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14.12.2015

Significance of hippocampus-derived sexual steroids in the male and female hippocampus

Estrogen receptors are widely expressed in the brain, in particular in the hippocampus, as shown in the figure above; on the protein level by using immunocytochemistry (left) and on the mRNA levels by using in situ hybridization (right). The hippocampus is an area of the brain that is closely associated with learning and memory. Estrogen receptors are transcription factors and are regulated by their ligands (Prange-Kiel et al., 2003). Estradiol effects, however, are not only mediated in the classical genomic way by either ERalpha and ERbeta (Rune et al., 2002) but also via membrane-bound receptors and other, as yet unknown, mechanisms. Estrogen signalling is far from being understood, in particular with regard to estrogen-induced synaptic plasticity in the hippocampus.

Hippocampal estradiol synthesis regulates synapse density in the hippocampus

Dendritic spines are the postsynaptic partners of most excitatory synapses in the CNS. We found that hippocampal neurons are able to synthesize estradiol and hippocampus-derived estradiol has a high impact on synaptic plasticity (Kretz et al., 2004), neurogenesis (Fester et al., 2006) and neuroprotection (Zhou et al., 2007). A reduced estradiol synthesis in hippocampal neurons, induced by inhibition of aromatase the final enzyme of estradiol synthesis, results in spine and synapse loss, downregulation of synaptic proteins, such as synaptopodin, impaired neurogenesis, enhanced susceptibility to neurotoxins and impaired long term potentiation (LTP), an electrophysiological parameter of memory, in female but not in male animals. Our current works focuses on this obvious sexual dimorphism regarding estrogen-related effects on hippocampal connectivity.

Cyclic GnRH release from the hypothalamus underlies cyclic spinogenesis in the
hippocampus via regulating estradiol synthesis in the hippocampus

In females, the densities of spines along the dendrites vary during the estrous cycle in the hippocampus. We found that hippocampal hippocampal estradiol synthesis is regulated in a cyclic manner via GnRH (Prange-Kiel et al. 2008). Such cyclicity does not exist in male animals, thus again pointing to the need for further studies.Estradiol regulates ReelinReelin is an extracellular matrix protein, that is synthesized by Cajal-Retzius cells (CRZ) and is essential for the proper migration of neurons during development and cortical layering. We found that CRCs express Estrogen receptors and that hippocampus-derived estradiol regulates reelin in the hippocampus (Bender et al., 2010). Treatment of hippocampal cultures with letrozole, an aromatase inhbitor, reduces reelin expression.The reelin deficient Reeler mouse shows a migratory defect of GnRH neurons, reduced synapse number in the hippocampus and impaired fertility. In this project we want to study the cross-talk between reelin and aromatase, the final enzyme of estradiol synythesis.

Project: Mental retardation in human phenylketonuria

Phenylketonuria (PKU) is an autosomal-recessive disorder with an incidence of 1:8000. An error in the genetic code of the hepatic enzyme phenylalanine hydroxylase (PAH) causes increased levels of the amino acid phenylalanine in the blood and cerebrospinal fluid. In humans, PKU is associated with severe mental retardation, brain damage and seizures. The underlying molecular mechanisms of this brain pathology are as yet, poorly understood.Our attention is currently centred on the effects on synaptic plasticity, such as the number of spine synapses, dendritogenesis and spine development, expression of various pre- and postsynaptic proteins and alterations in LTP, LTD, and PPF and behaviour, in response to elevated phenylalanine concentrations. The PAHenu2mouse is used as an experimental model. This mouse model was established in 1990 by Shedlosky et al. and has a loss-of-function mutation of the PAH and elevated brain phenylalanine concentrations similar to those found in man.

Participants in the PKU project:
Dr. med. Katja Horling
Gudrun Schlegel (PhD student)
Sarah Schulz (cand. med.)
Prof. Dr. med. Gabriele M. Rune

Collaborations:
Prof. Dr. med. K. Ullrich, Department of Paediatrics, University Medical Center Hamburg-Eppendorf
Prof. Dr. med. R. Santer, Department of Paediatrics, University Medical Center Hamburg-Eppendorf

Reelin

Reelin is an extracellular matrix protein that is synthesized by Cajal-Retzius cells (CRZ) and which is essential for the proper migration of neurons during development and cortical layering. We found that CRCs express estrogen receptors and that hippocampus-derived estradiol regulates reelin in the hippocampus (Bender et al., 2010). Treatment of hippocampal cultures with letrozole, an aromatase inhibitor, reduces reelin expression. The reelin deficient Reeler mouse shows a migratory defect of GnRH neurons, reduced synapse number in the hippocampus and impaired fertility. In this project we are studying the cross-talk between reelin and aromatase, the final enzyme of estradiol synthesis.