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Microinjection of Interleukin-6 into the Bloodstream of TSC Zebrafish Larvae to Study Neuropsychiatric Disorder-Like Behaviors
Published on: June 26, 2026
Tmlhe deficiency induces neurodevelopmental dysfunction and synaptic excitatory/inhibitory imbalance linked to
Jitong Li1, Xiaotong Zhao2, Jieru Wei3
1Henan Key Laboratory of Genetic and Developmental Disorders, Henan Engineering Research Center of Zebrafish Models for Human Disease and Drug Screening, Pediatric Research Institute, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital Zhengzhou Children's Hospital, Zhengzhou 450018, China; Department of Nephrology and Rheumatology, Zhengzhou Key Laboratory of Pediatric Kidney Disease Research, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital Zhengzhou Children's Hospital, Zhengzhou 450018, China; Institute of Children's Health, Henan Academy of Medical Sciences, Zhengzhou 451162, China.
Abstract:
Mutations in TMLHE, the initial enzyme for carnitine biosynthesis, are linked to autism spectrum disorder (ASD). However, the molecular mechanisms by which TMLHE defects contribute to neurodevelopmental abnormalities remain elusive. This study aimed to elucidate the role of tmlhe deficiency in vertebrate neural development and its link to ASD-like behaviors using a zebrafish model. We established a tmlhe knockdown zebrafish model using morpholino microinjection. The tmlhe gene is specifically expressed in the developing nervous system, as characterized by whole-mount in situ hybridization (WISH). Its knockdown induces severe morphological defects and significant ASD-like behaviors, including impaired social interaction and delayed environmental response. Metabolomic analysis confirmed a blockage in carnitine biosynthesis, leading to deficient long-chain acylcarnitine levels and impaired fatty acid transport. Transcriptomic profiling revealed downregulation of fatty acid transport and β-oxidation pathways and negative enrichment of peroxisome proliferator-activated receptor (PPAR) signaling. Consequently, tmlhe morphants exhibited severe neurodevelopmental defects, including blocked neuronal progenitor cell differentiation, increased apoptosis in the brain, and profound disruption of synaptic function. Transcriptional alterations in glutamatergic and GABAergic receptor-related genes suggest a potential excitatory/inhibitory (E/I) imbalance. Exogenous l-carnitine supplementation successfully rescued the morphological and behavioral deficits. Our findings demonstrate that tmlhe deficiency disrupts carnitine biosynthesis, impairing energy and glycerophospholipid metabolism, which is critical for early neurogenesis. This may lead to impaired neural development and a synaptic E/I imbalance, ultimately causing ASD-like phenotypes. This study establishes a crucial link between carnitine metabolism and ASD etiology, proposing a potential therapeutic target.
