BDNF Role in Synaptic Plasticity Learning and Memory

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

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 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.

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

Cell Biology of BDNF P 75 neurotrophin receptor (p 75 NTR) Promotes apoptosis Tropomyocin-related receptor tyrosine kinase (Trk) receptors (high affinity). Promotes cell survival

p 75 NTR activation: Intracellular transduction cascades activated: 1. NT-κB 2. Jun Kinase 3. Sphingomyelin hydrolysis Initiation of apoptosis (LTD)

Processing and Trafficking Overview (majority)

Val 66 met polymorphic substitution Val-BDNF Cell body Dendrites synapses Met-BDNF Cell body Proximal dendrites Rarely at distal dendrites Absent at synapses

Pro. BDNF & m. BDNF Elicit opposite effects on synaptic plasticity.

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 Trk. B trafficking

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

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

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 Trk. B results in learning impairments.

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

Learning Paradigms 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 2 X black compartment (10. 0 s) ▪ White compartment = black compartment (3. 0 s)

http: //www. youtube. com/watch? v=z. BNo. EB 1 X 0 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 overexpress mature BDNF in most forebrain regions 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

Western Blot Analysis Antibodies recognizing p 32 pro. BDNF No significant differences b/t genotypes for all structures WT: n=3, BDNF: n=3

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.

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.

Passive Avoidance Task STM/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.

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

Behavioral Performance Measure

Assessment of Spatial Memory MWM 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

Probe Trials (5 & 10 days)

Time Spent on Platform Zone

Summary of Results BDNF overexpression in forebrain regions leads to clearning 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)

Why the Detrimental Effects? Anxiety-like behavior present in this BDNF line Ratio of pro/mature BDNF in favor of pro form. Hyperactivation of p 75 receptors Decreased activation of Trk. B receptors Not a likely possibility

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

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