Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups.

Abstract

Early deficiency of the methyl donors folate and vitamin B12 produces hyperhomocysteinemia and cognitive and motor disorders in 21-day-old rat pups from dams fed a diet deficient in methyl donors during gestation and lactation. These disorders are associated with impaired neurogenesis and altered synaptic plasticity in cerebellum. We aimed to investigate whether these disorders could be related to impaired expression of neurosteroidogenesis-associated proteins, key regulator receptors, and some steroid content in the cerebellum. The methyl donor deficiency produced a decreased concentration of folate and vitamin B12, along with accumulation of homocysteine in Purkinje cells in both sexes, whereas the S-adenosylmethionine/S-adenosylhomocysteine ratio was reduced only in females. The transcription level and protein expression of StAR, aromatase, ERα, ERβ, and LH receptors were decreased only in females, with a marked effect in Purkinje cells, as shown by immunohistochemistry. Consistently, reduced levels of estradiol and pregnenolone were measured in cerebellar extracts of females only. The decreased expression levels of the transcriptional factors CREB, phospho-CREB, and SF-1, the lesser increase of cAMP concentration, and the lower level of phospho-PKC in the cerebellum of deficient females suggest that the activation of neurosteroidogenesis via cAMP-mediated signaling pathways associated with LHR activation would be altered. In conclusion, a gestational methyl donor deficiency impairs neurosteroidogenesis in cerebellum in a sex-dependent manner.

• Authors: Sarah El Hajj Chehadeh, Natacha Dreumont, Jérèmy Willekens, Laetitia Canabady-Rochelle, Elise Jeannesson, Jean-Marc Alberto, Jean-Luc Daval, Jean-Louis Guéant, Brigitte Leininger-Muller
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 307 Issue 11 Pg. E1009-19 (Dec 01 2014) ISSN: 1522-1555 [Electronic] United States
• PMID: 25294213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• Neurotransmitter Agents
• Phosphoproteins
• steroidogenic acute regulatory protein
• Estradiol
• Pregnenolone
• Cyclic AMP

Topics

• Animals
• Cerebellum (metabolism)
• Cyclic AMP (physiology)
• Estradiol (metabolism)
• Female
• Folic Acid Deficiency (metabolism)
• Microsomes (metabolism)
• Mitochondria (metabolism)
• Neurotransmitter Agents (biosynthesis)
• Phosphoproteins (biosynthesis, genetics)
• Pregnenolone (metabolism)
• Rats
• Rats, Wistar
• Signal Transduction (physiology)
• Transcription, Genetic (genetics, physiology)
• Vitamin B 12 Deficiency (metabolism)