Interactions between neuroactive steroids and reelin haploinsufficiency in Purkinje cell survival

Filippo Biamonte, Giovanni Assenza, Ramona Marino, Marcello D'Amelio, Roger Panteri, Donatella Caruso, Samuele Scurati, Josue Garcia Yague, Luis Miguel Garcia-Segura, Roberta Cesa, Piergiorgio Strata, Roberto Cosimo Melcangi, Flavio Keller

Research output: Contribution to journalArticlepeer-review

Abstract

We determined total Purkinje cell (PC) numbers in cerebella of wild-type (+/+) and heterozygous (rl/+) reeler mice of either sex during early postnatal development; in parallel, we quantified levels of neuroactive steroids in the cerebellum with mass spectrometry. We also quantified reelin mRNA and protein expression with RT-PCR and Western blotting. PC numbers are selectively reduced at postnatal day 15 (P15) in rl/+ males in comparison to +/+ males, +/+ females, and rl/+ females. Administration of 17β-estradiol (17β-E) into the cisterna magna at P5 increases PC numbers in rl/+ males, but not in the other groups; conversely, estrogen antagonists 4-OH-tamoxifen or ICI 182,780 reduce PC numbers in +/+ and rl/+ females, but have no effect in males. Testosterone (T) levels at P5 are much higher in males than in females, reflecting the perinatal testosterone surge in males. In addition, rl/+ male cerebella at P5 show a peculiar hormonal profile in comparison with the other groups, consisting of increased levels of T and 17β-E, and decreased levels of dihydrotestosterone. RT-PCR analysis indicated that heterozygosity leads to a 50% reduction of reelin mRNA in the cerebellum in both sexes, as expected, and that 17β-E upregulates reelin mRNA, particularly in rl/+ males; reelin mRNA upregulation is associated with an increase of all major reelin isoforms. These effects may represent a novel model of how reelin deficiency interacts with variable perinatal levels of neuroactive steroids, leading to gender-dependent differences in genetic vulnerability.

Original languageEnglish
Pages (from-to)103-115
Number of pages13
JournalNeurobiology of Disease
Volume36
Issue number1
DOIs
Publication statusPublished - Oct 2009

Keywords

  • Autism
  • Brain sexual dimorphisms
  • Epigenetic regulation
  • Mass spectrometry
  • Neuroactive steroids
  • Reelin
  • Schizophrenia
  • Stereology

ASJC Scopus subject areas

  • Neurology

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