BDNF: Role in Synaptic Plasticity, Learning, and Memory

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BDNF Role in Synaptic Plasticity, Learning, and
Memory

• Abby Suelflow
• 9 April 2010

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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.

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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

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Cell Biology of BDNF

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

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p75NTR activation

• Intracellular transduction cascades activated
• NT-?B
• Jun Kinase
• Sphingomyelin hydrolysis
• Initiation of apoptosis (LTD)

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Processing and Trafficking Overview
(majority)
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Val66met polymorphic substitution

• Val-BDNF
• Cell body
• Dendrites
• synapses
• Met-BDNF
• Cell body
• Proximal dendrites
• Rarely at distal dendrites
• Absent at synapses

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ProBDNF mBDNF

• Elicit opposite effects on synaptic plasticity.

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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

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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)

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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.

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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.

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Carla Cunha et al. (2009)

• Brain-derived neurotropic factor (BDNF)
  overexpression in the forebrain results in
  learning and memory impairments

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Learning Paradigms

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

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

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• 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)

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http//www.youtube.com/watch?vzBNoNoEB1X0

• 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

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• 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).

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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 (n10) and BDNF (n10) mice
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Western Blot Analysis

• Antibodies recognizing p32 proBDNF
• No significant differences b/t genotypes for all
  structures

WT n3, BDNF n3
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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.

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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.
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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.
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Assessment of Spatial Memory in the 8-Arm Radial
Maze Task

• Measured of correct visits, of errors,
  latency to complete the task.

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Behavioral Performance Measure
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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
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Probe Trials (5 10 days)
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Time Spent on Platform Zone
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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)

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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

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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

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Future Clinical Use

• Potential therapeutic molecule for
• Parkinsons
• Huntingtons
• Depression
• Substance abuse