title: Cyclic nucleotide-mediated regulation of hippocampal mossy fiber development: a target-specific guidance.
abstract: The mossy fibers (MFs) arising from dentate granule cells project primarily onto a narrow segment of the proximal dendrites of hippocampal CA3 pyramidal cells. The mechanisms underlying this specific MF target selection are not fully understood. To investigate the cellular basis for development of the stereotyped MF trajectories, we have arranged the fascia dentata and hippocampal Ammon's horn tissues in diverse topographical patterns in organotypic explant coculture systems. Here we show that cyclic nucleotide signaling pathways regulate the MF pathfinding. When the dentate gyrus explants were ectopically placed facing the CA3 stratum oriens of hippocampal slices, MFs crossed the border between cocultures and reached their appropriate target area in the Ammon's horn, as assessed by membrane tracer labeling, Timm staining, electrophysiological recording of synaptic responses, and optical analyses using a voltage-sensitive dye. This lamina-specific MF innervation was disrupted by pharmacological blockade of cGMP pathway. Similar apposition of the dentate grafts near the CA1 region of host slices rarely resulted in MF ingrowth into the Ammon's horn. Under blockade of cAMP pathway, however, the MFs were capable of making allopatric synapses with CA1 neurons. These data were further supported by the pharmacological data obtained from granule cells dispersed over hippocampal slice cultures. Thus, our findings suggest that the stereotyped MF extension is mediated by at least two distinct factors, i.e., an attractant derived from the CA3 region and a repellent from the CA1 region. These factors may be regulated differently by cAMP and cGMP signaling pathways.
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Mizuhashi
authors.forename: N
authors.initials: N
authors.lastname: Nishiyama
authors.forename: N
authors.initials: N
authors.lastname: Matsuki
authors.forename: Y
authors.initials: Y
authors.lastname: Ikegaya
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D018920:Coculture Techniques; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005341:Fibrinolysin / Q000494:pharmacology; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D009712:Nucleotides, Cyclic; D005576:Colforsin; D000242:Cyclic AMP; D005341:Fibrinolysin; D000262:Adenylyl Cyclases; D006152:Cyclic GMP