Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice
Abstract Background Neuropsychiatric disorders, such as schizophrenia (SZ) and autism spectrum disorder (ASD), are common, multi-factorial and multi-symptomatic disorders. Ample evidence implicates oxidative stress, deficient repair of oxidative DNA lesions and DNA damage in the development of these...
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | BMC Biology |
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| Online Access: | https://doi.org/10.1186/s12915-022-01377-1 |
| _version_ | 1818492082457673728 |
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| author | Flavia S. Mueller René Amport Tina Notter Sina M. Schalbetter Han-Yu Lin Zuzana Garajova Parisa Amini Ulrike Weber-Stadlbauer Enni Markkanen |
| author_facet | Flavia S. Mueller René Amport Tina Notter Sina M. Schalbetter Han-Yu Lin Zuzana Garajova Parisa Amini Ulrike Weber-Stadlbauer Enni Markkanen |
| author_sort | Flavia S. Mueller |
| collection | DOAJ |
| description | Abstract Background Neuropsychiatric disorders, such as schizophrenia (SZ) and autism spectrum disorder (ASD), are common, multi-factorial and multi-symptomatic disorders. Ample evidence implicates oxidative stress, deficient repair of oxidative DNA lesions and DNA damage in the development of these disorders. However, it remains unclear whether insufficient DNA repair and resulting DNA damage are causally connected to their aetiopathology, or if increased levels of DNA damage observed in patient tissues merely accumulate as a consequence of cellular dysfunction. To assess a potential causal role for deficient DNA repair in the development of these disorders, we behaviourally characterized a mouse model in which CaMKIIa-Cre-driven postnatal conditional knockout (KO) of the core base-excision repair (BER) protein XRCC1 leads to accumulation of unrepaired DNA damage in the forebrain. Results CaMKIIa-Cre expression caused specific deletion of XRCC1 in the dorsal dentate gyrus (DG), CA1 and CA2 and the amygdala and led to increased DNA damage therein. While motor coordination, cognition and social behaviour remained unchanged, XRCC1 KO in the forebrain caused increased anxiety-like behaviour in males, but not females, as assessed by the light–dark box and open field tests. Conversely, in females but not males, XRCC1 KO caused an increase in learned fear-related behaviour in a cued (Pavlovian) fear conditioning test and a contextual fear extinction test. The relative density of the GABA(A) receptor alpha 5 subunit (GABRA5) was reduced in the amygdala and the dorsal CA1 in XRCC1 KO females, whereas male XRCC1 KO animals exhibited a significant reduction of GABRA5 density in the CA3. Finally, assessment of fast-spiking, parvalbumin-positive (PV) GABAergic interneurons revealed a significant increase in the density of PV+ cells in the DG of male XRCC1 KO mice, while females remained unchanged. Conclusions Our results suggest that accumulation of unrepaired DNA damage in the forebrain alters the GABAergic neurotransmitter system and causes behavioural deficits in relation to innate and learned anxiety in a sex-dependent manner. Moreover, the data uncover a previously unappreciated connection between BER deficiency, unrepaired DNA damage in the hippocampus and a sex-specific anxiety-like phenotype with implications for the aetiology and therapy of neuropsychiatric disorders. |
| first_indexed | 2024-12-10T17:38:45Z |
| format | Article |
| id | doaj.art-c83009d44d3b4aa5b2786c4c265575f6 |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-12-10T17:38:45Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-c83009d44d3b4aa5b2786c4c265575f62022-12-22T01:39:27ZengBMCBMC Biology1741-70072022-07-0120111810.1186/s12915-022-01377-1Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in miceFlavia S. Mueller0René Amport1Tina Notter2Sina M. Schalbetter3Han-Yu Lin4Zuzana Garajova5Parisa Amini6Ulrike Weber-Stadlbauer7Enni Markkanen8Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of ZurichInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of ZurichNeuroscience Center Zurich, University of Zurich and ETH ZurichInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of ZurichInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of ZurichInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of ZurichInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of ZurichInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of ZurichInstitute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of ZurichAbstract Background Neuropsychiatric disorders, such as schizophrenia (SZ) and autism spectrum disorder (ASD), are common, multi-factorial and multi-symptomatic disorders. Ample evidence implicates oxidative stress, deficient repair of oxidative DNA lesions and DNA damage in the development of these disorders. However, it remains unclear whether insufficient DNA repair and resulting DNA damage are causally connected to their aetiopathology, or if increased levels of DNA damage observed in patient tissues merely accumulate as a consequence of cellular dysfunction. To assess a potential causal role for deficient DNA repair in the development of these disorders, we behaviourally characterized a mouse model in which CaMKIIa-Cre-driven postnatal conditional knockout (KO) of the core base-excision repair (BER) protein XRCC1 leads to accumulation of unrepaired DNA damage in the forebrain. Results CaMKIIa-Cre expression caused specific deletion of XRCC1 in the dorsal dentate gyrus (DG), CA1 and CA2 and the amygdala and led to increased DNA damage therein. While motor coordination, cognition and social behaviour remained unchanged, XRCC1 KO in the forebrain caused increased anxiety-like behaviour in males, but not females, as assessed by the light–dark box and open field tests. Conversely, in females but not males, XRCC1 KO caused an increase in learned fear-related behaviour in a cued (Pavlovian) fear conditioning test and a contextual fear extinction test. The relative density of the GABA(A) receptor alpha 5 subunit (GABRA5) was reduced in the amygdala and the dorsal CA1 in XRCC1 KO females, whereas male XRCC1 KO animals exhibited a significant reduction of GABRA5 density in the CA3. Finally, assessment of fast-spiking, parvalbumin-positive (PV) GABAergic interneurons revealed a significant increase in the density of PV+ cells in the DG of male XRCC1 KO mice, while females remained unchanged. Conclusions Our results suggest that accumulation of unrepaired DNA damage in the forebrain alters the GABAergic neurotransmitter system and causes behavioural deficits in relation to innate and learned anxiety in a sex-dependent manner. Moreover, the data uncover a previously unappreciated connection between BER deficiency, unrepaired DNA damage in the hippocampus and a sex-specific anxiety-like phenotype with implications for the aetiology and therapy of neuropsychiatric disorders.https://doi.org/10.1186/s12915-022-01377-1Neuronal DNA damageAnxietyGABAXRCC1DNA repair |
| spellingShingle | Flavia S. Mueller René Amport Tina Notter Sina M. Schalbetter Han-Yu Lin Zuzana Garajova Parisa Amini Ulrike Weber-Stadlbauer Enni Markkanen Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice BMC Biology Neuronal DNA damage Anxiety GABA XRCC1 DNA repair |
| title | Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice |
| title_full | Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice |
| title_fullStr | Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice |
| title_full_unstemmed | Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice |
| title_short | Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice |
| title_sort | deficient dna base excision repair in the forebrain leads to a sex specific anxiety like phenotype in mice |
| topic | Neuronal DNA damage Anxiety GABA XRCC1 DNA repair |
| url | https://doi.org/10.1186/s12915-022-01377-1 |
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