How Cortical Interneurons Develop: Current and Future Research

Inhibitory gamma-aminobutyric acid-containing (GABAergic) interneurons may comprise only around 20% of all cortical neurons, but they play important roles in cortical function. Not only do they control and orchestrate the activity of excitatory glutamatergic pyramidal cells of the neocortex, contributing to regulation of the overall activity levels of the brain, but they also mediate the precise processing of information in the different cortical networks.

Their importance is further manifested by increasing evidence that implicates them in brain disorders such as schizophrenia and epilepsy, as well as autism spectrum disorders.

Cortical GABAergic interneurons are highly heterogeneous, forming distinct functional classes with unique molecular, morphological, and electrophysiological characteristics. Recent transcriptomic analysis reveals that 20 molecularly distinct interneuron types exist in the mammalian neocortex. This remarkable heterogeneity is the outcome of a long developmental journey.

This journey starts with the genesis of specified progenitors in extra-cortical tissue, mainly the ganglionic eminences, which are well-defined domains of the basal telencephalon. (An additional source of interneurons has been identified in the pallium of primates.) These progenitors migrate tangentially to populate the cortex, where they are distributed into the different forming layers. Subsequently they are pruned by means including programmed cell death, dendritic and axonal morphogenesis, formation of synapses, and finally, circuit refinement. In the last twenty or so years, many of the molecular details of these processes have been revealed.

One area of intense research now is how cortical interneurons are specified. Early cascades of transcription factors, expression of which is under spatial and temporal control, have been identified to determine the fate of cardinal classes of interneurons. In addition, several studies have provided evidence that manipulating neuronal activity affects many aspects of the mature properties of interneurons, suggesting that cortical interneuron identity is not determined exclusively at the progenitor level.

Recent single-cell RNA-sequencing experiments support both the progenitor and the cardinal-definitive model of interneuron specification. Further research, which will also include the application of novel genomic methods to investigate the role of alternative splicing as well as micro- and long-coding RNAs, and to identify epigenomic regulators, is required.

Understanding cortical GABAergic interneuron specification will be valuable not only for understanding neocortical developmental but also for identifying genetic mechanisms underlying a number of neuropsychiatric disorders and for programming human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) into functional interneurons for in vitro clinical studies and cell-based therapies.

Recently, a lot of attention has focused on the elucidation of mechanisms controlling the number of interneurons. Cortical interneurons are generated in excess from basal forebrain progenitors, and their final number is adjusted via developmental cell death occurring over a critical early postnatal period. Although we are still at the beginning of understanding this developmental process, activity seems to have a fundamental role, because cell-autonomous activity that is dependent pro-survival pathways, pyramidal cell activity levels, and coordinated activity of synaptically connected cortical interneurons and pyramidal cells has been shown to control the survival of GABAergic interneurons of the mammalian neocortex.

Interneuron survival has a direct impact on establishing the correct ratio of pyramidal neurons and interneurons in mature cortical circuits, which is thought to be crucial for maintaining normal activity patterns in the brain.

Another intriguing issue that has emerged in the field is the intimate relationship of GABAergic interneurons with oligodendrocytes in the cerebral cortex. Oligodendrocytes, the glial cells that make myelin in the central nervous system (CNS), share with GABAergic interneurons several developmental attributes, despite the fact that they are distinct cell types. To name a few, they have common embryonic origins, they develop from precursors expressing similar transcriptional programs, they follow similar journeys as they settle in the cortex, and they interact extensively to influence each other's development.

Much progress has been made recently toward unveiling interneuron-oligodendrocyte interactions in the formation of inhibitory networks, as well as myelination. GABAergic fast-spiking parvalbumin-positive (PV) interneurons are heavily myelinated. Interestingly, PV interneurons as well as myelin defects have been implicated in severe neurodevelopmental pathologies such as schizophrenia. An exciting prospect for a novel putative mechanism underlying this disorder would be to link interneuron and myelin defects.

Since Steward Anderson, John Rubenstein and colleagues discovered the first cell fate determinant factors for neocortical interneurons in 1996, our understanding of cortical interneuron development has significantly increased, and many questions remain to be answered. One thing is for certain, these remarkable neurons and their long developmental journey will continue to intrigue developmental biologists and neuroscientists for some time to come.

About the Contributors

Myrto Denaxa, PhD

Myrto Denaxa is a PI at the Alexander Fleming Biomedical Sciences Research Center, Greece. Denaxa obtained her bachelor’s degree from the University of Patras, Greece, and her master’s and PhD from the University of Crete Medical School, Greece.

Domna Karagogeos, PhD

Domna Karagogeos is a professor of molecular biology and developmental neurobiology at the University of Crete Medical School and collaborating researcher at the Institute of Molecular Biology and Biotechnology, Greece. Karagogeos received her bachelor’s degree in biology and chemistry from Simmons College, her master’s and PhD in cell and developmental biology from Harvard University.