Abby Suelflow
9 April 2010
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
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 Leads to changes in neuronal circuitry by altering
number and/or strength of synaptic connections.
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Interactions between BDNF and neuronal
activity helps regulate complicated cognitive
functions
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Circadian rhythms and fear emotion
Learning and exercise
Conditions w/ altered neuronal activity
Regulation of cellular processes
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P75 neurotrophin receptor (p75NTR)
 Promotes apoptosis
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Tropomyocin-related receptor tyrosine
kinase (Trk) receptors (high affinity).
 Promotes cell survival
Intracellular transduction
cascades activated:
1. NT-κB
2. Jun Kinase
3. Sphingomyelin hydrolysis
Initiation of apoptosis (LTD)
(majority)
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Val-BDNF
 Cell body
 Dendrites
 synapses
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Met-BDNF
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Cell body
Proximal dendrites
Rarely at distal dendrites
Absent at synapses
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Elicit opposite effects on synaptic plasticity.
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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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E-LTP
 Short-lasting (1h)
 Depends on protein phosphorylation
 BDNF/TrkB mutations lead to impairments
▪ Reversed by acute application of recombinant BDNF
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L-LTP
 Last many hours
 Requires new protein synthesis
 Requires tPA and plasmin (proteases)
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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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BDNF expression increased in hippocampus
of rats after the following tests:
 Morris Water Maze (MWM)
 Radial arm maze
 Passive avoidance/contextual fear conditioning
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Gene ablation of BDNF or TrkB results in
learning impairments.
Brain-derived neurotropic factor (BDNF)
overexpression in the forebrain results in
learning and memory impairments
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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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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).
2.0
3.3
2.8
1.8
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
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Antibodies recognizing p32 proBDNF
No significant differences b/t genotypes for
all structures WT: n=3, BDNF: n=3
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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.
Both groups showed a
significant improvement
in motor coordination
over time.
Similar performances in
both directions; no
differences in
spontaneous exploratory
behavior.
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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Measured: # of correct visits, # of errors, & latency to complete the task.
BDNF transgenics generally slower reaching
target platform
Significant decrease in
mean velocity through the
test
BDNF transgenics had to swim a longer distance
to reach platform
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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 8arm memory impairment results)
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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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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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Potential therapeutic molecule for:
 Parkinson’s
 Huntington’s
 Depression
 Substance abuse