Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2001 Jul 1;21(13):4789-800.
doi: 10.1523/JNEUROSCI.21-13-04789.2001.

Neuronal hypertrophy in the neocortex of patients with temporal lobe epilepsy

S Bothwell  1 , G E Meredith, J Phillips, H Staunton, C Doherty, E Grigorenko, S Glazier, S A Deadwyler, C A O'Donovan, M Farrell
Affiliations

Neuronal hypertrophy in the neocortex of patients with temporal lobe epilepsy

S Bothwell et al. J Neurosci. .

Abstract

The underlying cause of neocortical involvement in temporal lobe epilepsy (TLE) remains a fundamental and unanswered question. Magnetic resonance imaging has shown a significant loss in temporal lobe volume, and it has been proposed that neocortical circuits are disturbed functionally because neurons are lost. The present study used design-based stereology to estimate the volume and cell number of Brodmann's area 38, a region commonly resected in anterior temporal lobectomy. Studies were conducted on the neocortex of patients with or without hippocampal sclerosis (HS). Results provide the surprising finding that TLE patients have significant atrophy of neocortical gray matter but no loss of neurons. Neurons are also significantly larger, dendritic trees appear sparser, and spine density is noticeably reduced in TLE specimens compared with controls. The increase in neuronal density we found in TLE patients is therefore attributable to large neurons occupying a much smaller volume than in normal brain. Neurons in the underlying white matter are also increased in size but, in contrast to other reports, are not significantly elevated in number or density. Neuronal hypertrophy affects HS and non-HS brains similarly. The reduction in neuropil and its associated elements therefore appears to be a primary feature of TLE, which is not secondary to cell loss. In both gray and white matter, neuronal hypertrophy means more perikaryal surface area is exposed for synaptic contacts and emerges as a hallmark of this disease.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Photograph of a 3-mm-thick coronal slice retrieved at autopsy. The slice passes through the temporal lobe close to area 38 at the border with areas 21 and 28. COS, Collateral sulcus; EC, entorhinal cortex; FusG, fusiform gyrus; HF, hippocampal formation;ITG, inferior temporal gyrus; MTG, middle temporal gyrus; STG, superior temporal gyrus;SF, Sylvian fissure.
Fig. 2.
Fig. 2.
A schematic diagram illustrating the steps required to establish a reference volume. A, Slices, 3-mm-thick, are selected in a uniformly random manner (1/3).B, A grid with points, 3 mm apart and each associated with a known area (a/p) is laid over the face of each slice. C, Points are counted, and the area is calculated. The area associated with the gray or white matter is then multiplied by the thickness of the slice to estimate the reference volume.
Fig. 3.
Fig. 3.
Illustrations of the methodology used to obtain estimates of total neuronal number, cortical depth, and somal volume. A, After outlining the region of interest inyellow, a grid with equidistant counting frames (red and green) is laid on the selected area. B, Using high magnification (100×, oil, 1.2 numerical aperture), a neuron is counted with the disector probe if the boundaries of its nucleus touch, lie within, or cross the green lines of a single counting frame. Cells are not counted (red X) if the nuclear envelope touches or crosses the red or forbidden lines. C, The depth of the gray matter is measured by estimating the mean cortical depth using a uniformly random placement of vertical lines, each of which is placed perpendicular to the pial surface. D,The somal volume of each cell is estimated using the nucleator. To do this, isotropic lines are generated from a central point in the nucleolus and extend through the somal boundary. The distance from the central point to the cell surface is measured, and because the depth of the tissue is known, the somal volume can be estimated. Scale bars: A, C, 100 μm; B,D, 10 μm.
Fig. 4.
Fig. 4.
Photomicrographs of layers I-VI of temporal neocortex in controls (A–C). Pictured are Brodmann's area 28 (A), 21 (B), and 38 (C). Note the lack of granule cells in layers II, IV in area 38 (C). D, The same layers of area 38 in TLE neocortex; note the decrease in cortical width, particularly in layers III-VI, when compared with C. Scale bar, 100 μm.
Fig. 5.
Fig. 5.
High-power photomicrographs of Nissl-stained sections from two autopsy cases (A, B) and two TLE cases (C, D). Note the differences in neuronal size and packing density in layers II, III, IV, and V between TLE neocortex (C, D) and control tissue (A, B). Scale bar, 20 μm.
Fig. 6.
Fig. 6.
Layer III pyramidal neurons filled intracellularly with LY and reacted with DAB. A, A filled neuron in an autopsy control specimen has the typical pyramidal shape and numerous dendritic branches. The inset to theright shows the densely spiny covering that is typical of these dendrites. B, An intracellularly filled pyramidal cell in layer III of TLE neocortex. The large primary, dorsal dendrite appears to have been severed during the preparation of the slice. Note the large, rounded cell soma. The thick primary dendrites and low number of processes are typical of cells in TLE cortex. Theinset to the right shows swellings along the course of the dendrites and the sparse covering of spines. Scale bar, 25 μm.
Fig. 7.
Fig. 7.
A, Total number of neurons in area 38 (gray matter) of control (CON) and TLE specimens.B, Density of neurons in area 38 (gray matter) expressed per cubic millimeter. Density is significantly increased in TLE neocortex as compared with controls (*p = 0.023;t test, F(−2.563,14) = 0.147). C, Mean somal volume (expressed as cubic micrometers) of neurons as estimated with the nucleator. Neurons in TLE cortex are significantly larger than those in control material (***p < 0.0001, Mann–Whitney Utest). D, Proportion of small (diameter, <10 μm), medium (diameter, 10–15 μm), and large (diameter, >15 μm) neurons in the gray matter of area 38 in control (CON) and TLE neocortex. The proportion that are medium-sized is significantly decreased (*p = 0.03;t test; F(−2.41,14) = 0.734), whereas that of large neurons is significantly increased (*p = 0.001, t test;F(−6.347,14) = 1.847) in TLE cortex when compared with controls.
Fig. 8.
Fig. 8.
A, Total number of neurons in the white matter of area 38 of control (CON) and TLE specimens. B, Density of neurons in the white matter as expressed per cubic millimeter. C, Mean somal volume (expressed as cubic micrometers) of neurons in the underlying white matter of area 38 is significantly larger in TLE neocortex than those in control material (***p < 0.0001, Mann–WhitneyU test). B, The proportion of neurons that are small or medium-sized is significantly reduced, whereas that of large cells is significantly increased in TLE white matter when compared with controls (small cells: **p < 0.05,t test, F(2.116,14) = 0.3858; medium-sized cells, ***p < 0.001,t test, F(3.727,14) = 0.022; large cells, ***p < 0.001, ttest, F(−4.036,14) = 7.599).
Fig. 9.
Fig. 9.
A schematic diagram illustrating the arrival of axons onto layer III neurons during normal development (top). Arriving terminals normally contact spines or distal dendrites. If neurons are hypertrophied and have lost dendrites and spines, as suggested in the bottom diagram, arriving axon terminals, many of which are excitatory, corticocortical connections, could be guided to synapse with the cell body instead.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abel TW, Rance NE. Stereologic study of the hypothalamic infundibular nucleus in young and older women. J Comp Neurol. 2000;424:679–688. - PubMed
    1. Allendoerfer KL, Shatz CJ. the subplate, a transient neocortical structure: its role in the development of connections between thalamus and cortex. Annu Rev Neurosci. 1994;17:185–218. - PubMed
    1. Anderson AJ, Su JH, Cotman CW. DNA damage and apoptosis in Alzheimer's disease: colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay. J Neurosci. 1996;16:1710–1719. - PMC - PubMed
    1. Arnold SE, Trojanowski JQ. Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathologica. 1996;92:217–231. - PubMed
    1. Babb TL, Brown WJ, Pretorius J, Davenport C, Lieb JP, Crandall PH. Temporal lobe volumetric cell densities in temporal lobe epilepsy. Epilepsia. 1984;25:729–740. - PubMed

Publication types

Substances

LinkOut - more resources