Abstract

The formation of appropriate neural connections during development is critical for the proper wiring and functioning of the brain. Although considerable research suggests that the specificity of synapse formation is supported by complex intercellular signaling between potential presynaptic and postsynaptic partners, the extracellular factors and the intracellular signal transduction pathways engaged in this process remain largely unknown. Using the sensory-motor neural circuit that contributes to learning in defensive withdrawal reflexes in Aplysia californica, we investigated the molecular processes governing the interactions between sensory neurons and both target and non-target motor neurons during synapse formation in culture. We found that evolutionarily-conserved intercellular and intracellular signaling mechanisms critical for learning-related plasticity are also engaged during synaptogenesis in this in vitro model system. Our results reveal a surprising bidirectional regulation of molecular signaling between sensory neurons and non-target motor neurons. This regulation is mediated by signaling via both paracrine and autocrine diffusible factors that induce differential effects on transcription and on protein expression/activation in sensory neurons and in target and non-target motor neurons. Collectively, our data reveal novel molecular mechanisms that could underlie the repression of inappropriate synapse formation, and suggest mechanistic similarities between developmental and learning-related plasticity.

Highlights

  • The formation of appropriate neural connections during development is critical for the proper wiring and functioning of the brain

  • These results suggest that sensory neurons (SNs) downregulate CCAAT-enhancer binding protein (C/EBP) mRNA levels in non-target motor neurons (MNs), but not in target MNs

  • The regulation induced by presynaptic SNs on non-target MNs is governed by (i) paracrine neuropeptidergic signaling from SNs (Figs. 4,5) and (ii) by autocrine growth factor signaling from MNs (Figs. 3, 4)

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Summary

Introduction

The formation of appropriate neural connections during development is critical for the proper wiring and functioning of the brain. The members of the neurotrophin family of growth factors were initially characterized as critical regulators of neuronal survival, differentiation, and growth[11,12], but were later shown to contribute to the molecular events underlying activity-dependent synaptic growth and restructuring in the mature nervous system[3,13] These findings raise important questions about the mechanistic similarities between neural development and adult plasticity, and offer opportunities for integrating findings from both fields of research. Our results reveal a surprising bidirectional regulation of molecular signaling between mismatched synaptic partners This regulation is mediated by signaling via both paracrine and autocrine diffusible factors that induce differential effects on transcription and on protein expression/activation in SNs and in target and non-target MNs. Collectively, our data reveal novel molecular mechanisms that could underlie the repression of inappropriate synapse formation

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