Age-related neurodegenerative changes in the central nervous system of estrogen-deficient follitropin receptor knockout mice.
Age-related neurodegenerative conditions are characterized by neuronal death and degeneration that lead to a progressive functional decline. Among the factors influencing degenerative processes during aging are altered levels of neurotrophic ovarian steroid 17beta-estradiol (E2). The follitropin receptor knockout (FORKO) female mouse displays hormonal imbalance characterized by very low levels of circulating E2 and high levels of testosterone. FORKO mice (24 days and 20 months) were used to investigate structural and functional changes in the central nervous system. We now show that the lifelong depletion of the sex hormone E2 in female FORKO mice correlates with abnormal behavior associated with defined alterations in brain morphology early in life, especially in aged animals. Immunohistochemical studies showed significant increases in the size and number of immunoreactive glial fibrillary acidic protein glial cells found in several brain regions (cortex and hippocampus) and a dramatic decline in estrogen receptors alpha and beta in the amygdala of FORKO females. These changes were associated with increased signs of anxiety in these animals. In the present study, we provide evidence that the chronic depletion of sex hormone E2 from early development leads to neural impairments in adult and aged FORKO mice that are associated with hypertrophy of glial cells, cell loss in distinct brain regions, and abnormal behavior. We suggest that the hormonal imbalance found in the female FORKO mouse provides an experimental paradigm for the study of morphological correlates of the behavioral changes that often accompany menopause in women.
Danilovich
Natalia
N
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Room 1314, McIntyre Building, H3G 1Y6, Montreal, Quebec, Canada.
Harada
Nobuhiro
N
Sairam
M Ram
MR
Maysinger
Dusica
D
D000367:Age Factors; D000679:Amygdala / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001007:Anxiety / Q000235:genetics; D001141:Aromatase / Q000096:biosynthesis; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000473:pathology*; D004958:Estradiol / Q000172:deficiency; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011962:Receptors, FSH / Q000172:deficiency* / Q000235:genetics; D014599:Uterus / Q000473:pathology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D005904:Glial Fibrillary Acidic Protein; D011960:Receptors, Estrogen; D011962:Receptors, FSH; D004958:Estradiol; D001141:Aromatase