Does genetic mouse model of constitutive Hint1 deficiency exhibit schizophrenia-like behaviors?

Abstract

The histidine triad nucleotide binding protein 1 (HINT1) is closely related to many neuropsychiatric disorders. Clinical studies supported that mutations in the Hint1 gene correlated potentially with schizophrenia. In addition, Hint1 gene knockout (KO) mice exhibited hyperactivity induced by amphetamine and apomorphine. However, it is still unclear whether this animal model exhibits schizophrenia-like behaviors and, if so, their underlying mechanisms remain to be elucidated. Thus, our study sought to evaluate schizophrenia-like behaviors in Hint1-KO mice, and explore the associated changes in neuronal structural plasticity and schizophrenia-related molecules. A series of behavioral tests were used to compare Hint1-KO and their wild-type (WT) littermates, alongside a number of morphological and molecular biological methods. Relative to WT mice, Hint1-KO mice exhibited reduced social interaction behaviors, aggressive behavior, sensorimotor gating deficits, apathetic and self-neglect behaviors, and increased MK-801-induced hyperactivity. Hint1-KO mice also showed partly increased dendritic complexity in the hippocampus (Hip) relative to WT mice. Total glutamate was decreased in the medial prefrontal cortex, nucleus accumbens (NAc), and Hip of KO mice. Expression of NR1, NR2A, and D4R was decreased whereas that of D1R was increased in the NAc of KO relative to WT mice. The expression level of NR2B was increased whereas that of D1R was decreased in the Hip of KO mice. Hint1-KO mice exhibited schizophrenia-like behaviors. Partly increased dendritic complexity and dysfunction in both the dopaminergic and glutamatergic systems may be involved in the abnormalities in Hint1-KO mice.