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Systematic analysis of neural circuitry in mouse models of autism

Pavel Osten, M.D., Ph.D.
Cold Spring Harbor Laboratory

Recent studies have implicated a growing number of genes in the development of autism, but the candidates form a motley collection. Understanding what these genes have in common and how they relate to clinical findings in children with autism will shed light on the biological mechanisms underlying the disorder.

Pavel Osten, of Cold Spring Harbor Laboratory, and his colleagues hypothesize that various genetic mutations result in more homogeneous core dysfunctions of neural circuitry responsible for the disorder’s clinical features, such as deficient language skills, impaired social interaction and restricted interests. The researchers are thus searching for causal links between genetic variants and neural circuit malfunctions in mouse models of autism.

Osten’s team plans to systematically screen neural circuits in the brains of ‘indicator’ mice, in which genes representative of neural activity — such as c-Fos and Arc — are tagged with a green fluorescent protein. A custom-built microscope will be used to capture three-dimensional images of whole mouse brains. The researchers will then use the images to screen and compare neural circuits — indicated by the green-lit areas — in autism model mice and their normal counterparts.

Osten and his team say that screening neural circuit activity in mice with various genetic mutations will allow them to identify the deficits common to these mice — and thus the brain regions that are affected by the core traits of autism. If successful, their work could help classify autism spectrum disorders based on the underlying damaged neural circuits, and certain circuits could be targets for new therapies. Osten and colleagues also hope to facilitate future mouse model work by helping the autism research community to focus attention on the most promising areas of the brain.

proposalCENTRAL #137480