Daniel Manrique-Castano, Neuroscientist, Germany

16 April 2020

This article was originally published in Spanish at https://hablemosdeneurociencia.com/companero-desconocido-las-interneuronas-los-circuitos-cerebrales/

Neurons are the best-known cells in the brain. Since pioneering studies such as those by Camilo Golgi and Santiago Ramón y Cajal in the late 19th and early 20th centuries, thousands of approaches have shown the wide functional and morphological variety of neurons. The most studied member of this group is the pyramidal neuron, named for their morphology. Varying in size and density, these cells are the reference for establishing the cytoarchitecture of the brain and for determining the functional properties of various regions through electrophysiological techniques.

First neuroanatomist to present

However, the first neuroanatomists also reported a group of neurons that have been less studied: the interneurons. Also called associative neurons, they are a large group of cells characterized by facilitating communication between sensory pyramidal neurons and motor pyramidal neurons. Using GABA as an inhibitory neurotransmitter, they are associated with reflexes and to neuronal circuit modulation. Some interneurons are the parvalbumin-positive neurons, stellate neurons, basket-shaped neurons or candelabra-shaped neurons.

Until about a decade ago, knowledge of this type of cell was merely descriptive. However, recent genetic and functional studies have established much better their properties and roles. Possibly, in the coming years, we will realize that they fulfill a more important function than we imagined, and like the little-studied glial cells, they could provide some clues about the genesis of CNS diseases.

“Cell diversity occurs through established genetic programs in cell parents that are regulated through environmental interactions”

Cellular Development and Neuronal Diversity

Studies on CNS development in different species suggest that cell diversity occurs through established genetic programs that are regulated through environmental interactions [4]. In the cerebral cortex, for example, it has been described that during development pyramidal neurons migrate in an orderly fashion from their area of origin to the cortical plate.

In contrast, interneurons have an intricate and complex migration program, where they are exposed to many more interactions with the surrounding environment, and achieve a greater dispersion throughout the telencephalon. Thanks to the existence of multiple signaling chains in the brain, it has been hypothesized that interneurons adapt finely to the microenvironments in which they eventually rest. This results in a wide morphological and functional variety among the different areas of the brain. 

Interneuron in the visual cortex expressing Green fluorescent protein (GFP)

Allen Lee et al. (2006). DOI: 10.1371/journal.pbio.0040029

Likewise, studying the relationship between the development cycle and cell diversity, it has been found that GABAergic interneurons are born from the medial ganglion eminence and the caudal ganglion eminence, places that, differentially, give birth to several types of interneurons [3]. Although most interneurons use GABA as a neurotransmitter, there are others that make use of neuromodulators such as acetylcholine, and others have even been reported to express glutamate vesicles (the main excitatory neurotransmitter in the brain). Interestingly, each of these subgroups appears to be derived from different regions.

On the other hand, genetic analyses of cortical and hippocampal neurons have reinforced the idea that the interneurons populating these brain regions have different developmental niches. They then migrate to the hippocampus or the cerebral cortex along migratory routes that scientists have not yet been able to establish [2]. For this reason, the emphasis has been placed on the need to map the diversity of interneurons with molecular mechanisms that allow a relationship to be established between areas of origin and specific migratory routes.

Interneurons and brain circuits

Interneurons are well known to be an active part of neural circuits in the brain. In particular, because of their GABA-based neurotransmission, they are considered to play a role in modulating the excitability of these circuits. For example, it has been proposed that the malfunctioning of interneurons is one of the explanations for pathologies such as epilepsy.

On the other hand, although it has not been possible to establish how interneurons are formed or incorporated into the high variety of synaptic companions throughout the brain, it is hypothesized that the responsible factors may be the extracellular matrix and signaling from pyramidal neurons [1]. In this sense, specific local signals are the determinants of the differentiation of interneurons. This idea is supported by the fact that genes such as Zep2, Dlx, Elmo and Mef2c are expressed in cortical interneurons, but not in those in the striatum (subcortical) [2].

Interneuron migration into the cerebral cortex.

Frazer, S. et al. (2015). DOI:10.1038/tp.2015.147

Interneurons and brain circuits

Once incorporated into the neural circuits, interneurons are usually responsible for establishing local connections. It is not yet clear whether these neurons are responsible for controlling complete brain circuits, as recent studies in electrophysiology have suggested, or whether they only modulate the connections between pyramidal neurons. The fact is that the inhibition provided by the interneurons offers a balance and enriches the dynamics of the pyramidal neuronal networks.

In addition, particular characteristics have been found in certain types of interneurons. For example, parvoalbumin positive neurons control the cadence of the action potential of pyramidal neurons, while Martinotti neurons inhibit pyramidal neurons in layers V and VI of the cerebral cortex and project their axons to layer I. 

Interneurons have varied electrophysiological properties that make them fundamental elements of study to understand the conformation of brain circuits. Although to date most electrophysiological studies in regions such as the hippocampus are performed with pyramidal neurons, some scientists to turn their attention to interneurons. For the time being, it could be said that in a few years we will draw a much more complete scheme of the brain’s interconnections.

References

1. Cancedda, L., Fiumelli, H., Chen, K., Poo, M. (2007). Excitatory GABA Action Is Essential for Morphological Maturation of Cortical Neurons In Vivo. Journal of Neuroscience, 27 (19) 5224-5235; DOI: 

2. Kepecs, A. y Fishell, G. (2014). Interneuron cell types are fit to function. Nature, 505, 318-326.

3. Nery, S. Fishell, G. & Corbin, J. (2002). The caudal ganglionic eminence is a source of distinct cortical and subcortical cell populations. Nature Neuroscience, 5, 1279 – 1287. doi:10.1038/nn971

4. Xu, Q., Cobos, I., De La Cruz, E., Rubenstein, J., & Anderson, S. (2004). Origins of Cortical Interneuron Subtypes. Journal of Neuroscience, 24 (11) 2612-2622.

 

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