Dataset Information

Proteomics data reveals Wnt signaling involvement in the hippocampal-dependent behavioral impairment in THRSP-overexpressing ADHD mouse model

ABSTRACT: Despite the predominance and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), its etiology remains elusive. Preclinical and clinical evidence partly points to impaired limbic system function, particularly that of the hippocampus (HPC). Children diagnosed with ADHD often struggle with deficits in executive function, temporal processing, and visuospatial memory, the defining hallmarks of the predominantly inattentive presentation (ADHD-PI), thought to be subserved by the HPC brain region. However, the specific genes/proteins involved and how they shape the hippocampal makeup to influence ADHD behavior are poorly understood. As an exploratory tool, hippocampal tissues from a mouse model overexpressing thyroid hormone-responsive protein (THRSP), with defining characteristics of ADHD-PI presentation, were utilized for proteomic analyses. Results revealed differential expressions of proteins involved in Wnt signaling. Compared to THRSP knockout (KO), THRSP OE mice have impaired attention and memory concomitant to dysregulated Wnt signaling affecting hippocampal cell proliferation (BrdU) and neurogenic markers expressions (i.e., NEU-N, GFAP), markers of neural stem cell (NSC) activity. Also, exposure to a combination of enriched environment and treadmill exercise improves behavioral deficits in THRSP OE mice and improves Wnt signaling and NSC activity.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Jiyeon Kim

LAB HEAD: Eugene C. Yi

PROVIDER: PXD038525 | Pride | 2023-01-18

REPOSITORIES: Pride

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Publications

Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model.

Custodio Raly James Perez RJP Kim Hee Jin HJ Kim Jiyeon J Ortiz Darlene Mae DM Kim Mikyung M Buctot Danilo D Sayson Leandro Val LV Lee Hyun Jun HJ Kim Bung-Nyun BN Yi Eugene C EC Cheong Jae Hoon JH

Communications biology 20230116 1

Children with attention-deficit/hyperactivity disorder (ADHD) often struggle with impaired executive function, temporal processing, and visuospatial memory, hallmarks of the predominantly inattentive presentation (ADHD-PI), subserved by the hippocampus. However, the specific genes/proteins involved and how they shape hippocampal structures to influence ADHD behavior remain poorly understood. As an exploratory tool, hippocampal dentate gyri tissues from thyroid hormone-responsive protein overexpr ...[more]

PMID: 36646879

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Project description:The purpose of this study was to determine whether there were differences in gene expression in the hippocampus, a part of the brain involved in memory consolidation, between male mice with age-related memory deficits (SAMP8 mice) and control mice with no age-related memory deficits. The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta peptide (Aβ) accumulation at 12 months compared to 4 months. To detect differences in gene expression in SAMP8 mice, we used a Control mouse that was a 50% cross between SAMP8 and CD-1 mice and which showed no memory deficits (50% SAMP8 mouse). We then compared gene expression in the hippocampus of 4 month and 12 month old SAMP8 and Control mice using Affymetrix gene arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (PI receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself. Global differential profiling of hippocampal gene expression (4 month and 12 month old SAMP8 and Control mice) was performed using Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (PI receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself. 2-way ANOVA (2 x 2 conditions, n=4). First variable was age (4 and 12 months) and second variable was mouse strain (Control and SAMP8). This results in 4 groups: Control-4 month, Control-12 month, SAMP8-4 month, and SAMP8-12 month. Each group had 4 biological replicates (4 mice). The ”Control” mice were a 50% backcross of the SAMP8 mice with CD-1 mice (50% SAMP8 mice). These mice were closely related to SAMP8 mice but exhibited no memory deficits at 4 or 12 months. The SAMP8 mice had memory deficits at 12 months but not at 4 months.

Project description:The purpose of this study was to determine the effect of peripheral (IV) administration of AβPP antisense on hippocampal gene expression as well as on learning and memory as measured by T-maze in adult male mice aged 12 months. The AβPP antisense treatment reversed learning and memory deficits and altered the expression of 944 hippocampal genes, which are involved in a coordinated set of signaling pathways. Expression and pathway findings were verified at the protein and functional (phosphorylation) levels. Global differential profiling of hippocampal gene expression (12 month old adult mice: Control, SAMP8, SAMP8 + Random antisense, SAMP8 + AβPP antisense) was performed using Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays. The AβPP antisense reversed the memory deficits and altered expression of 944 hippocampal genes. Pathway analysis showed significant gene expression changes in 9 pathways. These include the MAPK signaling pathway (P = 0.0078) and the phosphatidylinositol signaling pathway (P = 0.043), which we have previously shown to be altered in SAMP8 mice. The changes in these pathways contributed to significant changes in the Neurotropin (P = 0.0083) and Insulin Signaling (P = 0.015) pathways, which are known to be important in learning and memory. Changes in these pathways were accompanied by phosphorylation changes in the downstream target proteins p70S6K, GSK3β, ERK, and CREB. These changes in hippocampal gene expression and protein phosphorylation may suggest specific new targets for antisense therapy aimed at improving memory. One-way ANOVA (4 conditions, n=4). Variables were treatment (AβPP antisense, Random antisense, no treatment) and mouse strain (Control and SAMP8). This results in 4 groups: (All 12-month-old adult male mice) NT-Control, NT_SAMP8, Random_AS-SAMP8, and AβPP_AS-SAMP8. Each group had 4 biological replicates (4 mice). The 'Control' mice were a 50% backcross of the SAMP8 mice with CD-1 mice (50% SAMP8 mice). These mice were closely related to SAMP8 mice but exhibited no memory deficits at 4 or 12 months. The SAMP8 mice had memory deficits at 12 months but not at 4 months.

Dataset Information

Proteomics data reveals Wnt signaling involvement in the hippocampal-dependent behavioral impairment in THRSP-overexpressing ADHD mouse model

Publications

Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model.

Similar Datasets

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