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

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.