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Metabolomic Profiling of the Striatum in Shank3 Knockout ASD Rats: Effects of Early Swimming Regulation

ABSTRACT:

OBJECTIVE: This study aimed to investigate the regulatory impact of early swimming intervention on striatal metabolism in Shank3 gene knockout ASD model rats.

METHODS: Shank3 gene knockout exon 11-21 male 8-day-old SD rats were used as experimental subjects and randomly divided into three groups: Shank3 knockout control group (KC), wild-type control group (WC) from the same litter and Shank3 knockout swimming group (KS). Rats in the exercise group received early swimming intervention for 8 weeks starting at 8 days old. GC-MS metabolism was employed to detect the changes of metabolites in striatum.

RESULTS: There were 17 differential metabolites (14 down-regulated) between the KC and WC groups, 19 differential metabolites (18 up-regulated) between the KS and KC groups and 22 differential metabolites (18 up-regulated) between the KS and WC groups.

CONCLUSION: The metabolism of striatum in Shank3 knockout ASD model rats is disrupted, involving metabolites related to synaptic morphology, Glu and GABAergic synapses are abnormal. Early swimming intervention regulated the striatal metabolome group of ASD model rats, with differential metabolites primarily related to nerve development, synaptic membrane structure and synaptic signal transduction.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS8577 | MetaboLights | 2024-09-27

REPOSITORIES: MetaboLights

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Project description:Austism spectrum disorder (ASD) is a heterogeneous behavioral disease most commonly characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a common clinical outcome. Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA/lentivirus constructs. Whole genome expression analysis was conducted for each of the knock-down cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing luciferase. Gene set enrichment and a causal reasoning engine were employed to indentify pathway level perturbations generated by the transcript knock-down. Quantitation of the shRNA targets confirmed the successful knock-down at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by transfection and viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients. n=4 per group. Luciferase shRNA used as control group for shRNA to various gene targets.

			Action	DRS
	neg_KC1.raw	Raw
	neg_KC2.raw	Raw
	neg_KC3.raw	Raw
	neg_KS1.raw	Raw
	neg_KS2.raw	Raw

Dataset Information

Metabolomic Profiling of the Striatum in Shank3 Knockout ASD Rats: Effects of Early Swimming Regulation

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