CAMP Differentially Regulates Axonal and Dendritic Development of Dentate Granule Cells

Ryuji X Yamada,Norio Matsuki,Yuji Ikegaya

doi:10.1074/jbc.m503800200

Ryuji X Yamada, Norio Matsuki + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m503800200

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Abstract

Neurite polarity is a morphological characteristic of dentate gyrus granule cells, which extend axons to the hilar region and dendrites in the opposite direction, i.e. to the molecular layer. This remarkable polarity must require a differential system for axon and dendrite guidance. Here, we report that the axon and dendrites of a granule cell are differentially responsive to cAMP. In developing cultures of dispersed granule cells, dendritic growth cones were increased in number after pharmacological activation of cAMP signaling and decreased after blockade of cAMP signaling. Activation of cAMP signaling antagonized dendritic collapse induced by the potent repellents Sema3F and glutamate. In contrast to dendrites, axons were protected from Sema3F-induced collapse when cAMP signaling was inhibited. Axonal and dendritic growth cones both expressed type 1 adenylyl cyclase, but only axons showed a cAMP increase in response to Sema3F, and the elevated cAMP was sufficient to collapse axonal growth cones. Thus, the axons and dendrites of dentate granule cells differ in the regulation of cAMP levels as well as responsiveness to cAMP. cAMP may be crucial for shaping the information flow polarity in the dentate gyrus circuit.

Highlights

Our previous study suggests that local environmental cues present in stratum granulosum are essential for proper neurite polarization of dentate granule cells [3], but little is known about the intracellular mechanisms
We focused this study on the influence of cAMP on the behavior of axonal and dendritic growth cones because the cAMP signaling pathway is well known to modulate axonal outgrowth of various neuronal types
Neurogenesis of granule cells, which occurs in the subgranular zone of the adult dentate gyrus, persists throughout life [22,23,24], and newborn neurons are functionally incorporated into mature dentate networks [25], which means that neurite guidance of granule cells persists in adults

Summary

Introduction

Our previous study suggests that local environmental cues present in stratum granulosum are essential for proper neurite polarization of dentate granule cells [3], but little is known about the intracellular mechanisms. Activation of cAMP signaling blocks Sema3A-mediated growth cone collapse in chick dorsal root ganglion neurons [6], but has no significant effect in Xenopus spinal neurons [4] and retinal neurons [7] These reports show that cyclic nucleotides modulate the neurite responses to guidance cues, but that this modulation depends on the types of guidance cues and neurons. We have demonstrated that cAMP signaling regulates pathfinding and target selection by hippocampal mossy fibers, axons of granule cells [8] It is unknown whether cAMP affects dendrites as well. We report that Sema3F collapses growth cones of axons and dendrites with a similar potency, but we found that cAMP contributes differentially to Sema3F signaling in axonal and dendritic responses Such contrasting actions of cAMP could underlie the opposing extension of axons and dendrites of dentate granule cells

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