Melatonin ameliorates sleep-wake disturbances and autism-like behaviors in the Ctnnd2 knock out mouse model of autism spectrum disorders.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by atypical patterns of social interaction and communication, as well as restrictive and repetitive behaviors. In addition, patients with ASD often presents with sleep disturbances. Delta (δ) catenin protein 2 (CTNND2) encodes δ-catenin protein, a neuron-specific catenin implicated in many complex neuropsychiatric diseases. Our previous study demonstrated that the deletion of Ctnnd2 in mice led to autism-like behaviors. However, to our knowledge, no study has investigated the effects of Ctnnd2 deletion on sleep in mice. In this study, we investigated whether the knockout (KO) of exon 2 of the Ctnnd2 gene could induce sleep-wake disorders in mice and identified the effects of oral melatonin (MT) supplementation on Ctnnd2 KO mice. Our results demonstrated that the Ctnnd2 KO mice exhibited ASD-like behaviors and sleep-wake disorders that were partially attenuated by MT supplementation. Overall, our current study is the first to identify that knockdown of Ctnnd2 gene could induce sleep-wake disorders in mice and suggests that treatment of sleep-wake disturbances by MT may benefit to autism-like behaviors causing by Ctnnd2 gene deletion.

Effects of chronic sleep restriction on the neuro-phenotypes of Ctnnd2 knockout mice.

INTRODUCTION: Sleep abnormalities are highly correlated with neurodevelopmental disorders, such as intellectual disability, attention deficit hyperactivity disorder, and autism spectrum disorders (ASD). The severity of behavioral abnormalities is correlated with the presence of sleep abnormalities. Based on previous research, we investigated that Ctnnd2 gene deletion in mice lead to ASD-like behaviors and cognitive defects. Given the importance of sleep in individuals with ASD, this study aimed to determine the effects of chronic sleep restriction (SR) on wild-type (WT) mice and on Ctnnd2 deletion-induced, neurologically related phenotypes in mice. METHOD: WT and Ctnnd2 knockout (KO) mice were both subjected to manual SR (5 h per day) for 21 consecutively days separately, then we compared neurologically related phenotypes of WT mice, WT mice subjected to SR, KO mice, and KO mice subjected to SR using a three-chamber assay, direct social interaction test, open-field test, Morris water maze, Golgi staining, and Western blotting. RESULTS: The effects of SR on WT and KO mice were different. After SR, social ability and cognition were impaired in both WT and KO mice. Repetitive behaviors were increased, and exploration abilities were decreased in KO mice but not in WT mice. Moreover, SR reduced the density and area of mushroom-type dendritic spines in WT rather than KO mice. Finally, the PI3K/Akt-mTOR pathway was found to be involved in the effects induced by SR-impaired phenotypes in WT and KO mice. CONCLUSION: Overall, results of the present study may have implications for the role of disrupted sleep in patients with CTNND2 gene-related autism and the evolution of neurodevelopmental disorders.

Progranulin improves neural development via the PI3K/Akt/GSK-3ß pathway in the cerebellum of a VPA-induced rat model of ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disease featuring social interaction deficits and repetitive/stereotyped behaviours; the prevalence of this disorder has continuously increased. Progranulin (PGRN) is a neurotrophic factor that promotes neuronal survival and differentiation. However, there have not been sufficient studies investigating its effect in animal models of autism. This study investigated the effects of PGRN on autistic phenotypes in rats treated with valproic acid (VPA) and assessed the underlying molecular mechanisms. PGRN was significantly downregulated in the cerebellum at postnatal day 14 (PND14) and PND35 in VPA-exposed rats, which simultaneously showed defective social preference, increased repetitive behaviours, and uncoordinated movements. When human recombinant PGRN (r-PGRN) was injected into the cerebellum of newborn ASD model rats (PND10 and PND17), some of the behavioural defects were alleviated. r-PGRN supplementation also reduced cerebellar neuronal apoptosis and rescued synapse formation in ASD rats. Mechanistically, we confirmed that PGRN protects neurodevelopment via the PI3K/Akt/GSK-3ß pathway in the cerebellum of a rat ASD model. Moreover, we found that prosaposin (PSAP) promoted the internalisation and neurotrophic activity of PGRN. These results experimentally demonstrate the therapeutic effects of PGRN on a rat model of ASD for the first time and provide a novel therapeutic strategy for autism.

Abnormal spatiotemporal expression pattern of progranulin and neurodevelopment impairment in VPA-induced ASD rat model.

Some environmental risk factors have been proven to contribute to the etiology of autism spectrum disorder (ASD). Exposure to the antiepileptic drug valproic acid (VPA) during pregnancy significantly increases the risk of ASD in humans, and consequently is utilized as a validated animal model of ASD in rodents; however, the precise molecular and cellular mechanisms remain ill-defined. In the present study, we investigated the effect of prenatal VPA exposure on the spatiotemporal dynamics of Progranulin (PGRN) expression, neuronal apoptosis, synapse density, and AKT/GSK-3ß pathway activation in the brains of VPA-exposed offspring. Results from behavioral tests were consistent with prior studies showing impaired sociability, restricted interests and increased repetitive behaviors in VPA rats at postnatal days 28-32. Our data also indicated that VPA exposure resulted in abnormal dynamics of PGRN expression in different brain regions at the different development stages. The temporal and spatial patterns of PGRN expression were consistent with the spatiotemporal regularity of abnormalities, which observed in apoptosis-related protein levels, neuron numbers, dendritic spine density, synapse-related protein levels, and AKT/GSK-3ß phosphorylation in VPA rats. It suggests that prenatal VPA exposure may affect the spatiotemporal regularity of neuronal apoptosis and synaptic development/regression via interfering with the spatiotemporal process of PGRN expression and downstream AKT/GSK-3ß pathway activation. This may be a potential mechanism of the abnormal neuroanatomical changes and ASD-like behaviors in VPA-induced ASD.