Pro-Brain-Derived Neurotrophic Factor (proBDNF)-Mediated p75NTR Activation Promotes Depolarizing Actions of GABA and Increases Susceptibility to Epileptic Seizures

Cereb Cortex. 2018 Feb 1;28(2):510-527. doi: 10.1093/cercor/bhw385.


The brain-derived neurotrophic factor (BDNF) is synthesized as a precursor, namely proBDNF, which can be processed into mature BDNF (mBDNF). Evidences suggest that proBDNF signaling through p75NTR may account for the emergence of neurological disorders. These findings support the view that the relative availability of mBDNF and proBDNF forms is an important mechanism underlying brain circuit formation and cognitive functions. Here we describe novel insights into the proBDNF/p75NTR mechanisms and function in vivo in modulating neuronal circuit and synaptic plasticity during the first postnatal weeks in rats. Our results showed that increased proBDNF/p75NTR signaling during development maintains a depolarizing γ-aminobutyric acid (GABA) response in a KCC2-dependent manner in mature neuronal cells. This resulted in altered excitation/inhibition balance and enhanced neuronal network activity. The enhanced proBDNF/p75NTR signaling ultimately led to increased seizure susceptibility that was abolished by in vivo injection of function blocking p75NTR antibody. Altogether, our study shed new light on how proBDNF/p75NTR signaling can orchestrate the GABA excitatory/inhibitory developmental sequence leading to depolarizing and excitatory actions of GABA in adulthood and subsequent epileptic disorders.

Keywords: KCC2; chloride; epileptogenesis; proneurotrophins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / biosynthesis*
  • Female
  • GABA Agents / metabolism
  • GABA Agents / pharmacology
  • Male
  • Nerve Tissue Proteins
  • Organ Culture Techniques
  • Pregnancy
  • Protein Precursors / biosynthesis*
  • Rats
  • Rats, Wistar
  • Receptors, Growth Factor
  • Receptors, Nerve Growth Factor / biosynthesis*
  • Seizures / metabolism*
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / metabolism
  • gamma-Aminobutyric Acid / metabolism
  • gamma-Aminobutyric Acid / pharmacology*


  • Brain-Derived Neurotrophic Factor
  • GABA Agents
  • Nerve Tissue Proteins
  • Protein Precursors
  • Receptors, Growth Factor
  • Receptors, Nerve Growth Factor
  • brain-derived neurotrophic factor precursor
  • Ngfr protein, rat
  • gamma-Aminobutyric Acid