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BDNF: Role in Synaptic Plasticity, Learning, and Memory

Abby Suelflow 9 April 2010. BDNF: Role in Synaptic Plasticity, Learning, and Memory. BDNF Basics. Distributed in many regions of adult brain Multiple BDNF transcripts that encode exact same protein BDNF promotors involved in various processes

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BDNF: Role in Synaptic Plasticity, Learning, and Memory

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  1. Abby Suelflow 9 April 2010 BDNF: Role in Synaptic Plasticity, Learning, and Memory

  2. BDNF Basics • Distributed in many regions of adult brain • Multiple BDNF transcripts that encode exact same protein • BDNF promotors involved in various processes • Role in synaptic modulation recognized in late 1990s. • Regulation of synaptic transmission and plasticity and role in neuronal survival • Leads to changes in neuronal circuitry by altering number and/or strength of synaptic connections.

  3. Regulation by Neuronal Activity • Interactions between BDNF and neuronal activity helps regulate complicated cognitive functions • Circadian rhythms and fear emotion • Learning and exercise • Conditions w/ altered neuronal activity • Regulation of cellular processes

  4. Cell Biology of BDNF • P75 neurotrophin receptor (p75NTR) • Promotes apoptosis • Tropomyocin-related receptor tyrosine kinase(Trk) receptors (high affinity). • Promotes cell survival

  5. p75NTR activation: Intracellular transduction cascades activated: • NT-κB • Jun Kinase • Sphingomyelin hydrolysis Initiation of apoptosis (LTD)

  6. Processing and Trafficking Overview (majority)

  7. Val66met polymorphic substitution • Val-BDNF • Cell body • Dendrites • synapses • Met-BDNF • Cell body • Proximal dendrites • Rarely at distal dendrites • Absent at synapses

  8. ProBDNF & mBDNF • Elicit opposite effects on synaptic plasticity.

  9. Input Specificity • BDNF actions are local and synapse-specific • Activity dependent • Limited capacity of diffusion due to negative charge • BDNF exon II and IV transcripts can be targeted into dendrites of hippocampal neurons • Ensure better response of target synapses to BDNF by regulating TrkB trafficking

  10. Roles of BDNF in LTP • E-LTP • Short-lasting (1h) • Depends on protein phosphorylation • BDNF/TrkB mutations lead to impairments • Reversed by acute application of recombinant BDNF • L-LTP • Last many hours • Requires new protein synthesis • Requires tPA and plasmin (proteases)

  11. Learning, Memory, and Other Cognitive Functions • BDNF regulation of learning and memory • Spatial learning significantly impaired when BDNF signaling is disrupted. • BDNF/TrkB deletions lead to a decrease of contextual fear or spatial memories and hippocampal LTP.

  12. Learning Models in Rats • BDNF expression increased in hippocampus of rats after the following tests: • Morris Water Maze (MWM) • Radial arm maze • Passive avoidance/contextual fear conditioning • Gene ablation of BDNF or TrkB results in learning impairments.

  13. Brain-derived neurotropic factor (BDNF) overexpression in the forebrain results in learning and memory impairments Carla Cunha et al. (2009)

  14. Learning Paradigms • Accelerating Rota-Rod • Rotating cylinder covered with rubber • Speeds increasing from 4-40 rpm over 6 mins.

  15. Locomotor Activity • Contained UV photoelectric beams • Measured horizontal and vertical movements measured by total number of beam disruptions during 10 minute period.

  16. Passive Avoidance • Illuminated white compartment and black dark chamber permitting passage of electric foot shocks. • 2 different conditions: • White compartment 2X black compartment (10.0s) • White compartment = black compartment (3.0s)

  17. http://www.youtube.com/watch?v=zBNoNoEB1X0 • Eight-arm radial maze • Scored total number of errors (re-entering a previously visited arm) and total number of correct visits. • One trial per day for 12 consecutive days

  18. Morris Water Maze (MWM) (hidden platform) • Trained to swim to platform in 2 daily trials, with 30 minute interval, during 10 consecutive days. • Probe trials- hidden platform removed and swimming path recorded. • Measured latency to reach platform (s), total distance swam to the platform (cm), and average swim speed (cm/s).

  19. Transgenic mice overexpress mature BDNF in most forebrain regions 2.0 1.8 3.3 2.8 2.4 No difference Transgenic mice: Higher BDNF immunoreactivity in all forebrain structures analyzed in comparison to WT. WT (n=10) and BDNF (n=10) mice

  20. Western Blot Analysis • Antibodies recognizing p32 proBDNF • No significant differences b/t genotypes for all structures WT: n=3, BDNF: n=3

  21. Measurement of Body Weight • 35 WT and 30 BDNF males • WT: 27.47 ± 0.76 g • BDNF: 25.74 ± 0.58 g • Results: no significant difference in reduction of body weight for transgenics.

  22. Motor Performance of Transgenic Mice Both groups showed a significant improvement in motor coordination over time. Similar performances in both directions; no differences in spontaneous exploratory behavior.

  23. Passive Avoidance TaskSTM/LTM BDNF transgenics manifest impairments in long-term memory formation; preserved up to 10 days from learning. Impairments result of both short and long-term deficits in forming and stabilizing the memory trace.

  24. Assessment of Spatial Memory in the 8-Arm Radial Maze Task • Measured: # of correct visits, # of errors, & latency to complete the task.

  25. Behavioral Performance Measure

  26. Assessment of Spatial Memory MWM Task BDNF transgenics generally slower reaching target platform BDNF transgenics had to swim a longer distance to reach platform Significant decrease in mean velocity through the test

  27. Probe Trials (5 & 10 days)

  28. Time Spent on Platform Zone

  29. Summary of Results • BDNF overexpression in forebrain regions leads to clear learning impairments in instrumental and spatial memory tasks. • BDNF transgenics can learn the task but have apparent mild spatial memory impairments • Passive Avoidance analysis revealed deficit in acquisition of STM; not a true deficit in memory consolidation. • BDNF mice have a significant retarded acquisition in the MWM test (consistent with 8-arm memory impairment results)

  30. Why the Detrimental Effects? • Anxiety-like behavior present in this BDNF line • Ratio of pro/mature BDNF in favor of pro form. • Hyperactivation of p75 receptors • Decreased activation of TrkB receptors • Not a likely possibility

  31. More Plausible Explanation • Excess mature BDNF acts on inhibitory interneurons • TrkB receptors found in number of forebrain interneurons • Functions attributed to BDNF in non pyramidal cells

  32. Future Clinical Use • Potential therapeutic molecule for: • Parkinson’s • Huntington’s • Depression • Substance abuse

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