Prostaglandin E2 stimulates estradiol synthesis in the cerebellum postnatally with associated effects on Purkinje neuron dendritic arbor and electrophysiological properties.

Prostaglandins (PGs) are ubiquitous membrane-derived, lipid-signaling molecules with wide ranging effects throughout the body. In the brain, PGE(2) is the key regulator of fever after inflammation but is also implicated in neural development and synaptic plasticity. The steroid hormone estradiol is also a key regulator of neural development and synaptic plasticity. Recently, we showed that administering cyclooxygenase (COX) inhibitors to block PGE(2) production increased the total length of Purkinje cell dendrites, the number of dendritic spines, and the level of spinophilin protein, which is enriched in dendritic spines. Correspondingly, PGE(2) administration into the cerebellum decreased spinophilin protein content. We now report that PGE(2) stimulates estradiol synthesis in the immature rat cerebellum via enhanced activity of the aromatase enzyme. Treatment with cyclooxygenase inhibitors reduced cerebellar aromatase activity and estradiol content whereas PGE(2) administration increased both. Treatment with either PGE(2) or estradiol stunted Purkinje neuron dendritic length and complexity and produced a corresponding reduction in spinophilin content. Treatment with formestane to inhibit aromatase activity led to excessive sprouting of the dendritic tree, whereas elevated estradiol had the opposite effect. Electrophysiological measurements from Purkinje neurons revealed novel sex differences in input resistance and membrane capacitance that were abolished by estradiol exposure, whereas a sex difference in the amplitude of the afterhyperpolarization after an action potential was not. Correlated changes in action potential threshold suggest that prolonged alterations in neuronal firing activity could be a consequence of increased estradiol content during the second week of life. These findings reveal a previously unappreciated role for PG-stimulated steroidogenesis in the developing brain and a new potential route for inflammation-mediated disruption of neuronal maturation.

[1]  R. Mishra,et al.  Behavioral effects of non-viral mediated RNA interference of synapsin II in the medial prefrontal cortex of the rat , 2012, Schizophrenia Research.

[2]  M. McCarthy,et al.  Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period , 2012, The European journal of neuroscience.

[3]  Guy Mittleman,et al.  Connecting the dots of the cerebro‐cerebellar role in cognitive function: Neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex , 2011, Synapse.

[4]  J. G. Yague,et al.  Estradiol synthesis within the human brain , 2011, Neuroscience.

[5]  N. Harada,et al.  Human and quail aromatase activity is rapidly and reversibly inhibited by phosphorylating conditions. , 2011, Endocrinology.

[6]  J. Balthazart,et al.  Acute stress differentially affects aromatase activity in specific brain nuclei of adult male and female quail. , 2011, Endocrinology.

[7]  B. Cauli,et al.  Pyramidal Neurons Are “Neurogenic Hubs” in the Neurovascular Coupling Response to Whisker Stimulation , 2011, The Journal of Neuroscience.

[8]  C. Hansel,et al.  SK2 channel expression and function in cerebellar Purkinje cells , 2011, The Journal of physiology.

[9]  E. Rissman,et al.  Sex Differences in the Cerebellum and Frontal Cortex: Roles of Estrogen Receptor Alpha and Sex Chromosome Genes , 2011, Neuroendocrinology.

[10]  B. Schlinger,et al.  Injury-induced regulation of steroidogenic gene expression in the cerebellum. , 2010, Journal of neurotrauma.

[11]  S. Pellis,et al.  Juvenile peer play experience and the development of the orbitofrontal and medial prefrontal cortices , 2010, Behavioural Brain Research.

[12]  G. Mittleman,et al.  Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism , 2010, The European journal of neuroscience.

[13]  Flavio Keller,et al.  Interactions between neuroactive steroids and reelin haploinsufficiency in Purkinje cell survival , 2009, Neurobiology of Disease.

[14]  S. Thompson,et al.  Estradiol Induces Hypothalamic Dendritic Spines by Enhancing Glutamate Release: A Mechanism for Organizational Sex Differences , 2008, Neuron.

[15]  I. Sugihara,et al.  BCL‐2 counteracts Doppel‐induced apoptosis of prion‐protein‐deficient Purkinje cells in the Ngsk Prnp0/0 mouse , 2008, Developmental neurobiology.

[16]  Saak V Ovsepian,et al.  The leaner P/Q‐type calcium channel mutation renders cerebellar Purkinje neurons hyper‐excitable and eliminates Ca2+‐Na+ spike bursts , 2007, The European journal of neuroscience.

[17]  M. Hüll,et al.  Regional distribution of the prostaglandin E2 receptor EP1 in the rat brain , 2007, Journal of Molecular Neuroscience.

[18]  M. McCarthy,et al.  Focal adhesion kinase and paxillin: novel regulators of brain sexual differentiation? , 2007, Endocrinology.

[19]  C. Stocco,et al.  Prostaglandin E2 increases cyp19 expression in rat granulosa cells: Implication of GATA-4 , 2007, Molecular and Cellular Endocrinology.

[20]  Akiko Nagai,et al.  Differential expression of the estrogen receptors alpha and beta during postnatal development of the rat cerebellum , 2006, Brain Research.

[21]  L. Garcia-Segura,et al.  Sex differences, developmental changes, response to injury and cAMP regulation of the mRNA levels of steroidogenic acute regulatory protein, cytochrome p450scc, and aromatase in the olivocerebellar system. , 2006, Journal of neurobiology.

[22]  K. Ukena,et al.  Organizing actions of neurosteroids in the Purkinje neuron , 2004, Neuroscience Research.

[23]  M. McCarthy,et al.  Brain estradiol content in newborn rats: sex differences, regional heterogeneity, and possible de novo synthesis by the female telencephalon. , 2004, Endocrinology.

[24]  M. McCarthy,et al.  Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior , 2004, Nature Neuroscience.

[25]  K. Ukena,et al.  Dendritic growth and spine formation in response to estrogen in the developing Purkinje cell. , 2003, Endocrinology.

[26]  K. Ukena,et al.  Biosynthesis and action of neurosteroids in the cerebellar Purkinje neuron , 1997, The Journal of Steroid Biochemistry and Molecular Biology.

[27]  M. McCarthy,et al.  A Novel Mechanism of Dendritic Spine Plasticity Involving Estradiol Induction of Prostaglandin-E2 , 2002, The Journal of Neuroscience.

[28]  J. Adamski,et al.  Stiff-man syndrome: identification of 17β-hydroxysteroid dehydrogenase type 4 as a novel 80-kDa antineuronal antigen , 2002, Journal of Neuroimmunology.

[29]  N. Bazan,et al.  Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. , 2002, Journal of neurophysiology.

[30]  R. Brueggemeier,et al.  Molecular pharmacology of aromatase and its regulation by endogenous and exogenous agents , 2001, The Journal of Steroid Biochemistry and Molecular Biology.

[31]  M. Häusser,et al.  Compartmental models of rat cerebellar Purkinje cells based on simultaneous somatic and dendritic patch‐clamp recordings , 2001, The Journal of physiology.

[32]  R. Jakab,et al.  Estrogen receptor β immunoreactivity in differentiating cells of the developing rat cerebellum , 2001 .

[33]  R. Jakab,et al.  Estrogen receptor beta immunoreactivity in differentiating cells of the developing rat cerebellum. , 2001, The Journal of comparative neurology.

[34]  P. Greengard,et al.  Spinophilin regulates the formation and function of dendritic spines. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Mong,et al.  Gonadal Steroids Promote Glial Differentiation and Alter Neuronal Morphology in the Developing Hypothalamus in a Regionally Specific Manner , 1999, The Journal of Neuroscience.

[36]  K. Ukena,et al.  Expression and Activity of 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4-Isomerase in the Rat Purkinje Neuron during Neonatal Life. , 1999, Endocrinology.

[37]  S. Lye,et al.  Expression of prostaglandin E2 receptor subtypes in the developing sheep brainstem. , 1998, Brain research. Molecular brain research.

[38]  K. Ukena,et al.  Cytochrome P450 side-chain cleavage enzyme in the cerebellar Purkinje neuron and its neonatal change in rats. , 1998, Endocrinology.

[39]  J. Balthazart,et al.  A direct dopaminergic control of aromatase activity in the quail preoptic area , 1997, The Journal of Steroid Biochemistry and Molecular Biology.

[40]  Edmund M. Glaser,et al.  Analysis of thick brain sections by obverse—Reverse computer microscopy: Application of a new, high clarity Golgi—Nissl stain , 1981, Journal of Neuroscience Methods.

[41]  F. Crépel,et al.  Fate of the multiple innervation of cerebellar Purkinje cells by climbing fibers in immature control, x-irradiated and hypothyroid rats. , 1981, Brain research.

[42]  B. McEwen,et al.  Aromatization: Important for sexual differentiation of the neonatal rat brain , 1977, Hormones and Behavior.

[43]  J. Altman,et al.  Postnatal development of the cerebellar cortex in the rat. III. Maturation of the components of the granular layer , 1972, The Journal of comparative neurology.

[44]  J. Altman,et al.  Postnatal development of the cerebellar cortex in the rat. II. Phases in the maturation of Purkinje cells and of the molecular layer , 1972, The Journal of comparative neurology.

[45]  J. Altman,et al.  Postnatal development of the cerebellar cortex in the rat. I. The external germinal layer and the transitional molecular layer , 1972, The Journal of comparative neurology.

[46]  W. P. Schneider,et al.  The total synthesis of prostaglandins. , 1968, Journal of the American Chemical Society.

[47]  W. C. Young,et al.  Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. , 1959, Endocrinology.