Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor antagonist SB-399885
Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT₆ receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alter...
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| Format: | Article |
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Springer
2018
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| Online Access: | https://eprints.nottingham.ac.uk/49554/ |
| _version_ | 1848798023557054464 |
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| author | Shortall, Sinead E. Negm, Ola H. Fowler, Maxine J. Fairclough, Lucy C. Tighe, Patrick J. Wigmore, Peter King, Madeleine V. |
| author_facet | Shortall, Sinead E. Negm, Ola H. Fowler, Maxine J. Fairclough, Lucy C. Tighe, Patrick J. Wigmore, Peter King, Madeleine V. |
| author_sort | Shortall, Sinead E. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT₆ receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister-hooded rats (weaned on post-natal day 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a two week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms. |
| first_indexed | 2025-11-14T20:13:11Z |
| format | Article |
| id | nottingham-49554 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:13:11Z |
| publishDate | 2018 |
| publisher | Springer |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-495542020-05-04T19:31:17Z https://eprints.nottingham.ac.uk/49554/ Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor antagonist SB-399885 Shortall, Sinead E. Negm, Ola H. Fowler, Maxine J. Fairclough, Lucy C. Tighe, Patrick J. Wigmore, Peter King, Madeleine V. Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT₆ receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister-hooded rats (weaned on post-natal day 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a two week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms. Springer 2018-02-08 Article PeerReviewed Shortall, Sinead E., Negm, Ola H., Fowler, Maxine J., Fairclough, Lucy C., Tighe, Patrick J., Wigmore, Peter and King, Madeleine V. (2018) Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor antagonist SB-399885. Molecular Neurobiology . ISSN 1559-1182 5-HT₆ receptor social isolation schizophrenia cytokines hippocampus JNK Mitogen-Activated Protein Kinases https://link.springer.com/article/10.1007%2Fs12035-018-0940-0 doi:10.1007/s12035-018-0940-0 doi:10.1007/s12035-018-0940-0 |
| spellingShingle | 5-HT₆ receptor social isolation schizophrenia cytokines hippocampus JNK Mitogen-Activated Protein Kinases Shortall, Sinead E. Negm, Ola H. Fowler, Maxine J. Fairclough, Lucy C. Tighe, Patrick J. Wigmore, Peter King, Madeleine V. Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor antagonist SB-399885 |
| title | Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor
antagonist SB-399885 |
| title_full | Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor
antagonist SB-399885 |
| title_fullStr | Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor
antagonist SB-399885 |
| title_full_unstemmed | Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor
antagonist SB-399885 |
| title_short | Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor
antagonist SB-399885 |
| title_sort | characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-ht₆ receptor
antagonist sb-399885 |
| topic | 5-HT₆ receptor social isolation schizophrenia cytokines hippocampus JNK Mitogen-Activated Protein Kinases |
| url | https://eprints.nottingham.ac.uk/49554/ https://eprints.nottingham.ac.uk/49554/ https://eprints.nottingham.ac.uk/49554/ |