6IzzUr0ks6mbSSbEEXkT489Ulkrq1-RIirKUheYz8vsSvYMBerqM3vRjAId07jAOHUYL1Ad6ZmMYt4P1jnpDr3wc4t5BarT0DF20wz6rFL0KfkDr6NINGKCd5JEuOnAbnGTrYCfg-9Y6vMcsRgpuTRd-41K1Q3oxujuQJp8v4w6d7ZF-tS2-Ja8M9BFP7s9jcn1x_mPxOVt9-7RczFdZq5QUWasNCgFSaQUAJmdcS1U2BmSjsGlSZ83SUOi8Mq2pCiNbUXFdFNCkS8HkMfl48N2OzQ2uW3RDgL7eBnsDYV97sPW_E2e7euN3dZlXudKTQX4waIOPMaB5YDmrp9jqFFv9NLaEvX_87gP0N6ck0AfBre_T_8Zf_XiLoe4Q-qF7zjv_D3qnU7nIBBOMT0WWtsjlH-qVuMU</recordid><startdate>202010</startdate><enddate>202010</enddate><creator>Schaefer, Michele L.</creator><creator>Perez, Patric J.</creator><creator>Wang, Meina</creator><creator>Gray, Christy</creator><creator>Krall, Caroline</creator><creator>Sun, Xiaoning</creator><creator>Hunter, Elizabeth</creator><creator>Skinner, John</creator><creator>Johns, Roger A.</creator><general>the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc</general><general>Copyright by , the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc</general><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>5PM</scope></search><sort><creationdate>202010</creationdate><title>Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice</title><author>Schaefer, Michele L. ; Perez, Patric J. ; Wang, Meina ; Gray, Christy ; Krall, Caroline ; Sun, Xiaoning ; Hunter, Elizabeth ; Skinner, John ; Johns, Roger A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5532-c8fe22a3585aaaf4018357bfa3b5ebbaf4d03582849fcf96f3c291866abc29603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Anesthetics, Inhalation - toxicity</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Cognition - drug effects</topic><topic>Cognition - physiology</topic><topic>Dendritic Spines - drug effects</topic><topic>Dendritic Spines - pathology</topic><topic>Dendritic Spines - physiology</topic><topic>Disks Large Homolog 4 Protein - antagonists &amp; inhibitors</topic><topic>Disks Large Homolog 4 Protein - physiology</topic><topic>Female</topic><topic>Isoflurane - toxicity</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Organ Culture Techniques</topic><topic>Peptides - pharmacology</topic><topic>Post-Synaptic Density - drug effects</topic><topic>Post-Synaptic Density - pathology</topic><topic>Post-Synaptic Density - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schaefer, Michele L.</creatorcontrib><creatorcontrib>Perez, Patric J.</creatorcontrib><creatorcontrib>Wang, Meina</creatorcontrib><creatorcontrib>Gray, Christy</creatorcontrib><creatorcontrib>Krall, Caroline</creatorcontrib><creatorcontrib>Sun, Xiaoning</creatorcontrib><creatorcontrib>Hunter, Elizabeth</creatorcontrib><creatorcontrib>Skinner, John</creatorcontrib><creatorcontrib>Johns, Roger A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Anesthesiology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schaefer, Michele L.</au><au>Perez, Patric J.</au><au>Wang, Meina</au><au>Gray, Christy</au><au>Krall, Caroline</au><au>Sun, Xiaoning</au><au>Hunter, Elizabeth</au><au>Skinner, John</au><au>Johns, Roger A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice</atitle><jtitle>Anesthesiology (Philadelphia)</jtitle><addtitle>Anesthesiology</addtitle><date>2020-10</date><risdate>2020</risdate><volume>133</volume><issue>4</issue><spage>812</spage><epage>823</epage><pages>812-823</pages><issn>0003-3022</issn><eissn>1528-1175</eissn><abstract>BACKGROUND:Experimental evidence shows postnatal exposure to anesthesia negatively affects brain development. The PDZ2 domain, mediating protein–protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that early postnatal disruption of postsynaptic density-95 PDZ2 domain interactions has persistent effects on dendritic spines and cognitive function. METHODS:One-week-old mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active postsynaptic density-95 wild-type PDZ2 peptide along with their respective controls. A subset of these mice also received 4 mg/kg of the nitric oxide donor molsidomine. Hippocampal spine density, long-term potentiation, novel object recognition memory, and fear learning and memory were evaluated in mice. RESULTS:Exposure of 7-day-old mice to isoflurane or postsynaptic density-95 wild-type PDZ2 peptide relative to controls causes(1) a long-term decrease in mushroom spines at 7 weeks (mean ± SD [spines per micrometer])control (0.8 ± 0.2) versus isoflurane (0.4 ± 0.2), P &lt; 0.0001, and PDZ2MUT (0.7 ± 0.2) versus PDZ2WT (0.4 ± 0.2), P &lt; 0.001; (2) deficits in object recognition at 6 weeks (mean ± SD [recognition index])naïve (70 ± 8) versus isoflurane (55 ± 14), P = 0.010, and control (65 ± 13) versus isoflurane (55 ± 14), P = 0.045, and PDZ2MUT (64 ±11) versus PDZ2WT (53 ± 18), P = 0.045; and (3) deficits in fear learning at 7 weeks and memory at 8 weeks (mean ± SD [% freezing duration])Learning, control (69 ± 12) versus isoflurane (52 ± 13), P &lt; 0.0001, and PDZ2MUT (65 ± 14) versus PDZ2WT (55 ± 14) P = 0.011, and Memory, control (80 ± 17) versus isoflurane (56 ± 23), P &lt; 0.0001 and PDZ2MUT (73 ± 18) versus PDZ2WT (44 ± 19) P &lt; 0.0001. Impairment in long-term potentiation has fully recovered here at 7 weeks (mean ± SD [% baseline])control (140 ± 3) versus isoflurane (137 ± 8), P = 0.560, and PDZ2MUT (136 ± 17) versus PDZ2WT (128 ± 11), P = 0.512. The isoflurane induced decrease in mushroom spines was preventable by introduction of a nitric oxide donor. CONCLUSIONS:Early disruption of PDZ2 domain-mediated protein–protein interactions mimics isoflurane in decreasing mushroom spine density and causing learning and memory deficits in mice. Prevention of the decrease in mushroom spine density with a nitric oxide donor supports a role for neuronal nitric oxide synthase pathway in mediating this cellular change associated with cognitive impairment.</abstract><cop>United States</cop><pub>the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc</pub><pmid>32773681</pmid><doi>10.1097/ALN.0000000000003482</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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subjects Anesthetics, Inhalation - toxicity
Animals
Animals, Newborn
Cognition - drug effects
Cognition - physiology
Dendritic Spines - drug effects
Dendritic Spines - pathology
Dendritic Spines - physiology
Disks Large Homolog 4 Protein - antagonists & inhibitors
Disks Large Homolog 4 Protein - physiology
Female
Isoflurane - toxicity
Male
Mice
Mice, Inbred C57BL
Organ Culture Techniques
Peptides - pharmacology
Post-Synaptic Density - drug effects
Post-Synaptic Density - pathology
Post-Synaptic Density - physiology
title Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice
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