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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.

Background: Motor 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., Methods: Here, 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., Results: We 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., Conclusions: Our 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.

The view that the functional maturation of the brain is the result of an environmentally driven adaptation of genetically preprogrammed neuronal networks is an important current concept in developmental neuroscience and psychology. This hypothesis proposes that early traumatic experiences or early life stress (ELS) as a negative environmental experience provide a major risk factor for the development of dysfunctional brain circuits and as a consequence for the emergence of behavioral dysfunctions and mental disorders in later life periods. This view is supported by an increasing number of clinical as well as experimental animal studies revealing that early life traumas can induce functional 'scars' in the brain, especially in brain circuits, which are essential for emotional control, learning, and memory functions. Such gene × environment interactions are modulated by specific epigenetic mechanisms, which are suggested to be the key factors of transgenerational epigenetic inheritance. Indeed, there is increasing evidence for inter- and transgenerational cycles of environmentally driven neuronal and behavioral adaptations mediated by epigenetic mechanisms. Finally, recent concepts postulate that, dependent on type, time point, and duration of ELS exposure, also positive functional adaptations may occur in the relevant brain pathways, leading to better stress coping and resilience against adversities later in life.

The development of the brain depends on an individual's nature (genes) and nurture (environments). This interaction between genetic predispositions and environmental events during brain development drives the maturation of functional brain circuits such as sensory, motor, emotional, and complex cognitive pathways. Adverse environmental conditions such as early life stress can interfere with the functional development of emotional and cognitive brain systems and thereby increase the risk of developing psychiatric disorders later in life. In order to develop more efficient and individualized protective and therapeutic interventions, it is essential to understand how environmental stressors during infancy affect cellular and molecular mechanisms involved in brain maturation. Animal models of early life stress have been able to reveal brain structural and metabolic changes in prefrontolimbic circuits, which are time, brain region, neuron, and sex specific. By focusing on animal models of separation stress during infancy, this review highlights epigenetic and cytoarchitectural modifications which are assumed to mediate lasting changes of brain function and behavior., (© 2016 S. Karger AG, Basel.)