Morphological abnormalities in the brains of estrogen receptor beta knockout mice

Abstract

Estrogen receptor beta (ERbeta) is expressed at high levels in both neurons and glial cells of the central nervous system. The development of ERbeta knockout (BERKO) mice has provided a model to study the function of this nuclear receptor in the brain. We have found that the brains of BERKO mice show several morphological abnormalities. There is a regional neuronal hypocellularity in the brain, with a severe neuronal deficit in the somatosensory cortex, especially layers II, III, IV, and V, and a remarkable proliferation of astroglial cells in the limbic system but not in the cortex. These abnormalities are evident as early as 2 mo of age in BERKO mice. As BERKO mice age, the neuronal deficit becomes more pronounced, and, by 2 yr of age, there is degeneration of neuronal cell bodies throughout the brain. This is particularly evident in the substantia nigra. We conclude that ERbeta is necessary for neuronal survival and speculate that this gene could have an important influence on the development of degenerative diseases of the central nervous system, such as Alzheimer's disease and Parkinson's disease, as well as those resulting from trauma and stroke in the brain.

Figure 1

(a) Coronal sections (30 μm, Nissl stain) of the somatosensory cortex show histology comparison of 2-mo-old wild-type (+/+) and BERKO (−/−) male mice. Note the decreased number of neurons in layer II, III, IV, and V in BERKO mice. (Scale bar = 100 μm.) (b) Mean number of neurons in the layers II, III, IV, and V of somatosensory cortex (n = 3; error bar, SD; *, P < 0.01; **, P < 0.05, Student's t test). (c) Landmark points for morphometry at the dorsal view of the brain and schematic illustrations of coronal slices of levels A and B.

Figure 2

(a) Coronal sections (30 μm, Nissl stain) of MPA (Top), PVN (Middle), and MeA (Bottom) show histology comparison of 2-yr-old wild-type (+/+) and BERKO (−/−) male mice. Note the decreased number of neurons in these nuclei in BERKO mice. (Scale bar = 170 μm.) (b) Mean number of neurons in MPA, PVN, and MeA (n = 3; error bar, SD; **, P < 0.05, Student's t test).

Figure 3

(a) Coronal sections (12 μm, Nissl stain) of the somatosensory cortex show histology comparison of 2-yr-old wild-type (+/+) and BERKO (−/−) male mice. Note the decreased number of neurons in layers II, III, IV, and V in BERKO mice. (Scale bar = 100 μm.) (b) High magnification views of neurons in substantia nigra of 2-yr-old wild-type and BERKO male mice. Note the shrinkage of neurons in BERKO mice. (Scale bar = 25 μm.)

Figure 4

GFAP immunostaining comparison in the brains of 2-mo-old wild-type (+/+) and BERKO (−/−) male mice. (a) GFAP immunoreactivity in coronal sections (30 μm) of MPA (Top), PVN (Middle), and MeA (Bottom). Note the increased GFAP immunoreactivity in these nuclei in BERKO mice. (Scale bar = 170 μm.) (b) Mean number of GFAP-immunoreactive cells (GFAP-IR) in MPA, PVN, and MeA (n = 3; error bar, SD; *, P < 0.01; **, P < 0.05, Student's t test).