More than 100 genes have been associated with autism, but one challenge is to understand how gene mutations alter signaling between neurons to cause deficient social interaction, communication and repetitive behaviors. Partha Mitra, Josh Huang and their colleagues at Cold Spring Harbor Laboratory in New York propose to use systematic and large-scale techniques to develop a detailed neuroanatomical map in mouse models of autism.

Inhibitory neurons have crucial roles in the nervous system: turning off activated neurons or preventing a neuron from turning on inadvertently, providing global as well as specific inhibitory control of neuronal activity. Much evidence has suggested that there is an imbalance of excitatory and inhibitory neurons in autism, leading the researchers to study how the activity of inhibitory neurons changes in models of autism.

The researchers propose a brain-wide screen to map changes in the distribution and connectivity of neurons that produce the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA, in mouse models of autism compared with normal mice. To perform this screen systematically, Mitra and his colleagues plan to use industrial automation methods that were developed as part of the Mouse Brain Architecture Project. This automated approach to whole-brain neuroanatomy maps the patterns of long-range neuronal projections and the spatial distributions of classes of neurons.

In parallel, Huang and his colleagues will systematically generate mouse lines by genetically inserting a marker to follow the development and activity of the major classes of inhibitory GABAergic neurons.

Mitra, Huang and their colleagues plan to characterize the architecture of inhibitory neurons at key postnatal developmental stages. The researchers also propose to profile a specific inhibitory cell type — chandelier cells — that has broad and powerful effects in the cortex and is implicated in several brain disorders.

The researchers hope to fill in the current gap of knowledge between genes and anatomy by understanding how inhibitory neurons, key players in brain activity, change in autism at the level of whole-brain neuronal architecture.