573d80c14b463fdee28ba6317fd76e47 CerCor_a2024v34n1pbhad431.pdf ebe226c3f50e292d25737ed5871e052187ed5321 CerCor_a2024v34n1pbhad431.pdf 7783e515a65b89b65ae7a61be380075cb4f431fc34db152605beb16f90463977 CerCor_a2024v34n1pbhad431.pdf Title: Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A Subject: AcademicSubjects/MED00310, AcademicSubjects/MED00385, AcademicSubjects/SCI01870, DOI: 10.1093/cercor/bhad431, Cerebral Cortex, 34, 1, 23 11 2023. Abstract: In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum. Through computational modeling, we determined that these alterations resulted in reduced storage capacity and compromised integration of inputs, with decreased high γ oscillations. Contrary to prevailing assumptions, our model suggests that deficits in neuronal architecture, rather than over-inhibition, primarily contribute to the reduced network. We explored the potential of environmental enrichment (EE) as a therapeutic intervention and found that it normalized the excitation-inhibition balance, restored LTP, and improved short-term recognition memory. Interestingly, we observed transient significant dendritic remodeling, leading to recovered high γ. However, these effects were not sustained after EE discontinuation. Based on our findings, we conclude that Dyrk1A overexpression-induced layer-specific neuromorphological disturbances impair the encoding of place and temporal context. These findings contribute to our understanding of the underlying mechanisms of Dyrk1A-related hippocampal deficits and highlight the challenges associated with long-term therapeutic interventions for cognitive impairments. Keywords: Author: Creator: LaTeX with hyperref package Producer: Acrobat Distiller 23.0 (Windows); modified using iTextSharp 4.1.6 by 1T3XT CreationDate: Fri Jan 12 09:05:34 2024 CET ModDate: Wed Apr 17 11:46:56 2024 CEST Custom Metadata: yes Metadata Stream: yes Tagged: yes UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.26 x 782.337 pts Page rot: 0 File size: 4481837 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- NCOIJF+CaeciliaLTStd-LightItalic Type 1C Custom yes yes yes 62 0 NCOIIE+CaeciliaLTStd-Heavy Type 1C Custom yes yes yes 63 0 NCOIGE+MTMI Type 1C Custom yes yes yes 64 0 NCOHOG+CaeciliaLTStd-Light Type 1C Custom yes yes yes 65 0 NCOHKH+CaeciliaLTStd-Italic Type 1C Custom yes yes yes 66 0 NCOHGH+CaeciliaLTStd-Roman Type 1C Custom yes yes yes 120 0 NCOHGG+CaeciliaLTStd-Bold Type 1C Custom yes yes yes 67 0 AAEHCN+ArialMT TrueType WinAnsi yes yes no 1 0 NCOJGB+MTSYN Type 1C Custom yes yes yes 61 0 NCOKJL+BLEX Type 1C Custom yes yes no 133 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-04-19 02:44:10 CEST RepresentationInformation: CerCor_a2024v34n1pbhad431.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-04-17 11:50:21 CEST Size: 4481837 Format: PDF Version: 1.7 Status: Well-Formed, but not valid SignatureMatches: PDF-hul ErrorMessage: Invalid indirect destination - referenced object 'reciaff2' cannot be found ID: PDF-HUL-149 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'reciaff2' cannot be found ID: PDF-HUL-122 Offset: 4096550 MIMEtype: application/pdf Profile: Tagged PDF PDFMetadata: Objects: 2616 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: true NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseOutlines Language: en Outlines: Item: Title: Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A Destination: toc.chapter Children: Item: Title: Introduction Destination: section.30.1.1 Item: Title: Materials and methods Destination: section.37.1.2 Item: Title: Results Destination: section.57.1.3 Item: Title: Discussion Destination: section.66.1.4 Item: Title: Acknowledgments Destination: section.67.1.5 Item: Title: Author contributions Destination: section.68.1.6 Item: Title: Lead contact Destination: section.69.1.7 Item: Title: Supplementary material Destination: section.70.1.8 Item: Title: Funding Destination: section.71.1.9 Item: Title: Data availability Destination: section.72.1.10 Info: Title: Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A Author: Subject: AcademicSubjects/MED00310, AcademicSubjects/MED00385, AcademicSubjects/SCI01870, DOI: 10.1093/cercor/bhad431, Cerebral Cortex, 34, 1, 23 11 2023. Abstract: In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum. Through computational modeling, we determined that these alterations resulted in reduced storage capacity and compromised integration of inputs, with decreased high γ oscillations. Contrary to prevailing assumptions, our model suggests that deficits in neuronal architecture, rather than over-inhibition, primarily contribute to the reduced network. We explored the potential of environmental enrichment (EE) as a therapeutic intervention and found that it normalized the excitation-inhibition balance, restored LTP, and improved short-term recognition memory. Interestingly, we observed transient significant dendritic remodeling, leading to recovered high γ. However, these effects were not sustained after EE discontinuation. Based on our findings, we conclude that Dyrk1A overexpression-induced layer-specific neuromorphological disturbances impair the encoding of place and temporal context. These findings contribute to our understanding of the underlying mechanisms of Dyrk1A-related hippocampal deficits and highlight the challenges associated with long-term therapeutic interventions for cognitive impairments. Keywords: Creator: LaTeX with hyperref package Producer: Acrobat Distiller 23.0 (Windows); modified using iTextSharp 4.1.6 by 1T3XT CreationDate: Fri Jan 12 09:35:34 CET 2024 ModDate: Wed Apr 17 11:46:56 CEST 2024 ID: 0xf6bd6fccd2299cc06a45009427b738ce, 0x2a98855e7ba54769bcdf52045536e7c3 Filters: FilterPipeline: FlateDecode FilterPipeline: DCTDecode Images: Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 837 ImageHeight: 735 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 387 ImageHeight: 187 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 1221 ImageHeight: 155 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 787 ImageHeight: 791 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 281 ImageHeight: 136 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 525 ImageHeight: 489 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 807 ImageHeight: 801 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 1202 ImageHeight: 158 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Fonts: Type1: Font: BaseFont: NCOIGE+MTMI FontSubset: true FirstChar: 2 LastChar: 181 FontDescriptor: FontName: NCOIGE+MTMI Flags: Serif, Symbolic, Italic FontBBox: 0, -213, 987, 680 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NCOHOG+CaeciliaLTStd-Light FontSubset: true FirstChar: 35 LastChar: 250 FontDescriptor: FontName: NCOHOG+CaeciliaLTStd-Light Flags: Serif, Symbolic FontBBox: -164, -266, 1130, 908 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NCOHKH+CaeciliaLTStd-Italic FontSubset: true FirstChar: 49 LastChar: 133 FontDescriptor: FontName: NCOHKH+CaeciliaLTStd-Italic Flags: Serif, Symbolic, Italic FontBBox: -166, -270, 1053, 915 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NCOHGG+CaeciliaLTStd-Bold FontSubset: true FirstChar: 40 LastChar: 133 FontDescriptor: FontName: NCOHGG+CaeciliaLTStd-Bold Flags: Serif, Symbolic, ForceBold FontBBox: -166, -273, 1141, 938 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NCOKJL+BLEX FontSubset: true FirstChar: 2 LastChar: 6 FontDescriptor: FontName: NCOKJL+BLEX Flags: Symbolic FontBBox: 13, -2354, 1373, 46 FontFile3: true EncodingDictionary: Differences: true Font: BaseFont: NCOHGH+CaeciliaLTStd-Roman FontSubset: true FirstChar: 40 LastChar: 241 FontDescriptor: FontName: NCOHGH+CaeciliaLTStd-Roman Flags: Serif, Symbolic FontBBox: -167, -270, 1136, 926 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NCOJGB+MTSYN FontSubset: true FirstChar: 2 LastChar: 215 FontDescriptor: FontName: NCOJGB+MTSYN Flags: Symbolic FontBBox: 0, -954, 1043, 900 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NCOIJF+CaeciliaLTStd-LightItalic FontSubset: true FirstChar: 44 LastChar: 144 FontDescriptor: FontName: NCOIJF+CaeciliaLTStd-LightItalic Flags: Serif, Symbolic, Italic FontBBox: -166, -267, 1033, 909 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NCOIIE+CaeciliaLTStd-Heavy FontSubset: true FirstChar: 46 LastChar: 124 FontDescriptor: FontName: NCOIIE+CaeciliaLTStd-Heavy Flags: Serif, Symbolic, ForceBold FontBBox: -170, -277, 1146, 970 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true TrueType: Font: BaseFont: AAEHCN+ArialMT FontSubset: true FirstChar: 32 LastChar: 121 FontDescriptor: FontName: AAEHCN+ArialMT Flags: Nonsymbolic FontBBox: -664, -324, 2000, 1039 FontFile2: true Encoding: WinAnsiEncoding XMP: application/pdf Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A Pons-Espinal MeritxellGener ThomasBallesteros-Yañez InmaculadaLagrán María Martínez deDierssen Mara AcademicSubjects/MED00310, AcademicSubjects/MED00385, AcademicSubjects/SCI01870, DOI: 10.1093/cercor/bhad431, Cerebral Cortex, 34, 1, 23 11 2023. Abstract: In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum. Through computational modeling, we determined that these alterations resulted in reduced storage capacity and compromised integration of inputs, with decreased high γ oscillations. Contrary to prevailing assumptions, our model suggests that deficits in neuronal architecture, rather than over-inhibition, primarily contribute to the reduced network. We explored the potential of environmental enrichment (EE) as a therapeutic intervention and found that it normalized the excitation-inhibition balance, restored LTP, and improved short-term recognition memory. Interestingly, we observed transient significant dendritic remodeling, leading to recovered high γ. However, these effects were not sustained after EE discontinuation. Based on our findings, we conclude that Dyrk1A overexpression-induced layer-specific neuromorphological disturbances impair the encoding of place and temporal context. These findings contribute to our understanding of the underlying mechanisms of Dyrk1A-related hippocampal deficits and highlight the challenges associated with long-term therapeutic interventions for cognitive impairments. CA1dendritic morphologydown syndromeenvironmental enrichmentgamma oscillations © The Author(s) 2023. Published by Oxford University Press. 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