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 1990 s.  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-κB 2. Jun Kinase 3. 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 BDNF  L-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 No difference

 Antibodies recognizing p32 proBDNF  No significant differences b/t genotypes for all structures WT: n=3, BDNF: n=3

 35 WT and 30 BDNF males  WT: ± 0.76 g  BDNF: ± 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