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Review
. 2016 Dec 15;524(18):3865-3895.
doi: 10.1002/cne.24040. Epub 2016 Jun 16.

The Search for True Numbers of Neurons and Glial Cells in the Human Brain: A Review of 150 Years of Cell Counting

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Free PMC article
Review

The Search for True Numbers of Neurons and Glial Cells in the Human Brain: A Review of 150 Years of Cell Counting

Christopher S von Bartheld et al. J Comp Neurol. .
Free PMC article

Abstract

For half a century, the human brain was believed to contain about 100 billion neurons and one trillion glial cells, with a glia:neuron ratio of 10:1. A new counting method, the isotropic fractionator, has challenged the notion that glia outnumber neurons and revived a question that was widely thought to have been resolved. The recently validated isotropic fractionator demonstrates a glia:neuron ratio of less than 1:1 and a total number of less than 100 billion glial cells in the human brain. A survey of original evidence shows that histological data always supported a 1:1 ratio of glia to neurons in the entire human brain, and a range of 40-130 billion glial cells. We review how the claim of one trillion glial cells originated, was perpetuated, and eventually refuted. We compile how numbers of neurons and glial cells in the adult human brain were reported and we examine the reasons for an erroneous consensus about the relative abundance of glial cells in human brains that persisted for half a century. Our review includes a brief history of cell counting in human brains, types of counting methods that were and are employed, ranges of previous estimates, and the current status of knowledge about the number of cells. We also discuss implications and consequences of the new insights into true numbers of glial cells in the human brain, and the promise and potential impact of the newly validated isotropic fractionator for reliable quantification of glia and neurons in neurological and psychiatric diseases. J. Comp. Neurol. 524:3865-3895, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: cell counts; glia number; glia-neuron ratio; history; human brain; neuron number; quantification.

Conflict of interest statement

There are no conflicts of interest.

Figures

Fig. 1
Fig. 1
A–B Photomicrographs of Nissl-stained neurons and glial cells. A. Purkinje cells (P) and granule cells (arrow) in the cerebellum of an adult mouse brain. B. Motoneuron (M), interneuron (I) and glial cells (arrows) in the trochlear nucleus of an adult mouse brain. Note that the neuronal granule cell (arrow) in panel A is virtually indistinguishable in size and shape from glial cells (arrows) in panel B. Thionin stains of 40 μm paraffin sections. Digital images obtained on a Nikon Eclipse E600 microscope, with no digital adjustments or manipulations of the images. Scale bar = 10 μm. Histological sections kindly provided by Dr. Larisa M. Wiggins.
Fig. 2
Fig. 2
A–D Flow chart of the isotropic fractionator (IF) cell counting method. The major steps of the procedure are illustrated. A. Example of fixed brain tissue. Scale bar = 1 cm. B. Tenbroek glass homogenizer. C. Appearance of DAPI-stained nuclei (left) and two nuclei double-labeled with DAPI (upper panel) and NeuN (lower panel). Scale bar = 20 μm. D. Neubauer counting chamber. DAPI, 4,6-diamidino-2-phenylindole; Fr, fraction; NeuN+, neuronal nuclear antigen positive; PBS, phosphate-buffered saline; Vol, volume; Modified from Herculano-Houzel and Lent (2005), Bahney and von Bartheld (2014), and Herculano-Houzel et al. (2015).
Fig. 3
Fig. 3
This graph summarizes the essence of Table 6. From the 1960s until 2009, the number of glial cells in human brains was reported to be about one trillion, 10 times more than neurons (100 billion), as detailed in Table 6. The number of glia, based on published data, is in fact lower than the number of neurons, resulting in a glia-neuron ratio of less than 1 rather than 10:1.

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