Neu1 deficiency induces abnormal emotional behavior in zebrafish

Abstract

NEU1 sialidase hydrolyzes sialic acids from glycoconjugates in lysosomes. Deficiency of NEU1 causes sialidosis with symptoms including facial dysmorphism, bone dysplasia, and neurodegeneration. However, the effects of NEU1 deficiency on emotional activity have not been explored. Here, we conducted the behavioral analysis using Neu1-knockout zebrafish (Neu1-KO). Neu1-KO zebrafish showed normal swimming similar to wild-type zebrafish (WT), whereas shoaling was decreased and accompanied by greater inter-fish distance than WT zebrafish. The aggression test showed a reduced aggressive behavior in Neu1-KO zebrafish than in WT zebrafish. In the mirror and 3-chambers test, Neu1-KO zebrafish showed more interest toward the opponent in the mirror and multiple unfamiliar zebrafish, respectively, than WT zebrafish. Furthermore, Neu1-KO zebrafish also showed increased interaction with different fish species, whereas WT zebrafish avoided them. In the black–white preference test, Neu1-KO zebrafish showed an abnormal preference for the white region, whereas WT zebrafish preferred the black region. Neu1-KO zebrafish were characterized by a downregulation of the anxiety-related genes of the hypothalamic–pituitary–adrenal axis and upregulation of lamp1a, an activator of lysosomal exocytosis, with their brains accumulating several sphingoglycolipids. This study revealed that Neu1 deficiency caused abnormal emotional behavior in zebrafish, possibly due to neuronal dysfunction induced by lysosomal exocytosis.

Correlation Between Sialidase NEU1 mRNA Expression Changes in Autism Spectrum Disorder

“…Studies in zebrafish reported that NEU1-KO zebrafish developed behavioral traits opposite to ASD, including excessive exploratory/boldness behavior on various tests. Furthermore, anxiety induction upregulated NEU1 expression in zebrafish ( 35 ), which is consistent with our findings.…”

NEU1—A Unique Therapeutic Target for Alzheimer’s Disease

“…It is intriguing that the role of NEU1 in AD may be supported by very recent studies performed on the Neu1-KO zebrafish model. Ikeda et al suggested the link of Neu1 with altered emotional activity, pointing to a deregulated lysosomal exocytosis, probably as suggested 8 years earlier (Annunziata et al, 2013;Ikeda et al, 2021).…”

“…Importantly, this process has been implicated in pathologies related to the central nervous system, such as neurodegeneration ( d’Azzo et al, 2015 ; Khan and Sergi, 2018 ) and changes in the emotional behavior of an animal model ( Ikeda et al, 2021 ). It is intriguing that the role of NEU1 in AD may be supported by very recent studies performed on the Neu1-KO zebrafish model.…”

“…Studies investigating the effect of NEU1 deficiency on emotional activity remain limited. However, in one exciting study, behavioral analysis was performed on Neu1-knockout zebrafish ( Neu1 -KO) ( Ikeda et al, 2021 ). It was noticed that although Neu1-KO zebrafish exhibited normal swimming patterns similar to wild-type (WT) zebrafish, there was a decline in shoals, as well as altered patterns of interaction with different fish species.…”

“…Interestingly, studies have also reported that induction of anxiety may cause an upregulation of Neu1 in the zebrafish brain along with a simultaneous reduction in Lamp1 levels. It suggests that the significance of enhanced Neu1 and reduced lysosomal exocytosis might be crucial to suppressing boldness/exploratory activity under circumstances that require caution ( Ikeda et al, 2021 ). Overall, it can be suggested that NEU1 deficiency may also lead to abnormal emotional behavior.…”