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Proteomic analysis of Adnp mutant mice

ABSTRACT: We report age-differential synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIa hyperactivity in Adnp-mutant mice. These mice show impaired and inflexible contextual learning and memory additional to social and anxiety-related deficits in adults long after a marked decrease in ADNP protein levels to ~10% of newborn levels in juveniles. In addition, Adnp-mutant adults show abnormally enhanced long-term potentiation in adults but not in juveniles. This accompanies CaMKIIa hyperactivity involving increased baseline autophosphorylation, as revealed by unbiased proteomic analyses.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jin Young Kim

PROVIDER: MSV000090257 | MassIVE |

SECONDARY ACCESSION(S): PXD036544

REPOSITORIES: MassIVE

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Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits.

Cho Heejin H Yoo Taesun T Moon Heera H Kang Hyojin H Yang Yeji Y Kang MinSoung M Yang Esther E Lee Dowoon D Hwang Daehee D Kim Hyun H Kim Doyoun D Kim Jin Young JY Kim Eunjoon E

Molecular psychiatry 20230626 8

ADNP syndrome, involving the ADNP transcription factor of the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). Although Adnp-haploinsufficient (Adnp-HT) mice display various phenotypic deficits, whether these mice display abnormal synaptic functions remain poorly understood. Here, we report synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-HT mice. Thes ...[more]

PMID: 37365244

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Phosphoproteomic analysis of ADNP-mutant mice

Project description:We report age-differential synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIa hyperactivity in Adnp-mutant mice. These mice show impaired and inflexible contextual learning and memory along with social and anxiety-related deficits in adults, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. Adnp-mutant mice show abnormally enhanced long-term potentiation in adults but not in juveniles. This is accompanied by CaMKIIa hyperactivity involving increased baseline autophosphorylation and altered phosphorylation of CaMKIIa substrates, as revealed by unbiased proteomic analyses.

2023-07-11 | PXD037325 | Pride

Transcriptome analysis of Adnp-heterozygous mice in the hippocampus

Project description:ADNP syndrome, involving the ADNP transcription factor in the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). In ASD, ADNP is a highly penetrant risk gene, accounting for ~0.17% cases. Although Adnp-haploinsufficient mice display various phenotypic deficits, the underlying synaptic mechanisms are poorly understood. Here we report age-differential synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-mutant mice. These mice show impaired and inflexible contextual learning and memory additional to social and anxiety-related deficits in adults long after a marked decrease in ADNP protein levels to ~10% of newborn levels in juveniles. In addition, Adnp-mutant adults show abnormally enhanced long-term potentiation in adults but not in juveniles. This accompanies CaMKIIα hyperactivity involving increased baseline autophosphorylation, as revealed by unbiased proteomic analyses. Therefore, ADNP haploinsufficiency in mice leads to cognitive inflexibility involving altered synaptic plasticity and signaling in adults long after a marked decrease in Adnp expression in juveniles.

2023-07-11 | GSE213354 | GEO

Transcriptome analysis of Chd8 S62X heterozygote mutant and wild-type mice

Project description:Autism spectrum disorders (ASD) are ~4-times more common in males than females, and CHD8 (a chromatin remodeler)-related ASD shows a strong male bias (~5:1), although the underlying mechanism remains unclear. Chd8-mutant mice with a C-terminal protein-truncating mutation (N2373X) display male-preponderant behavioral deficits as juveniles and adults, although whether this also applies to other Chd8 mutations remains unknown. Here we report that new Chd8-mutant mice with a stronger N-terminal protein-truncating mutation (S62X) display male-preponderant autistic-like behaviors at juvenile stages, but as adults, both males and females share behavioral deficits. Excitatory synaptic transmission is suppressed and enhanced in male and female juvenile Chd8+/S62X mice, respectively, but similarly enhanced in adults. ASD-like transcriptomic changes occur monophasically in newborn and juvenile (but not adult) males but biphasically in newborn and adult (not juvenile) females. Therefore, a strong CHD8 mutation induces early-onset ASD-like phenotypes in males but late-onset phenotypes in females after juvenile-stage female protection.

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2023-03-08 | PXD034176 | Pride

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [mouse P1]

Project description:Williams syndrome (WS), caused by a heterozygous microdeletion in 7q11.23, is a neurodevelopmental disorder characterized by hypersociability and neurocognitive abnormalities. Of the deleted genes, general transcription factor II-i (Gtf2i) has been linked to hypersociability in WS, though the underlying mechanisms are poorly understood. We show that selective deletion of Gtf2i in forebrain excitatory neurons caused neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, 70% of the genes with significantly decreased mRNA levels in the mutant mouse cortex are involved in myelination, and mutant mice had reduced mature oligodendrocyte cell numbers, reduced myelin thickness and impaired axonal conductivity. Restoring myelination properties with clemastine or increasing axonal conductivity rescued the behavioural deficits. Frontal cortex from WS patients similarly showed reduced myelin thickness, mature oligodendrocyte cell numbers and mRNA levels of myelination-related genes. Our study provides molecular and cellular evidence for myelination deficits in WS linked to neuronal deletion of Gtf2i.

2019-03-26 | GSE128838 | GEO

Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [human]

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2019-03-26 | GSE128839 | GEO

MAPK Signaling Determines Anxiety in the Juvenile Mouse Brain but Depression-like Behavior in Adults

Project description:MAP kinase signaling has been implicated in brain development, long-term memory, and the response to antidepressants. Inducible Braf knockout mice enabled us to unravel a new role of neuronal MAPK signaling for emotional behavior. Braf mice that were induced during adulthood showed normal anxiety but increased depression-like behavior, in accordance with pharmacological findings. In contrast, the inactivation of Braf in the juvenile brain leads to normal depression-like behavior but decreased anxiety in adults. In these mutants we found no alteration of GABAergic neurotransmission but reduced neuronal arborization in the dentate gyrus. Analysis of gene expression in the hippocampus revealed nine downregulated MAPK target genes that represent candidates to cause the mutant phenotype. Our results reveal the differential function of MAPK signaling in juvenile and adult life phases and emphasize the early postnatal period as critical for the determination of anxiety in adults. Moreover, these results validate inducible gene inactivation as new valuable approach, allowing to discriminate between gene function in the adult and the developing postnatal brain.

2012-04-19 | GSE33618 | GEO

Gene expression profiling of NCAM-deficient mouse brain

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2009-12-01 | GSE16647 | GEO

p140Cap Interactome - Synaptic Interactome Mining Reveals p140Cap as a New Hub for PSD Proteins Involved in Psychiatric and Neurological Disorders

Project description:p140Cap is an adapter protein that is highly expressed in the brain. In particular, p140Cap localizes at dendritic spines where it contributes to the regulation of spine shape and maturation. We recently described that p140Cap knock-out mice present cognitive deficits, impaired long-term potentiation and long-term depression, and immature filopodia-like dendritic spines, indicating that p140Cap is relevant for synaptic plasticity. Although a few p140Cap interacting proteins have been identified in the brain, a comprehensive view of its molecular partners remains largely unknown. Thus, we performed a mass spectrometry-based proteomic analysis of the p140Cap interactome.

2017-07-19 | PXD004215 | Pride

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