Scientific Understanding of Consciousness
Embryonic Development of Cortical Microcircuits via Chandelier Interneurons
Science 31 May 2013: Vol. 340 no. 6136 pp. 1058-1059
Neuronal Birth to Cortical Circuitry
1Department of Psychiatry, Children's Hospital of Philadelphia–University of Pennsylvania School of Medicine, Philadelphia, PA 19104-5127, USA.
2Division of Pediatric Neurology, Children's Hospital of Philadelphia–University of Pennsylvania School of Medicine, Philadelphia, PA 19104-5127, USA.
Neuropsychiatric diseases, such as schizophrenia and autism, likely involve dysfunction in cerebral cortical microcircuits. Although some of this dysfunction probably results from disruptions near the time of symptom onset, some also likely evolves from abnormalities that occurred earlier during cortical neuron development. However, a major challenge has been to link microcircuitry dysfunction to a disruption in the developmental trajectories of constituent neuronal subtypes. Recent research studies describe a method for reliably labeling a distinct subtype of cortical neuron, the chandelier interneuron, from its genesis through postnatal development. The work advances understanding of cortical microcircuitry development, and highlights the potential challenges of using the current genetic armamentarium to label increasingly specific subsets of cortical neurons.
The neocortex is composed of diverse neuronal subtypes with distinct patterns of connectivity and activity. This complexity has hindered our ability to understand the development and function of cortical circuitry, and thus how it malfunctions in disease. The neuronal cytoarchitecture of the neocortex involves projection neurons that are mainly excitatory, and local circuit neurons (interneurons) that are mainly inhibitory. Neuronal subgrouping is often defined by single characteristics, such as laminar location, expression of a particular protein, morphology, or electrophysiological properties. Subtypes of neurons are then categorized by clustering these characteristics, such as layer 5, callosally projecting pyramidal neurons expressing Dkk3, or vertically oriented, vasoactive intestinal peptide (VIP)–expressing interneurons with regular and nonaccommodating spiking features.
Recent advances in the labeling and manipulation of neuronal subgroups are enabling characterization according to their function in cortical microcircuits. For example, in mice, labeling of somatostatin (SST)–expressing interneurons with a fluorescent protein revealed that cortical layer 3 SST interneurons primarily inhibited the activity of pyramidal neuron dendrites, whereas layer 4 SST interneurons selectively targeted fast-spiking inhibitory interneurons. Thus, within the SST-expressing subgroup, neuronal subtypes residing in distinct cortical layers can have apposing influences on cortical excitation.
Although genetic labeling of cortical neuronal subgroups and elucidation of their functional connectivity in microcircuits are resulting in many insightful studies, the labeling methods are often restricted to later stages of the target cell's development. This is an important limitation, because symptoms of neuropsychiatric disorders can be the manifestations of disruptions that began much earlier.
Recent research studies take this approach to a new level—the selective labeling of a subtype of interneuron, the chandelier cell, from its birth within the subcortical telencephalon to its maturation within the postnatal neocortex. Chandelier cells innervate the axon initial segment of cortical pyramidal neurons. Notably, this interneuron subtype also has dense, sometimes conjoint innervation of most of the pyramidal neurons within its axonal field, and displays synaptic abnormalities in schizophrenia. Chandelier cells derive from Nkx2.1-expressing progenitors of the subcortical forebrain, especially within the most ventral portion of the medial ganglionic eminence (MGE) late in the period of cortical neurogenesis.
These research results suggest that chandelier cells play a previously unrecognized role in the development of cortical circuitry.
Postmortem studies of schizophrenia have identified abnormalities in chandelier cells, but whether the abnormalities are a cause or an effect of the core etiology is unclear. Thus, the ability to selectively label these cells enables the study of whether chandelier cell–specific mutations of interneuron-expressed schizophrenia risk genes, can induce schizophrenia-related phenotypes in mice.
The evidence to date is that fate commitment of both cortical pyramidal neuron and interneuron subtypes generally occurs before or shortly after cell cycle exit. Although the genetic code responsible for maintaining neuronal subtype fate through the migration and maturation processes may be combinatorial, it should be possible to identify genes with adequately selective expression patterns that, together with the temporal restriction of labeling, will enable developmental studies of the microcircuitry involving most cortical neurons. These approaches are likely to revolutionize the discovery of the etiological antecedents of neuropsychiatric disease.
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