Deficiency of Kdm1a Induces Locomotor Abnormalities and Learning and Memory Deficits in Zebrafish Larvae

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Background: Lysine-Specific Demethylase 1A (Kdm1a) is the first discovered histone lysine-specific demethylase, and mutations in kdm1a have been detected in neurodevelopmental disorders. However, the effect of kdm1a on neurobehaviors and the underlying mechanisms remain largely unknown. Methods: In this study, kdm1a deficient zebrafish were constructed using (clustered regularly interspaced short palindromic repeat) Clustered Regularly Interspaced Short Palindromic Repeats/CRISPRassociated protein 9 (CRISPR/Cas9) and the neurodevelopment was systematically assessed by a series of behavioral tests. Results: We found that kdm1a knockout zebrafish exhibited developmental toxicity and abnormal neurobehaviors, including locomotor abnormalities, and learning and memory deficits. Kdm1a deficiency suppressed central nervous system (CNS) neurogenesis in Tg (HuC:egfp) zebrafish, reduced motor neuron axon length in Tg (hb9:egfp) zebrafish and downregulated the expression of neurodevelopment related genes at 96 hours post fertilization (hpf). In addition, the expression of genes related to autophagy and apoptosis increased significantly in kdm1a knockout zebrafish. Conclusions: These results indicated that kdm1a deficiency induced locomotor abnormalities and learning and memory deficits in zebrafish larvae accompanied by activation of autophagy and apoptosis. These findings indicate a key role of kdm1a in neurodevelopment, providing novel insights into the mechanisms underlying the neurodevelopmental disorders.

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