When “Inhibitory” Interneurons Are Actually Excitatory

Brain function depends not only on excitatory neurons but also on the inhibitory neurons that balance excitation. These inhibitory neurons help with the processing of information as well as with preventing runaway seizures. However, in a George Washington University study published today in Science Advances, scientists report that in some critical structures of the developing brain, the inhibitory neurons cause excitation rather than suppression of brain activity. The findings could have implications for the treatment of neonatal seizures.

Inhibition in the mammalian brain is mediated by GABAergic interneurons. Despite their importance in adults and implication in neurodevelopmental disorders such as autism, the role of interneurons during brain development is poorly understood. In fact, treatments designed to combat neonatal seizures by augmenting GABA receptor function are often ineffective. So the researchers tested a longstanding hypothesis that the brain’s inhibitory system is actually excitatory during development.

“This is the first evidence that these neurons are actually excitatory in vivo,” says senior author Matthew Colonnese. “The inhibitory system within the fetal brain, which in the adult acts as a kind of braking system, instead can act as an accelerator in the young brain.”

In this study, the researchers locally manipulated interneuron activity in a murine model. Their results prove that GABAergic neurons are excitatory in the hippocampus at ages equivalent to the early third trimester and only later become inhibitory. The study also showed that interneurons in a closely related but different region—the visual cortex—are inhibitory throughout early development.

The team’s evidence of GABA’s heterogeneity across regions of the brain gives one potential explanation as to why simply trying to change early excitatory GABA into inhibitory GABA may not work. “It’s really going to depend on the origin of the seizures, whether they originate in the cortical or hippocampal tissue, their spread, the infant's age, and the type of seizure,” Colonnese says.

The researchers see the potential for their data to inform development of drugs for neonatal seizures; however, having examined just two regions in this study, they note that a more global mapping of where and when interneurons are excitatory or inhibitory is needed, as well as an understanding of what determines whether neurons act as an accelerator or a brake.