Dataset Information

Phosphoproteomic analysis of Ank2-mutant mice

ABSTRACT: Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Yeji Yang

LAB HEAD: Eunjoon Kim

PROVIDER: PXD041769 | Pride | 2023-07-20

REPOSITORIES: Pride

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Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice.

Oh Hyoseon H Lee Suho S Oh Yusang Y Kim Seongbin S Kim Young Seo YS Yang Yeji Y Choi Woochul W Yoo Ye-Eun YE Cho Heejin H Lee Seungjoon S Yang Esther E Koh Wuhyun W Won Woojin W Kim Ryunhee R Lee C Justin CJ Kim Hyun H Kang Hyojin H Kim Jin Young JY Ku Taeyun T Paik Se-Bum SB Kim Eunjoon E

Nature communications 20230615 1

Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and j ...[more]

PMID: 37321992

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Project description:Shank3 is an abundant excitatory postsynaptic scaffolding proteins implicated in various neurodevelopmental and psychiatric disorders, including ASD, Phelan-McDermid syndrome, intellectual disability, and schizophrenia. Shank3-mutant mice with a homozygous deletion of exons 14-16 (Shank3-HM mice) show ASD-like behavioral deficits and altered synaptic and neuronal functions, but little is known about how different ages, brain regions, and gene dosages contribute to transcriptomic phenotypes in these mice. Here, we performed RNA-Seq-based transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank3 heterozygous- and homozygous-mutant mice. In addition, juvenile and adult Shank3 homozygous-mutant forebrain transcriptomes were compared. Juvenile and adult forebrain transcriptomes from Shank3 homozygous-mutant mice showed the patterns that are opposite and similar to those observed in ASD: reverse-ASD and ASD-like patterns, respectively. Here, the juvenile reverse-ASD pattern involved synaptic gene upregulations and ribosomal and mitochondrial downregulations, whereas the adult ASD-like pattern involved opposite changes. Gene set enrichment analyses (GSEA) of brain regional transcripts in adult Shank3-HT and Shank3-HM mice revealed that the cortical, hippocampal, and striatal transcripts show distinctly altered biological functions and ASD-related/risk gene expressions. The cortex and striatum display ASD-like patterns whereas the hippocampus displays reverse-ASD patterns. The cortical ASD-like pattern more strongly involves ASD-risk genes whereas the striatal ASD-like pattern more strongly involves astrocyte/microglia genes. Shank3-HT and Shank3-HM transcripts in a given brain region display largely similar patterns in biological functions and ASD-related/risk gene expressions, suggestive of small gene dosage effects. These results suggest that heterozygous and homozygous Shank3 deletions in mice lead to age, brain region, and gene dosage-differential transcriptomic changes.

Project description:<h4><strong>INTRODUCTION: </strong>Approximately 1% of the world's population is impacted by epilepsy, a chronic neurological disorder characterized by seizures. One-third of epileptic patients are resistant to AEDs, or have medically refractory epilepsy (MRE). One non-invasive treatment that exists for MRE includes the ketogenic diet, a high-fat, low-carbohydrate diet. Despite the KD's success in seizure attenuation, it has a few risks and its mechanisms remain poorly understood. The KD has been shown to improve metabolism and mitochondrial function in epileptic phenotypes. Potassium channels have implications in epileptic conditions as they have dual roles as metabolic sensors and control neuronal excitation.</h4><h4><strong>OBJECTIVES: </strong>The goal of this study was to explore changes in the lipidome in hippocampal and cortical tissue from Kv1.1-KO model of epilepsy.</h4><h4><strong>METHODS: </strong>FT-ICR/MS analysis was utilized to examine nonpolar metabolome of cortical and hippocampal tissue isolated from a Kv1.1 channel knockout mouse model of epilepsy (n = 5) and wild-type mice (n = 5).</h4><h4><strong>RESULTS: </strong>Distinct metabolic profiles were observed, significant (p < 0.05) features in hippocampus often being upregulated (FC ≥ 2) and the cortex being downregulated (FC ≤ 0.5). Pathway enrichment analysis shows lipid biosynthesis was affected. Partition ratio analysis revealed that the ratio of most metabolites tended to be increased in Kv1.1-/-. Metabolites in hippocampal tissue were commonly upregulated, suggesting seizure initiation in the hippocampus. Aberrant mitochondrial function is implicated by the upregulation of cardiolipin, a common component in the mitochondrial membrane.</h4><h4><strong>CONCLUSION: </strong>Generally, our study finds that the lipidome is changed in the hippocampus and cortex in response to Kv1.1-KO indicating changes in membrane structural integrity and synaptic transmission.</h4>

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