Perineuronal nets (PNNs) are structures that contain extracellular matrix chondroitin sulfate proteoglycan and surround the soma and dendrites of various neuronal cell types. They are involved in synaptic plasticity and undertake important physiological functions. Altered expression of PNNs has been demonstrated in the brains of autism-related animal models. However, the underlying mechanism is still unknown. In this study, we demonstrated that the PNNs in the cerebellum are involved in modulating social and repetitive/inflexible behaviors in Shank3B mice, an established animal model of autism spectrum disorder. First, we performed wisteria floribunda agglutinin staining of the whole brain of Shank3B mice, and found wisteria floribunda agglutinin-positive PNNs are significantly increased in the cerebellar interpositus nucleus (IntP) in Shank3B mice compared to control littermates. After degradation of PNNs in the IntP by chondroitinase ABC, the repetitive behaviors of Shank3B mice were decreased, while their social behaviors were ameliorated. These results suggested that PNNs homeostasis is involved in the regulation of social behavior, revealing a potential therapeutic strategy targeting PNNs in the IntP for the treatment of autism spectrum disorder.
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