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. 2014 Sep 18:2:141.
doi: 10.1186/s40478-014-0141-7.

Stereological study of the neuronal number and volume of 38 brain subdivisions of subjects diagnosed with autism reveals significant alterations restricted to the striatum, amygdala and cerebellum

Jerzy Wegiel, Michael Flory, Izabela Kuchna, Krzysztof Nowicki, Shuang Yong Ma, Humi Imaki, Jarek Wegiel, Ira L Cohen, Eric London, Thomas Wisniewski, William Ted Brown

Stereological study of the neuronal number and volume of 38 brain subdivisions of subjects diagnosed with autism reveals significant alterations restricted to the striatum, amygdala and cerebellum

Jerzy Wegiel et al. Acta Neuropathol Commun. .

Abstract

Introduction: A total of 38 brain cytoarchitectonic subdivisions, representing subcortical and cortical structures, cerebellum, and brainstem, were examined in 4- to 60-year-old subjects diagnosed with autism and control subjects (a) to detect a global pattern of developmental abnormalities and (b) to establish whether the function of developmentally modified structures matches the behavioral alterations that are diagnostic for autism. The volume of cytoarchitectonic subdivisions, neuronal numerical density, and total number of neurons per region of interest were determined in 14 subjects with autism and 14 age-matched controls by using unbiased stereological methods.

Results: The study revealed that significant differences between the group of subjects with autism and control groups are limited to a few brain regions, including the cerebellum and some striatum and amygdala subdivisions. In the group of individuals with autism, the total number and numerical density of Purkinje cells in the cerebellum were reduced by 25% and 24%, respectively. In the amygdala, significant reduction of neuronal density was limited to the lateral nucleus (by 12%). Another sign of the topographic selectivity of developmental alterations in the brain of individuals with autism was an increase in the volumes of the caudate nucleus and nucleus accumbens by 22% and 34%, respectively, and the reduced numerical density of neurons in the nucleus accumbens and putamen by 15% and 13%, respectively.

Conclusions: The observed pattern of developmental alterations in the cerebellum, amygdala and striatum is consistent with the results of magnetic resonance imaging studies and their clinical correlations, and of some morphometric studies that indicate that detected abnormalities may contribute to the social and communication deficits, and repetitive and stereotypical behaviors observed in individuals with autism.

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Figures

Figure 1
Figure 1
Delineation of the striatum subdivisions, the amygdala nuclei and anterior portion of the entorhinal cortex. Panel A shows three serial coronal sections (271, 313, and 334) stained with cresyl violet. Rectangles mark inserts that are shown enlarged in panel B. Section 271 shows delineation of the caudate nucleus (CN), putamen (Pu) and nucleus accumbens (Ac). Enlargements of sections 313 and 334 demonstrate the borders of the lateral (L), basal (B), accessory basal (AB), and central (C) nuclei within the amygdaloid complex. The adjacent median (M) nucleus, preamygdaloid cortex (PAC), and ventral claustrum (VCl) are marked. The borders of the enorhinal cortex (EC) are delinated including the borderline with the transentorhinal cortex (TEC) and PAC. Higher magnification (Panel C) shows EC layers typical for the mid-level of the rostrocaudal EC extension including layer I (molecular layer); islands of stellate neurons in layer II; a broad layer III; and acellular layer IV. On this level large darkly stained neurons form narrow layer (V), whereas the broad layer VI is built up of the smallest neurons, with decreasing gradient of neuronal density in the deeper part of this layer and a diffuse border with white matter (WM). Other examined structures: globus pallidus (GP), claustrum (Cl), and thalamus (Th). Calibration bar length: 10 mm, 5 mm, and 500 μm.
Figure 2
Figure 2
Delination of the Ammons horn sectors and the posterior portion of the entorhinal cortex. Panel A shows CV-stained hemispheric sections on the level of the hippocampal head (s. 376), body (s. 412) and tail (s. 490). The rectangle in panel A marks an area that was enlarged 5-fold and is shown in panel B. Stereologically examined structures are labeled as: sectors CA1, 2, 3, 4; EC, entorhinal cortex; CN, caudate nucleus; Pu, putamen; GP, globus pallidus; Cl, claustrum; Th, thalamus; and SN, substantia nigra. The subicular complex is labeled as Sub C. Calibration bar length: 10 mm and 5 mm.
Figure 3
Figure 3
Brain structure volume, total number of neurons and neuronal density. Range of the volume of examined regions from the largest (thalamus, putamen, and caudate) to the smallest (inferior olive). The volume of all four striatum subdivisions, including putamen, caudate nucleus, globus pallidus, and nucleus accumbens, is greater in subjects with autism, but the difference in this volume between affected and control subjects is significant only in the caudate and nucleus accumbens (black stars). The total number of neurons was found to be significantly less only in the second layer of the entorhinal cortex (white star) when covariates were not entered in the analysis. Although the total number of neurons does not reveal significant differences, the numerical density is significantly reduced in the nucleus accumbens and putamen of subjects with autism. The significantly lower numerical density of neurons is observed in the lateral nucleus of the amygdala (white star), but not in other amygdala nuclei. Cerebellar volume and the volume of the molecular and granule cell layers, cerebellar white matter, and cerebellar nuclei do not reveal differences between affected and control subjects; however, the total number of Purkinje cells was 25% less (p < 0.03) in the group with autism (12.1 million) than in the control group (16.0 million). The numerical density of Purkinje cells was also significantly less (p < 0.004) in the affected group than in the control group (488/mm3 and 645/mm3, respectively). Th, Thalamus; Pu, putamen; CN, caudate nucleus; AH, Ammons horn; EC, entorhinal cortex; GP, globus pallidus, Cl, claustrum; Am, amygdala; DN, dentate nucleus; Ac, nucleus accumbens; SN, substantia nigra; MBC, magnocellular basal complex; LGB, lateral geniculate body; IO, inferior olive; Crb, cerebellum; ML, molecular layer; GCL, granule cell layer; WM, white matter; Nu, cerebellar nuclei.
Figure 4
Figure 4
Numerical density of Purkinje cells, and neurons in the lateral nucleus in the amygdala, nucleus accumbens and in the putamen. Box plots demonstrate the considerable differences between the median numerical density (thick line within the box) of Purkinje cells (n/mm3), and between the number of neurons in the lateral nucleus in the amygdala, nucleus accumbens and putamen (thousands/mm3) in the group with autism and control groups. In the majority of individuals diagnosed with autism, the numerical density of neurons is less than the median numerical density in the control group. The upper and lower boundaries of each box represent the 75th and 25th percentiles of the data, respectively; the depth of the box thus represents the interquartile range (IQR). The “whisker” above the box is the maximum value unless any data point lies more than 1.5 times the IQR above the 75th percentile, in which case the maximum value is the 75th percentile plus 1.5 times the IQR, and the points outside it (outliers) are indicated by circles. The lower whisker and outliers are computed analogously.
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