BackgroundMotor impairments are amongst the earliest and most consistent signs of autism spectrum disorders but are not used as diagnostic criteria. In addition, the relationship between motor and cognitive impairments and their respective neural substrates remain unknown.MethodsHere, we aimed at determining whether a well-acknowledged animal model of autism spectrum disorders, the valproic acid model, displays motor impairments and whether they may correlate with social deficits and neuronal loss within motor brain areas. For this, pregnant female mice (C57BL/6J) received valproic acid (450 mg/kg) at embryonic day 12.5 and offspring underwent a battery of behavioral analyses before being killed for histological correlates in motor cortex, nigrostriatal pathway, and cerebellum.ResultsWe show that while valproic acid male mice show both social and motor impairments, female mice only show motor impairments. Prenatal valproic acid exposure induces specific cell loss within the motor cortex and cerebellum and that is of higher magnitude in males than in females. Finally, we demonstrate that motor dysfunction correlates with reduced social behavior and that motor and social deficits both correlate with a loss of Purkinje cells within the Crus I cerebellar area.ConclusionsOur results suggest that motor dysfunction could contribute to social and communication deficits in autism spectrum disorders and that motor and social deficits may share common neuronal substrates in the cerebellum. A systematic assessment of motor function in autism spectrum disorders may potentially help the quantitative diagnosis of autism spectrum disorders and strategies aimed at improving motor behavior may provide a global therapeutic benefit.

Infections during gestation and the consequent maternal immune activation (MIA) increase the risk of developing neuropsychiatric disorders in infants and throughout life, including autism spectrum disorders (ASD). ASD is a neurodevelopmental disorder that affects three times more males than females and is mainly characterized by deficits in social communication and restricted interests. Consistent findings also indicate that ASD patients suffer from movement disorders, although these symptoms are not yet considered as diagnosis criteria. Here we used the double-stranded RNA analog polyinosinic:polycytidylic acid (poly I:C) MIA animal model of ASD in mice and explored its effects in males and females on social and motor behavior. We then investigated brain areas implicated in controlling and coordinating movements, namely the nigro-striatal pathway, motor cortex and cerebellum. We show that male mice are more affected by this treatment than females as they show reduced social interactions as well as motor development and coordination deficits. Reduced numbers of Purkinje cells in the cerebellum was found more widespread and within distinct lobules in males than in females. Moreover, a reduced number of neurons was found in the motor cortex of males only. These results suggest that females are better protected against developmental insults leading to ASD symptoms in mice. They also point to brain areas that may be targeted to better manage social and motor consequences of ASD.

Hyperinsulinemia plays a causal role in adiposity tissue expansion. We have previously shown that mice with reduced insulin gene dosage have increased energy expenditure, but the tissue-specific molecular mechanisms involved in the effects of abrogated hyperinsulinemia have remained unclear. Herein we investigated the effects of genetically reducing insulin production on the abundance of oxidative mitochondrial complex proteins in liver, skeletal muscle, white adipose tissue and brown adipose tissue. To suppress insulin levels, we manipulated Ins1 gene dosage in mice lacking both Ins2 alleles to prevent compensation. Male Ins1+/+ or Ins1+/-littermates were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 4 weeks, starting at 8 weeks of age. As expected, HFD increased fasting hyperinsulinemia, and Ins1+/-mice had significantly lower circulating insulin compared with Ins1+/+ littermate controls. Fasting glucose and body weight were not significantly different between genotypes at any time over the 4 weeks of study. In liver and skeletal muscle, protein abundances reflecting complex I (Ndufb8), II (Sdhb), III (Uqcrc2), and V (Atp5a1) were not consistently different between groups. In mesenteric white adipose tissue, Ins1+/-mice had reduced abundance of Ndufb8 and Sdhb proteins. Ucp1 protein abundance was increased in the context of the HFD, and HFD alone had a dramatic inhibitory effect on Pparg protein levels. In inguinal white adipose tissue, Ins1+/-mice exhibited significant increases in all oxidative mitochondrial complexes measured, independent of diet. No changes in Ucp1 or Pparg protein, or Prdm16:Pparg association were found. While HFD increased the abundance of nuclear Sirt1, no effects on total Sirt3 protein levels were observed in this tissue. In brown adipose tissue, lowered insulin increased Sdhb protein levels that had been reduced by HFD. Ucp1 protein levels, Prdm16:Pparg association, and Sirt3 abundance were all increased in the absence of diet-induced hyperinsulinemia. Our data show that in young mice, reducing insulin upregulates oxidative proteins in inguinal fat without affecting Ucp1, while in mesenteric white fat and brown adipose tissue, reducing insulin upregulates Ucp1 in the context of HFD. Collectively, our results show that preventing hyperinsulinemia have depot-specific effects on adipose tissue metabolism and help explain the increased energy expenditure previously reported in Ins1+/-mice. Insulin is secreted from pancreatic β-cells in response to nutrient intake to regulate anabolism in multiple tissues. In addition to glucose homeostasis, insulin is a potent regulator of lipid homeostasis (42). Insulin signaling is required for glucose and lipid uptake into fat, as well as for the development and hypertrophy of adipocytes. Indeed, mice lacking insulin receptors in adipose tissue are protected against high fat diet and glucose intolerance (4, 34). Chronically elevated insulin levels are associated with obesity in human populations and preclinical models (2,3,7,27,31,39). Ph...