Abby Suelflow9 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 Leads to changes in neuronal circuitry by

altering number and/or strength of synaptic connections.

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

P75 neurotrophin receptor (p75NTR) Promotes apoptosis

Tropomyocin-related receptor tyrosine kinase (Trk) receptors (high affinity). Promotes cell survival

Intracellular transduction cascades activated:

1.NT-κB2.Jun Kinase3.Sphingomyelin

hydrolysis

Initiation of apoptosis (LTD)

(majority)

Val-BDNF Cell body Dendrites synapses

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

Elicit opposite effects on synaptic plasticity.

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

E-LTP Short-lasting (1h) Depends on protein phosphorylation BDNF/TrkB mutations lead to impairments▪ Reversed by acute application of recombinant

BDNFL-LTP

Last many hours Requires new protein synthesis Requires tPA and plasmin (proteases)

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.

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.

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

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

mins.

Locomotor Activity Contained UV photoelectric beams Measured horizontal and vertical

movements measured by total number of beam disruptions during 10 minute period.

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)

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

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).

Transgenic mice: Higher BDNF immunoreactivity in all forebrain structures analyzed in comparison to WT.

WT (n=10) and BDNF (n=10) mice

2.4

3.3 2.8 1.8

2.0

No difference

Antibodies recognizing p32 proBDNFNo significant differences b/t

genotypes for all structuresWT: n=3, BDNF: n=3

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.

Measured: # of correct visits, # of errors, & latency to complete the 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

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)

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

Excess mature BDNF acts on inhibitory interneurons TrkB receptors found in number of

forebrain interneurons Functions attributed to BDNF in non

pyramidal cells

Potential therapeutic molecule for: Parkinson’s Huntington’s Depression Substance abuse