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).