Estrogen Influences on the Developing Rat Hippocampus Through Interactions with the Brain Derived Neurotrophic Factor and P160 Coactivator Proteins

In addition to their primary role in the maintenance and regulation of reproductive capacity, ovarian steroid hormones acting through specific nuclear receptors influence more general neurobiological functions, such as perceptual-spatial skills and learning and memory. Estrogens act to alter certain aspects of cognitive performance and pathology such as epileptic seizure activity and Alzheimer’s disease. Furthermore, ovarian steroids act during development to alter the neuronal cytoarchitecture and synaptic connectivity. These early influences of steroids on the brain are essentially permanent and in part determine the steroid responsiveness of the adult brain. The mechanism and sites of action for the effects of estradiol on cognitive performance and epileptic seizure activity have not been established, but one probable site is the hippocampus, a steroid-responsive region of the brain. Estrogen receptors have been found in cells of the hippocampus using a variety of techniques. Furthermore, there is a transient increase in the expression of estrogen receptors during the first postnatal week of life; a period that is active in neuronal differentiation and synaptogenesis. During this time period estrogen has been shown to have a number of transcriptional effects, mediated by steroid receptor coregulatory proteins, on morphological and biochemical properties of hippocampal neurons that would predict an excitatory action of this steroid on synaptic physiology in the hippocampus. Additionally, the neurotrophins, including brain-derived neurotrophic factor (BDNF), also affect the long-term survival and differentiation of hippocampal cells during development, and their viability in adulthood. Neurotrophins are widely expressed in the CNS and are involved in complex and activity-dependent modulation of dendritic and axonal growth. Moreover, the expression of neurotrophic factors has the ability to acutely modulate synaptic transmission by presynaptic as well as postsynaptic mechanisms. In addition to the modulation of synaptic transmission and plasticity, BDNF may also be involved in hippocampal synaptogenesis. In the adult rat, estrogen regulates mRNA levels of BDNF and its high affinity receptor, trkB, in several regions of the rat brain. It follows, then, that estrogen induced changes in neurotrophin synthesis is an important mediator of differentiation of the brain, and specifically the hippocampus. Furthermore, hormonally mediated changes in neurotrophin expression during development may be causally related to plasticity in the adult hippocampus. The cellular mechanisms by which estrogen can influence the developing hippocampus have not been examined and is the focus of this outline. Information obtained will be contribute to a greater understanding of the hippocampus, and may illuminate some of the cellular and molecular events involved in the development, maintenance and decline of normal cognitive function