Investigating Interneuron Siblings
Material below is adapted from the SfN Short Course Clonally Related Interneurons Are Not Constrained by Functional or Anatomical Boundaries, by Christian Mayer, PhD, Rachel C. Bandler, MD, PhD, and Gordon Fishell, PhD. Short Courses are daylong scientific trainings on emerging neuroscience topics and research techniques held the day before SfN’s annual meeting.
Two types of cells, excitatory and inhibitory neurons, come from distinct lineages during the development of the cortex. Scientists know that the precursors to excitatory neurons divide and then stay associated with sister cells to form functional circuits. In contrast, inhibitory cells travel longer distances and contribute to multiple brain structures.
Recently, several different groups of researchers explored whether inhibitory interneuron lineages restrict where these cells end up in the cortex and what circuits they contribute to. The research teams concluded different things about the role of lineage in determining an interneuron’s cortical position. Two older studies suggested that lineage does play a role in final cortical location, and that cells of the same lineage cluster together. The authors of two more recent studies concluded that assembly of interneurons into circuits does not depend on lineage.
The variable conclusions from these four studies are likely due to different methods used to establish interneuron lineage. Both older studies used techniques that limited their analysis of sister cells location-wise and did not allow identification of related cells that may have migrated to more distant areas of the cortex or regions of the brain.
The more recent studies used a technique in which scientists inject retroviral libraries with unique barcodes and a fluorescent protein into brain regions that will give rise to interneurons at an early stage of development. Then the authors isolated and sequenced fluorescent cells at later developmental stages. They detected some cells that expressed the same barcode and were therefore siblings from the same lineage.
Both recent studies identified interneurons that were not directly next to sister cells. But interneurons from the same lineage were not distributed randomly throughout the cortex. Instead, where they were born and their migration paths restricted their final geography. A follow-up analysis of physical distance between sibling cells demonstrated that related interneurons are separated by spans similar to those that separate unrelated cells. This finding supports the idea that final neuron location is not dependent upon cell lineage.
Not only did the authors of the recent studies show that interneurons of the same lineage can be physically distant from one another, they also showed that at least a tenth of the cells that come from the same lineage are located in different areas of the brain. Because more interneurons are found in the cortex and hippocampus than in other brain structures, most interneurons that the two research teams identified were localized to these areas. However, they also identified sibling interneurons in structures as diverse as the striatum and olfactory bulb.
Interneurons do not appear to be distributed randomly, yet are found in multiple brain areas and in functional circuits with unrelated cells. They also do not seem to cluster with cells of the same lineage, which raises questions about whether related interneurons share physical characteristics or circuit connectivity. The methods used even in the most recent studies of these cells fall short in that the interneuron lineages investigated were incomplete. Much more research, using methods that clearly show sibling relationships, is needed in order to determine the principles that guide interneuron location and function during neuronal development.