They identify the involvement of a minority type of neurons in brain development

The cerebral cortex is the most evolved region of the brain and is made up of millions of neurons that communicate through electrical signals. This activity, which is generated in the excitatory neurons, counts to avoid overloading the circuit with a second and much less abundant inhibitory type (inhibitory neurons or interneurons), which modulates and restricts the activity, or so it was postulated until now. A finding from the Higher Council for Scientific Research (CSIC) in Spain has identified how inhibitory neurons determine the stabilization or elimination of excitatory communication structures by filtering the signals that excitatory neurons receive during their maturation and, therefore, determine the structure end of the adult brain.

The study provides new and revealing data on how alterations in the early stages of life can induce neurodiversity, alternative circuits and permanent defects in the adult neuronal circuit.

Marta Nieto, director of this work and CSIC researcher at the National Center for Biotechnology (CNB) of the CSIC, details the relevance of the study: “During development, this immense number of neurons, still immature, must connect correctly. The excitatory ones initially extend connections to explore whether they form local circuits with their neighbors or long-range circuits with the opposite hemisphere. Vital functions such as sensory and motor perception, or social and emotional interaction depend on this decision. In short, the ability to relate to the world around us; hence the importance of understanding the mechanism of formation and regulation of these processes.”

“Paradoxically,” Nieto continues, “it is observed that many patients with neurodevelopmental diseases, such as autism, schizophrenia or bipolar disorders, share much more symptoms than one would expect. Even more so when, in some cases, we know that the disease is due to genetic involvement exclusively in the excitatory neurons, or in the inhibitory ones. It is not yet understood why patients with these diseases constitute a spectrum or continuum of disorders, and it is difficult to offer them an accurate diagnosis.

Today, the researcher points out that it is almost impossible to predict their disabilities, their diversity and their specific needs. This uncertainty generates a great economic and social impact, which falls on the patient, their families, their caregivers and the countries’ health system. “Currently, one of the priorities is to address this diversity,” emphasizes Nieto.

Furthermore, Lorena Bragg-Gonzalo, one of the first authors of the work, explains that “our data demonstrate that early manipulations in inhibitory neurons induce structural changes in their excitatory neighbors. These alterations consequently cause persistent changes in the way they connect that affect the correct processing and computation of sensory information. “Early inhibition in the developing brain therefore determines the structure of the adult brain.”

Alfonso Aguilera, also one of the first authors of the study along with Bragg-Gonzalo, and a CNB researcher, clarifies that “these data place inhibitory neurons as fundamental foundations for the assembly and formation of communication modules between areas of the brain in the early stages of development. At the same time, alterations in these inhibitory neurons, previously associated with neurodevelopmental diseases, but unknown how, are capable of inducing permanent defects in the adult neuronal circuit.”

Microscopy image of a brain section with the connections formed by neurons (red). (Photo: Lorena Bragg-Gonzalo / CNB / CSIC)

These data, the result of collaboration between the CNB, the team of Dr. Gertrudis Perea at the Cajal Institute and the team of Félix Leroy at the Institute of Neurosciences of Alicante, in Spain, all these entities, provide a new vision of the training of the complex circuits of the brain. “They have a direct impact on our approach to mental illnesses and neurodevelopmental disorders. They bring us closer to understanding the neurodiversity of the adult individual, and even encourage us to further explore the use of early intervention to correct defects in the formation of cortical circuits,” concludes Nieto.

The study is titled “Early cortical GABAergic interneurons determine the projection patterns of L4 excitatory neurons.” And it has been published in the academic journal Science Advances. (Source: Susana de Lucas / CNB / CSIC)