There is no such thing as a cell culture of single neurons. Neurons in order to survive and differentiate need the presence of other neurons, so a threshold number of them is needed for a successful cell culture. These clusters or nests of cells may acquire a 3-dimensional architecture when using a device called a rotational bioreactor. In essence the resulting cluster has more of a resemblance to miniature organs (also called organoids) with different cell types and more complex anatomical features than those encountered in regular cell cultures.

The technique for developing organ-buds of the brain was only established recently (2013) by Madeline Lancaster. These organ buds or organoids are thought to directly model the development of the brain, especially its cerebral cortex. This past week a group of researchers, headed by Yale University neuroscientist Flora Vaccarino, used brain organoids to investigate alterations in gene function during brain development in a small group of individuals with autism spectrum disorder (ASD). The results showed that the organoids derived from the ASD subjects had abnormalities of cell proliferation and differentitation which ultimately resulted in an excess of inhibitory neurons as well as their projections.

The way neurons aggregate in these cultures may bear little resemblance to the circuitry observed in the human brain. I take exception to those individuals who use this technique to explore the development of the highly orchestrated events that lead to the formation of the cerebral cortex. In mammals, the cerebral cortex results, in part, from the convergence of radial and tangential migratory streams forming minicolumns and dyads of excitatory-inhibitory cells. Self-aggregation, as in organoids, is only seen under abnormal conditions in the human brain. The end result of self- aggregations are clusters of cells in nucelar configurations that bear little resemblance to the cerebral cortex. Still the idea of simplifying research in autism by studying a reductionist model of the brain is commendable. There are many limitations to postmortem studies including the total number of specimens available and the multiple confounds brought about by medication usage and the agonal/preagonal conditions of the subjects. The brain organoids overcome many of these limitations, allows for the use of molecular techniques, and prompts close observation of developmental stages not otherwise available to investigators.

The study by Vaccarino and collegues provides valuable insights into autism by suggesting a bias in favor of the production of inhibitory neurons caused by a particular gene (FOXG1). This may prove a maladaptive response in the human brain as these supernumerary neurons may not be properly integrated into existing circuitry. This is very commonly seen in disorders of neurodevelopment that affect the proliferation of precursor cells and their later migration to the cerebral cortex. Rather than an increase in inhibition, a diminution of the same is suggested by the presence of seizures and sensory abnormalities. The implications of this study and the doors it opens for future studies are incredibly large and significant. Follow up studies with larger samples are clearly needed.

Reference

Mariani and Coppola et al. FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell; DOI: 10.1016/j.cell.2015.06.034 (open access)