Elsevier

Neuroscience

Volume 96, Issue 4, March 2000, Pages 825-836
Neuroscience

Postnatal decrease in transforming growth factor α is associated with enlarged ventricles, deficient amygdaloid vasculature and performance deficits

https://doi.org/10.1016/S0306-4522(99)00558-8Get rights and content

Abstract

It is well established that transforming growth factor α is involved prenatally in development of the nervous system, but its role in the postnatal brain is less well understood. Here, we document the occurrence of late-onset, morphological and behavioral deficits in the naturally occurring murine mutant, Waved-1 (Wa-1), whose transforming growth factor α levels decrease naturally between early postnatal and adolescent ages. Morphological analyses suggest that reduction in the growth factor postnatally is associated temporally with the onset of enlarged lateral ventricles, a reduction in vasculature in the region of the amygdala and a reduction in size of the central nucleus. Onset of the morphological deficits corresponds to the appearance of a performance deficit in contextual fear conditioning. In contrast, the transforming growth factor α gene-targeted null mutants exhibit neither morphological nor performance deficits.

These data suggest that transforming growth factor α during postnatal maturation of the brain may contribute to maintenance of limbic morphology and vasculature, which may in turn affect some behaviors associated with these specific brain structures.

Section snippets

Subjects

Three strains of male mice, C57BL/6J (C57), gene-targeted TGFα null mutant C57BL/6J-Tgfαtm/Ard (TGFα−/−) and APB/Le/ a/a Tyrp1b/Tyrp1b bt/bt p/p Bmp5se/Bmp5se Tgfαwa1/Tgfαwa1 (Wa-1) were obtained from the Jackson Laboratory (Bar Harbor, MA, U.S.A.). Mice were housed in a 12-h/12-h light–dark cycle with free access to food and water. Litters for analysis were produced by standard homozygous matings of each strain. Litters larger than 10 pups were trimmed. Mice were weaned at 21 days and housed

Results

Wa-1 mice are phenotypically similar to gene-targeted TGFα−/− null mutants in that each have wavy coats and exhibit ocular abnormalities. The Wa-1 mice, unlike the gene-targeted nulls or C57 mice, exhibit enlarged lateral ventricles (Fig. 1) and show reduced fear conditioning (Figs 8 and 9). Qualitatively, brains of the Wa-1 mice appeared normal and contained gross structures of the olfactory bulbs, neocortex, hippocampus, basal ganglia, septum, thalamus, brainstem and cerebellum. Nissl-stained

Discussion

In the present study, we investigated the potential role of TGFα in maintaining the morphological and vascular integrity of the limbic system. To do so, we studied three strains of mice: the gene-targeted TGFα null mutant, which completely lacks TGFα from the onset of development; the naturally occurring mutant Wa-1, which has a reduction in TGFα in adulthood; and the C57/BL6J strain, which has a normal complement of TGFα.

Conclusion

The present results demonstrate that the Wa-1 animal, a hypomorphic mutant, has a CNS phenotype distinct from the TGFα−/− null mutant, including late-onset enlargement of the lateral ventricles, loss of nuclear volume and vascular alterations in the amygdala, accompanied by age-related behavioral deficits. The late adolescent onset of the selective loss of function in the Wa-1 mouse may be due to initial and adequate levels of growth factor during development, followed by a reduction in growth

Acknowledgements

We would like to thank Lindsey Lair and Eric Parsons for expert technical assistance. This work was supported by NIMH 45507 and NIDA 09555 (to P.L.), NIMH MH59970 and IBN 9511-27 (to T.J.S.), and a predoctoral NRSA MH10777 (to R.C.B.).

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    Present address: Department of Radiology, Box 356004, University of Washington School of Medicine, Seattle, WA 98195, U.S.A.

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