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Human Excitation and Inhibition

The rise of mammals followed the global extinction of the dinosaurs 66 million years ago. Since then, there has been an expansion in the size and complexity of the cerebral cortex in primates. Classic pulse-chase experiments using radioactive DNA precursors to trace the birthdates of excitatory neurons in the macaque brain first powerfully linked early developmental events to the functional architecture of the excitatory neurons in the primate cortex. Subsequent experiments in the mouse showed that inhibitory neurons were derived from a different region, the so-called ganglionic eminence of the ventral forebrain.

Most assumed that the organization in the mouse was also true in human brain. Recent work suggests our perspective must change. This issue of neuroDEVELOPMENTS reviews a new study based on experiments with human fetal cortex; the work suggests a large proportion of inhibitory neurons are derived from the dorsal neuroepithelium along with their excitatory neuron siblings. This study required access to primary human fetal brain tissue, a limited and regulated resource, but the rapid development of new stem cell technologies promise powerful access to the early stages of human cortical development. Remarkable progress using pluripotent stem cells to model psychiatric genetic risk in cortical development is illustrated by the second paper we discuss. In previous issues we have emphasized how new DNA sequencing tools provide high resolution maps of the neuronal lineages that construct the cortex. We now know genetic alteration specifically in these lineages causes highly penetrant psychiatric risk. Progress on these related tools raises the prospect of experimentally defining how this variation alters subsequent computations based on the interaction of excitatory and inhibitory neurons in cortical columns. In the commentary below and the insight from our board we hope to bring you a sense of this progress in our understanding of these risk mechanisms in the emerging vista of primate cortical development.

-Ron McKay, PhD, Chief Editor
Lieber Institute for Brain Development

-Venkata S. Mattay, MD
Managing Editor

-Michele Solis, PhD
Science Writer

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Editorial Board

Fred ‘Rusty’ Gage, PhD
President, The Salk Institute for Biological Studies

Daniel Geschwind, MD, PhD
Professor, UCLA School of Medicine

Elizabeth Grove, PhD
Professor, University of Chicago

Jürgen Knoblich, PhD
Interim Scientific Director, Institute of Molecular Biotechnology, Austrian Academy of Sciences

Arnold Kriegstein, MD
Professor, UCSF

Pat Levitt, PhD
Professor, Keck School of Medicine of USC

Mu-Ming Poo, PhD
Director, Institute of Neuroscience, Chinese Academy of Sciences

John Rubenstein, MD, PhD
Professor of Psychiatry, UCSF

Nenad Sestan, MD, PhD
Professor, Yale University

Flora Vaccarino, MD
Professor, Yale University

Chris Walsh, MD, PhD
Chief, Division of Genetics & Genomics, Boston Children’s Hospital

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