Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit
Abstract Background Disruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has...
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-022-00835-w |
| _version_ | 1827983219987841024 |
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| author | Ming-Chia Chu Han-Fang Wu Chi-Wei Lee Yueh-Jung Chung Hsiang Chi Po See Chen Hui-Ching Lin |
| author_facet | Ming-Chia Chu Han-Fang Wu Chi-Wei Lee Yueh-Jung Chung Hsiang Chi Po See Chen Hui-Ching Lin |
| author_sort | Ming-Chia Chu |
| collection | DOAJ |
| description | Abstract Background Disruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD. Methods The F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques. Results Social deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference. Conclusions Taken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD. |
| first_indexed | 2024-04-09T22:44:16Z |
| format | Article |
| id | doaj.art-de4a1e87b9234b019a8a08da718d3fe6 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-04-09T22:44:16Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-de4a1e87b9234b019a8a08da718d3fe62023-03-22T11:59:19ZengBMCJournal of Biomedical Science1423-01272022-07-0129111610.1186/s12929-022-00835-wGenerational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficitMing-Chia Chu0Han-Fang Wu1Chi-Wei Lee2Yueh-Jung Chung3Hsiang Chi4Po See Chen5Hui-Ching Lin6Department and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung UniversityDepartment and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung UniversityDepartment of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDepartment and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung UniversityAbstract Background Disruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD. Methods The F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques. Results Social deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference. Conclusions Taken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.https://doi.org/10.1186/s12929-022-00835-wGABAARExcitatory/inhibitory imbalanceGephyrinGenerational effectValproateAutism spectrum disorder |
| spellingShingle | Ming-Chia Chu Han-Fang Wu Chi-Wei Lee Yueh-Jung Chung Hsiang Chi Po See Chen Hui-Ching Lin Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit Journal of Biomedical Science GABAAR Excitatory/inhibitory imbalance Gephyrin Generational effect Valproate Autism spectrum disorder |
| title | Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit |
| title_full | Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit |
| title_fullStr | Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit |
| title_full_unstemmed | Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit |
| title_short | Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit |
| title_sort | generational synaptic functions of gabaa receptor β3 subunit deteriorations in an animal model of social deficit |
| topic | GABAAR Excitatory/inhibitory imbalance Gephyrin Generational effect Valproate Autism spectrum disorder |
| url | https://doi.org/10.1186/s12929-022-00835-w |
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