The serine protease inhibitor neuroserpin regulates the growth and maturation of hippocampal neurons through a non-inhibitory mechanism

J Neurochem. 2012 May;121(4):561-74. doi: 10.1111/j.1471-4159.2011.07639.x. Epub 2012 Feb 9.

Abstract

Neuroserpin is a brain-specific serine protease inhibitor that is expressed in the developing and adult nervous system. Its expression profile led to suggestions that it played roles in neuronal growth and connectivity. In this study, we provide direct evidence to support a role for neuroserpin in axon and dendritic growth. We report that axon growth is enhanced while axon and dendrite diameter are reduced following neuroserpin treatment of hippocampal neurons. More complex effects are seen on dendritic growth and branching with neuroserpin-stimulating dendritic growth and branching in young neurons but switching to an inhibitory response in older neurons. The protease inhibitory activity of neuroserpin is not required to activate changes in neuronal morphology and a proportion of responses are modulated by an antagonist to the LRP1 receptor. Collectively, these findings support a key role for neuroserpin as a regulator of neuronal development through a non-inhibitory mechanism and suggest a basis for neuroserpin's effects on complex emotional behaviours and recent link to schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / metabolism
  • Axons / ultrastructure
  • Blotting, Western
  • Cells, Cultured
  • Dendrites / drug effects
  • Dendrites / metabolism
  • Dendrites / ultrastructure
  • Disks Large Homolog 4 Protein
  • Female
  • Hippocampus / cytology*
  • Hippocampus / drug effects
  • Hippocampus / growth & development*
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1 / antagonists & inhibitors
  • Low Density Lipoprotein Receptor-Related Protein-1 / biosynthesis
  • Membrane Proteins / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / ultrastructure
  • Neuropeptides / metabolism
  • Neuropeptides / pharmacology*
  • Neuroserpin
  • Pregnancy
  • Protease Inhibitors / pharmacology
  • RNA / biosynthesis
  • RNA / isolation & purification
  • Rats
  • Rats, Wistar
  • Real-Time Polymerase Chain Reaction
  • Recombinant Proteins / pharmacology
  • Serine Proteinase Inhibitors / metabolism
  • Serine Proteinase Inhibitors / pharmacology*
  • Serpins / metabolism
  • Serpins / pharmacology*
  • Subcellular Fractions / metabolism
  • Synapsins / metabolism

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Membrane Proteins
  • Neuropeptides
  • Protease Inhibitors
  • Recombinant Proteins
  • Serine Proteinase Inhibitors
  • Serpins
  • Synapsins
  • RNA