We are studying the autism spectrum disorder (ASD) model of common marmoset (New World monkey) to understand ASD and develop treatments for it. The causes of ASD are not well understood, but it is suggested that 60% of ASD is caused by genetic mutations and 40% by changes in the maternal environment during fetal life. It is well documented that valproic acid (VPA) increases the risk of ASD by interfering with normal gene expression during fetal brain development. We have developed a marmoset model of ASD by administering VPA to marmoset mothers (VPA marmoset). The VPA marmoset shows many characteristics similar to human ASD, including autistic behavior.

Of particular interest is the altered gene expression in the brain of the VPA marmoset. In order to evaluate how well an animal model of ASD reproduces human ASD, an objective assay can be performed by comparing the transcriptome of individuals with ASD and ASD model animals. The VPA marmoset has features that reproduce the transcriptome of the postmortem brain in ASD (particularly, idiopathic ASD). Namely, neuron- and oligodendrocyte-related modules were down-regulated, and astrocyte- and microglia-related modules were up-regulated both in the VPA marmoset and human ASD. The transcriptome currently available in the ASD rodent model was concordant with that of human ASD, with only modules involving at most two cell types. Therefore, we expect that the study of VPA marmosets will lead to the understanding of the mechanism of ASD and the development of therapeutic drugs with high translational value.

We are currently conducting research on the following points

1. Development of a test for autism-like behavior in the VPA marmoset

Marmosets, like humans, form complex societies through the interaction of multiple individuals. Therefore, the VPA marmoset has the potential to replicate the symptoms that people with ASD have trouble with in society, and to develop appropriate treatment methods for individual symptoms. To this end, we are developing a variety of methods to study autistic behaviors similar to those of humans.

2. Lifelong time course in ASD

ASD is a lifelong condition. We are investigating autism-like behaviors and biological disturbance of the brain from neonatal, childhood to adulthood in VPA marmosets. The brain undergoes significant changes as it grows, and the symptoms and pathophysiology of ASD change accordingly. Understanding the developmental time course of ASD is important in developing age-appropriate diagnostic and therapeutic methods. In particular, the importance of early diagnosis and treatment is becoming increasingly recognized. The methods include analysis of gene expression, brain morphology, synapses, and behavior. For synapses in particular, we use in vivo two-photon microscopy.

3. Analysis of VPA marmosets by brain imaging used in humans

The morphology and function of the marmoset brain are similar to that of humans. Analyzing VPA marmosets with brain imaging for human ASD is expected to accelerate the translation of marmoset research findings to humans. We are currently investigating the brains of VPA marmosets using nuclear magnetic resonance imaging (MRI), cortical electroencephalography (ECoG), and positron emission tomography (PET).