Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis.
Electroconvulsive seizure (ECS) induces structural remodelling in the adult mammalian brain, including an increase in adult hippocampal neurogenesis. The molecular mechanisms that underlie this increase in the proliferation of adult hippocampal progenitors are at present not well understood. We hypothesized that ECS may recruit the Sonic hedgehog (Shh) pathway to mediate its effects on adult hippocampal neurogenesis, as Shh is known to enhance the proliferation of neuronal progenitors and is expressed in the adult basal forebrain, a region that sends robust projections to the hippocampus. Here we demonstrate that the ECS-induced increase in proliferation of adult hippocampal progenitors was completely blocked in animals treated with cyclopamine, a pharmacological inhibitor of Shh signalling. Our results suggest that both acute and chronic ECS enhance Shh signalling in the adult hippocampus, as we observed a robust upregulation of Patched (Ptc) mRNA, a component of the Shh receptor complex and a downstream transcriptional target of Shh signalling. This increase was rapid and restricted to the dentate gyrus, where the adult hippocampal progenitors reside. In addition, both acute and chronic ECS decreased Smoothened (Smo) mRNA, the other component of the Shh receptor complex, selectively within the dentate gyrus. However, ECS did not appear to influence Shh expression within the basal forebrain, the site from which it has been suggested to be anterogradely transported to the hippocampus. Together, our findings demonstrate that ECS regulates the Shh signalling cascade and indicate that the Shh pathway may be an important mechanism through which ECS enhances adult hippocampal neurogenesis.
Banerjee
Sunayana B
SB
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
Rajendran
Rajeev
R
Dias
Brian G
BG
Ladiwala
Uma
U
Tole
Shubha
S
Vaidya
Vidita A
VA
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004597:Electroshock / Q000009:adverse effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000528:radiation effects; D053823:Hedgehog Proteins; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D009474:Neurons / Q000502:physiology / Q000528:radiation effects*; D038081:Organogenesis / Q000187:drug effects / Q000528:radiation effects*; D000072079:Patched Receptors; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012640:Seizures / Q000209:etiology* / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D000072086:Smoothened Receptor; D013234:Stem Cells / Q000528:radiation effects; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014704:Veratrum Alkaloids / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011810:Quinoxalines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C498555:Smo protein, rat; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014704:Veratrum Alkaloids; C056723:FG 9041; D016291:Dizocilpine Maleate; D001973:Bromodeoxyuridine; C000541:cyclopamine