Neu1 sialidase regulates heterospecific social interaction in zebrafish via D1 dopamine receptor

Neu1 sialidase catalyzes the removal of sialic acids from oligosaccharides and glycoproteins in lysosomes and plasma membranes. Recently, the association between Neu1 and psychiatric disorders, such as manic depression and schizophrenia, has attracted attention. neu1^−/− zebrafish (Neu1-KO) exhibit low anxiety, low aggressiveness, and increased social interaction with unfamiliar conspecific and heterospecific groups; however, the underlying mechanisms of action remain unclear. This study investigated alterations in monoamine levels in the Neu1-KO zebrafish brain and their significance in the unique behavioral response toward heterospecifics. The dopamine (DA) and serotonin (5-HT) levels were significantly elevated in the brains of Neu1-KO zebrafish compared with those of wild-type (WT) zebrafish, accompanied by a decrease in noradrenaline (NE). Immunohistochemical (IHC) analysis revealed increased numbers of DA and 5-HT neurons in the Neu1-KO zebrafish brain. Behavioral analysis revealed that treatment with a D1 receptor antagonist significantly suppressed heterospecific interactions in Neu1-KO zebrafish, whereas treatment with D2 and 5-HT receptor antagonists did not. IHC showed that polysialic acid (PSA), a known regulator of DA neuronal function, was predominantly distributed in the hypothalamus of zebrafish, with markedly enhanced signals in Neu1-KO zebrafish. These findings elucidate the role of Neu1 sialidase in regulating social interaction behaviors via DA neurons, potentially as a mechanism for mitigating risks in social environments.