The Role of Testosterone in the Development of Neuroanatomical Lesions Associated With Specific Learning Disorders

Keir, Stuart D (1993) The Role of Testosterone in the Development of Neuroanatomical Lesions Associated With Specific Learning Disorders. PhD thesis, University of Glasgow.

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Developmental learning disorders have attracted interest since they were first described in the late 19th century. An anatomical basis was suggested for acquired dyslexia, dysphasia and other language related syndromes, a view strengthened by the discovery of cerebral asymmetry for language and by detailed cytoarchitectonic investigations which revealed specific cortical abnormalities in the brains of dyslexic individuals. These anomalies consisted mainly of clusters of ectopic neurons in layer I of the cerebral cortex, located principally in the perisylvian and frontal areas. The presence of these abnormalities is considered to be typical of the condition. The developmental learning disorders are increased in males, certain families, twins and left-handers. In addition, an increased incidence of autoimmune disorders has been reported in dyslexic individuals. It was my purpose in this Thesis to investigate whether the male sex homrione testosterone plays a role in the development of the cortical ectopias which are associated with these disorders. For this I used an animal model, consisting of mouse strains in which similar ectopias in comparable areas have been demonstrated, together with strains in which they are absent. Mice with ectopias show behavioural disturbances including impaired learning abilities, so that although at first it seems inconceivable that there could be a mouse model for human developmental problems of learning, such as dyslexia, it is nevertheless possible to study the aetiology of related cortical abnormalities. I started by confirming the reported incidence of cortical ectopias in the BXSB mouse and found that 31% had ectopias, which is similar to the figure of 29% previously reported. The DBA strain was confirmed to have no ectopias. Ectopias were also demonstrated in 33% of AJ mice, a strain reported to have high adult serum testosterone levels. The incidence of ectopias was confirmed to be more common in males than in females, with 58% of BXSB and 62.5% of AJ mice with ectopias being male. Preliminary results also indicate that the uterine proximity of male fetuses may be important in determining which females develop ectopias. In light of the finding of ectopias in the AJ strain I examined serum testosterone levels in males and females of other strains known to develop ectopias along with a number that do not, in order to determine if high testosterone levels were a general phenomenon associated with strains that develop ectopias. No such association was found in normal adult animals; however, testosterone levels were found to be increased at late gestation in mothers of two strains that develop ectopias, the BXSB and the NZB, compared to the DBA strain which does not, although the increase was significant only for the BXSB. Testosterone related effects upon the nervous system were also studied by examining the spinal nucleus of bulbocavernosus (SNB), a sexually dimorphic motor nucleus (L5-S1) which is directly influenced by perinatal testosterone levels. Neuronal numbers in the SNB were compared between strains that developed ectopias and those that did not. A significant correlation was found between the incidence of ectopias and numbers of neurons in the SNB, with the presence of ectopias being associated with increased numbers of neurons. This probably indicates an androgenic inhibition of neuronal cell death in these strains. Finally, I increased the testosterone levels during pregnancy in the BXSB and DBA strains by daily injections of testosterone propionate, in order to study the effect that this would have on the incidence of ectopias. A significant increase in the incidence of ectopias (from 30% to 62%) was seen in the BXSB strain after treatment with testosterone; no such increase was seen in the DBA strain. In the latter, however, a significant proportion of animals developed hydrocephalus upon treatment with testosterone. In conclusion, the results of this work confirm that cortical ectopias in mice are associated with high levels of testosterone in utero and that their incidence can be increased by the prenatal administration of testosterone. It is suggested that testosterone plays an important role in the development of the human cortical ectopias which are characteristic of developmental learning disorders.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: W M H Behan
Keywords: Neurosciences, Psychobiology
Date of Award: 1993
Depositing User: Enlighten Team
Unique ID: glathesis:1993-75585
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 19:22
Last Modified: 19 Nov 2019 19:22

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