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The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior

Joanna I Giza1, Jihye Kim1, Heidi C Meyer1

  • 1Department of Psychiatry, Weill Cornell Medicine, New York, NY 10065, USA.

Neuron
|June 19, 2018
PubMed

Insights

The BDNF Met variant disrupts brain development, impairing fear extinction. This variant causes synapse loss and underdeveloped neural circuits in adolescent mice.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • The BDNF Val66Met variant (rs6265) is linked to impaired fear extinction.
  • The BDNF Met prodomain's cellular mechanisms in synaptic plasticity remain unclear.

Purpose of the Study:

  • Investigate how the BDNF Met prodomain affects hippocampal neuron morphology and fear extinction.
  • Elucidate the developmental role of BDNF-SorCS2/p75NTR interactions in peri-adolescence.

Main Methods:

  • Super-resolution imaging of hippocampal neurons.
  • In vivo manipulation of BDNF prodomain in ventral CA1 (vCA1) neurons.
  • Analysis of dendritic spine density and prelimbic (PL) projections.
  • Fiber photometry to assess neural activity during fear extinction in wild-type and BDNF Met/Met mice.

Main Results:

  • BDNF Met prodomain disassembles dendritic spines and eliminates synapses.
  • Peri-adolescent vCA1 neurons co-express SorCS2/p75NTR, mediating these changes.
  • Infusion of BDNF Met prodomain reduces spine density and PL projections, impairing fear extinction.
  • Adolescent BDNF Met/Met mice exhibit similar deficits and lack adaptive neural activity during extinction recall.

Conclusions:

  • The BDNF Met prodomain causes underdeveloped vCA1-PL projection neurons during a critical developmental window.
  • This underdevelopment prevents the necessary circuit modulation for effective fear extinction.
  • The findings highlight a critical period for BDNF's role in shaping neural circuits for emotional regulation.
Keywords:
BDNFSorCS2fear extinctionfiber photometryp75(NTR)peri-adolescencepolymorphismprodomainsynapse eliminationventral CA1

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