Axon targeting of the alpha 7 nicotinic receptor in developing hippocampal neurons by Gprin1 regulates growth

Authors

  • Jacob C. Nordman,

    1. Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, USA
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  • Wiktor S. Phillips,

    1. Systems Neuroscience Laboratory, Department of Applied Science, The College of William & Mary, Williamsburg, Virginia, USA
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  • Nathan Kodama,

    1. Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, USA
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  • Sarah G. Clark,

    1. Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, USA
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  • Christopher A. Del Negro,

    1. Systems Neuroscience Laboratory, Department of Applied Science, The College of William & Mary, Williamsburg, Virginia, USA
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  • Nadine Kabbani

    Corresponding author
    1. Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, USA
    • Address correspondence and reprint requests to Nadine Kabbani, Ph.D., Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, 4400 University Dr, Mail Stop 2A1, Fairfax, VA 22032, USA. E-mail: nkabbani@gmu.edu

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Abstract

Cholinergic signaling plays an important role in regulating the growth and regeneration of axons in the nervous system. The α7 nicotinic receptor (α7) can drive synaptic development and plasticity in the hippocampus. Here, we show that activation of α7 significantly reduces axon growth in hippocampal neurons by coupling to G protein-regulated inducer of neurite outgrowth 1 (Gprin1), which targets it to the growth cone. Knockdown of Gprin1 expression using RNAi is found sufficient to abolish the localization and calcium signaling of α7 at the growth cone. In addition, an α7/Gprin1 interaction appears intimately linked to a Gαo, growth-associated protein 43, and CDC42 cytoskeletal regulatory pathway within the developing axon. These findings demonstrate that α7 regulates axon growth in hippocampal neurons, thereby likely contributing to synaptic formation in the developing brain.

image

Stages in the development of CA3 neurons illustrate how the α7 nicotinic receptor (nAChR) can contribute to axon growth. Protein expression of α7 and G protein-regulated inducer of neurite outgrowth 1 (Gprin1) peaks between E18 and P10 in rodents. This time period is characterized by significant changes in synaptic structure and circuit development in the hippocampus. α7-mediated elevations in intracellular calcium within the growth cone (GC) are proposed to serve as ‘stop’ signal for axon growth, thereby possibly contributing to synaptic pruning. Interaction with Gprin1 ensures localization of α7 at the GC, and mediates coupling to a Gαo, GAP-43, and CDC42 signaling pathway.

Ancillary