Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
| العنوان: | Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors |
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| المؤلفون: | Henry H. Yin, Erin Gaidis, Ramona M. Rodriguiz, Rebecca L Passman, Yilin Yang, Namsoo Kim, Yong-hui Jiang, Alexandra L. Bey, Lara J. Duffney, Aaron J. Towers, William C. Wetsel, Xiaoming Wang, Haidun Yan, Xinyu Cao, Samuel W Hulbert |
| المصدر: | Translational Psychiatry Translational Psychiatry, Vol 8, Iss 1, Pp 1-17 (2018) |
| بيانات النشر: | Nature Publishing Group UK, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Dissociation (neuropsychology), Autism Spectrum Disorder, Nerve Tissue Proteins, Striatum, Hippocampal formation, Biology, Inhibitory postsynaptic potential, Hippocampus, Receptors, N-Methyl-D-Aspartate, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Prosencephalon, Homer Scaffolding Proteins, Biological neural network, Animals, Social Behavior, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Mice, Knockout, Neurons, Behavior, Animal, Receptors, Dopamine D2, Receptors, Dopamine D1, Microfilament Proteins, Excitatory Postsynaptic Potentials, Corpus Striatum, Psychiatry and Mental health, Electrophysiology, Disease Models, Animal, 030104 developmental biology, Phenotype, nervous system, Forebrain, Synapses, Excitatory postsynaptic potential, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | We previously reported a new line of Shank3 mutant mice which led to a complete loss of Shank3 by deleting exons 4−22 (Δe4−22) globally. Δe4−22 mice display robust ASD-like behaviors including impaired social interaction and communication, increased stereotypical behavior and excessive grooming, and a profound deficit in instrumental learning. However, the anatomical and neural circuitry underlying these behaviors are unknown. We generated mice with Shank3 selectively deleted in forebrain, striatum, and striatal D1 and D2 cells. These mice were used to interrogate the circuit/brain-region and cell-type specific role of Shank3 in the expression of autism-related behaviors. Whole-cell patch recording and biochemical analyses were used to study the synaptic function and molecular changes in specific brain regions. We found perseverative exploratory behaviors in mice with deletion of Shank3 in striatal inhibitory neurons. Conversely, self-grooming induced lesions were observed in mice with deletion of Shank3 in excitatory neurons of forebrain. However, social, communicative, and instrumental learning behaviors were largely unaffected in these mice, unlike what is seen in global Δe4−22 mice. We discovered unique patterns of change for the biochemical and electrophysiological findings in respective brain regions that reflect the complex nature of transcriptional regulation of Shank3. Reductions in Homer1b/c and membrane hyper-excitability were observed in striatal loss of Shank3. By comparison, Shank3 deletion in hippocampal neurons resulted in increased NMDAR-currents and GluN2B-containing NMDARs. These results together suggest that Shank3 may differentially regulate neural circuits that control behavior. Our study supports a dissociation of Shank3 functions in cortical and striatal neurons in ASD-related behaviors, and it illustrates the complexity of neural circuit mechanisms underlying these behaviors. |
| اللغة: | English |
| تدمد: | 2158-3188 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::db62496c2687a5a89e07910263d8d874 http://europepmc.org/articles/PMC5919902 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....db62496c2687a5a89e07910263d8d874 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21583188 |
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