Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone
<p dir="ltr">Schizophrenia is a neurodevelopmental disorder likely caused by environmental and genetic risk factors but functional interactions between the risk factors are unclear. We tested the hypothesis that dysbindin-1 (Dtnbp1) gene mutation combined with postnatal exposure to v...
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| مؤلفون آخرون: | , , , |
| منشور في: |
2018
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| _version_ | 1864513557653094400 |
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| author | Abeer R. Al-Shammari (11405339) |
| author2 | Sanjeev K. Bhardwaj (288221) Ksenia Musaelyan (8670873) Lalit K. Srivastava (13881896) Francis G. Szele (9463190) |
| author2_role | author author author author |
| author_facet | Abeer R. Al-Shammari (11405339) Sanjeev K. Bhardwaj (288221) Ksenia Musaelyan (8670873) Lalit K. Srivastava (13881896) Francis G. Szele (9463190) |
| author_role | author |
| dc.creator.none.fl_str_mv | Abeer R. Al-Shammari (11405339) Sanjeev K. Bhardwaj (288221) Ksenia Musaelyan (8670873) Lalit K. Srivastava (13881896) Francis G. Szele (9463190) |
| dc.date.none.fl_str_mv | 2018-07-23T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41537-018-0057-5 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Schizophrenia-related_dysbindin-1_gene_is_required_for_innate_immune_response_and_homeostasis_in_the_developing_subventricular_zone/27050362 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Neurosciences Behavioral changes Inflammation Subventricular zone (SVZ) Prepulse inhibition Locomotion Novel object recognition |
| dc.title.none.fl_str_mv | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Schizophrenia is a neurodevelopmental disorder likely caused by environmental and genetic risk factors but functional interactions between the risk factors are unclear. We tested the hypothesis that dysbindin-1 (Dtnbp1) gene mutation combined with postnatal exposure to viral mimetic polyI:C results in schizophrenia-related behavioural changes in adulthood, and mediates polyI:C-induced inflammation in the subventricular zone (SVZ). Adult Sandy (Sdy, Dtnbp1 mutant) mice given early postnatal polyI:C injections displayed reduced prepulse inhibition of startle, reduced locomotion and deficits in novel object recognition. PolyI:C induced a canonical immune response in the SVZ; it increased mRNA expression of its toll-like receptor 3 (Tlr3) and downstream transcription factors RelA and Sp1. PolyI:C also increased SVZ Dtnbp1 mRNA expression, suggesting dysbindin-1 regulates immune responses. Dysbindin-1 loss in Sdy mice blocked the polyI:C-induced increases in mRNA expression of Tlr3, RelA and Sp1 in the SVZ. Dtnbp1 overexpression in SVZ-derived Sdy neurospheres rescued Tlr3, RelA and Sp1 mRNA expression supporting a functional interaction between dysbindin-1 and polyI:C-induced inflammation. Immunohistochemistry showed higher Iba1+ immune cell density in the SVZ of Sdy mice than in WT postnatally. PolyI:C did not alter SVZ Iba1+ cell density but increased CD45+/Iba1− cell numbers in the SVZ of Sdy mice. Finally, polyI:C injections in Sdy, but not WT mice reduced postnatal and adult SVZ proliferation. Together, we show novel functional interactions between the schizophrenia-relevant dysbindin-1 gene and the immune response to polyI:C. This work sheds light on the molecular basis for amplified abnormalities due to combined genetic predisposition and exposure to environmental schizophrenia risk factors.</p><h2>Other Information</h2><p dir="ltr">Published in: npj Schizophrenia<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41537-018-0057-5" target="_blank">https://dx.doi.org/10.1038/s41537-018-0057-5</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_53dd4c271c75666daf3fdc4da81c26f1 |
| identifier_str_mv | 10.1038/s41537-018-0057-5 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/27050362 |
| publishDate | 2018 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zoneAbeer R. Al-Shammari (11405339)Sanjeev K. Bhardwaj (288221)Ksenia Musaelyan (8670873)Lalit K. Srivastava (13881896)Francis G. Szele (9463190)Biomedical and clinical sciencesClinical sciencesNeurosciencesBehavioral changesInflammationSubventricular zone (SVZ)Prepulse inhibitionLocomotionNovel object recognition<p dir="ltr">Schizophrenia is a neurodevelopmental disorder likely caused by environmental and genetic risk factors but functional interactions between the risk factors are unclear. We tested the hypothesis that dysbindin-1 (Dtnbp1) gene mutation combined with postnatal exposure to viral mimetic polyI:C results in schizophrenia-related behavioural changes in adulthood, and mediates polyI:C-induced inflammation in the subventricular zone (SVZ). Adult Sandy (Sdy, Dtnbp1 mutant) mice given early postnatal polyI:C injections displayed reduced prepulse inhibition of startle, reduced locomotion and deficits in novel object recognition. PolyI:C induced a canonical immune response in the SVZ; it increased mRNA expression of its toll-like receptor 3 (Tlr3) and downstream transcription factors RelA and Sp1. PolyI:C also increased SVZ Dtnbp1 mRNA expression, suggesting dysbindin-1 regulates immune responses. Dysbindin-1 loss in Sdy mice blocked the polyI:C-induced increases in mRNA expression of Tlr3, RelA and Sp1 in the SVZ. Dtnbp1 overexpression in SVZ-derived Sdy neurospheres rescued Tlr3, RelA and Sp1 mRNA expression supporting a functional interaction between dysbindin-1 and polyI:C-induced inflammation. Immunohistochemistry showed higher Iba1+ immune cell density in the SVZ of Sdy mice than in WT postnatally. PolyI:C did not alter SVZ Iba1+ cell density but increased CD45+/Iba1− cell numbers in the SVZ of Sdy mice. Finally, polyI:C injections in Sdy, but not WT mice reduced postnatal and adult SVZ proliferation. Together, we show novel functional interactions between the schizophrenia-relevant dysbindin-1 gene and the immune response to polyI:C. This work sheds light on the molecular basis for amplified abnormalities due to combined genetic predisposition and exposure to environmental schizophrenia risk factors.</p><h2>Other Information</h2><p dir="ltr">Published in: npj Schizophrenia<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41537-018-0057-5" target="_blank">https://dx.doi.org/10.1038/s41537-018-0057-5</a></p>2018-07-23T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41537-018-0057-5https://figshare.com/articles/journal_contribution/Schizophrenia-related_dysbindin-1_gene_is_required_for_innate_immune_response_and_homeostasis_in_the_developing_subventricular_zone/27050362CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/270503622018-07-23T03:00:00Z |
| spellingShingle | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone Abeer R. Al-Shammari (11405339) Biomedical and clinical sciences Clinical sciences Neurosciences Behavioral changes Inflammation Subventricular zone (SVZ) Prepulse inhibition Locomotion Novel object recognition |
| status_str | publishedVersion |
| title | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone |
| title_full | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone |
| title_fullStr | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone |
| title_full_unstemmed | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone |
| title_short | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone |
| title_sort | Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone |
| topic | Biomedical and clinical sciences Clinical sciences Neurosciences Behavioral changes Inflammation Subventricular zone (SVZ) Prepulse inhibition Locomotion Novel object recognition |