Most neuron circuits express a balance between excitation and inhibition. Gamma-aminobutyric acid (GABA)-releasing, or GABAergic, interneurons mediate inhibition in the mammalian brain. Their connectivity is essential in sensation, movement, and cognition. Despite their importance in adults and connection to neurodevelopmental disorders, the role of interneurons during brain development is not fully understood.
Researchers at George Washington University have now proven that in some structures of the developing brain, the inhibitory neurons—that balance or suppress excitation—do cause excitation, which had not previously been proven in vivo.
Their study, “GABAergic interneurons excite neonatal hippocampus in vivo,” has been published in Science Advances, and could have implications for the treatment of neonatal seizures.
“GABAergic interneurons are proposed to be critical for early activity and synapse formation by directly exciting, rather than inhibiting, neurons in developing hippocampus and neocortex. However, the role of GABAergic neurons in the generation of neonatal network activity has not been tested in vivo, and recent studies have challenged the excitatory nature of early GABA,” the researchers wrote.
To test the role of local GABAergic neurons in early activity, the researchers used a variety of chemogenetic and optogenetic approaches to manipulate the activity of GABAergic interneurons while recording network activity locally using multielectrode array recordings in unanesthetized neonatal mice. The researchers showed that GABAergic neurons are excitatory in CA1 hippocampus at postnatal day 3. Hippocampal interneurons become inhibitory by postnatal day 7, whereas visual cortex interneurons were already inhibitory by P3 and remained inhibitory throughout development.
The team’s observation of GABA’s heterogeneity across regions of the brain potentially explains why trying to alter early excitatory GABA into inhibitory GABA, as anti-seizure treatments currently do, 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,” explained Matthew Colonnese, PhD, assistant professor of pharmacology and physiology at the George Washington School of Medicine and Health Sciences and senior author of the study.
Their study revealed that GABAergic interneuron excitation is critical for network activity in neonatal hippocampus and confirms that visual cortical interneurons are inhibitory throughout early postnatal development. Their findings lead to a better understanding of interneurons and may eventually lead to an effective treatment for neonatal seizures.
“My hope is that we can use these findings to develop more targeted therapies for infants suffering from seizure disorders,” explained Yasunobu Murata, PhD, first author and research scientist of Colonnese’s lab at George Washington University.
The researchers noted that although their findings may aid in the development of treatment for neonatal seizures, global mapping of where and when interneurons are excitatory or inhibitory is still required, as well as understanding what determines whether neurons act as an accelerator or a brake.