The integration of interneurons into cortical microcircuits

The underlying causes of autism spectrum disorders are poorly understood, but one appealing hypothesis is that an imbalance of excitation and inhibition in the brain’s cortex underlies a significant proportion of autism cases.

Gordon Fishell of New York University School of Medicine and his colleagues suspect that abnormal development of cortical interneurons — specialized nerve cells that relay signals from sensory neurons to motor neurons — is involved in this imbalance. More than 30 percent of people with autism also have epilepsy — a condition in which interneuron dysfunction has been implicated. Genes involved in interneuron function, such as ARX, GABAB receptor and neuroligin, have also been linked to the disorder.

The researchers are attempting to understand how specific subclasses of cortical interneurons develop, and how they are integrated into cortical networks. They previously discovered that knocking out certain autism-linked genes in cortical interneurons of mice results in behavioral traits, including seizures, hyperactivity and poor coordination, that mimic the disorder’s symptoms.

To explore whether abnormal cortical interneuron development is an immediate cause of autism, Fishell and colleagues are building a profile of the genes expressed in this cell population in mice. Cortical interneurons arise from two areas of the fetal brain: the medial and caudal ganglionic eminences. The researchers have already profiled the genes expressed in interneurons formed from the medial ganglionic eminence — many of which are implicated directly in autism or are functionally homologous to autism-linked genes — and are profiling cells derived from the caudal ganglionic eminence.

Fishell’s team is also using a new fluorescent labeling technique to map specific subclasses of cortical interneurons and their connections, combined with measurements of electric signal strength, to examine how disruptions in autism-linked genes can affect cortical networks in mouse models of autism.

The researchers hope that this multi-pronged approach will allow them to identify direct links between autism-linked genes and malfunctions in cortical microcircuits.