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rain

B. rain. D. erived. N. eurotrophic. F. actor. Monoamine. Steroid. Neuropeptide. -Norepinephrine. -Testosterone. -Neuropeptide Y. -Estrogen. -Hypocretin. -Serotonin. - BDNF. -Dopamine. -Corticosterone. What does it do?. Similar to a neurotransmitter Secreted by cells

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  1. B rain D erived N eurotrophic F actor

  2. Monoamine Steroid Neuropeptide -Norepinephrine -Testosterone -Neuropeptide Y -Estrogen -Hypocretin -Serotonin -BDNF -Dopamine -Corticosterone

  3. What does it do? • Similar to a neurotransmitter • Secreted by cells • Acts on receptors • Binding causes changes in the cell Autocrine Paracrine Receptor Cell BDNF

  4. Where is it? • Definitely in brain and CNS • Small levels in systemic circulation • Hormone action? • Receptors in • Heart • Lungs • Kidney

  5. Advice from Dr. Amelia Eisch GOOD!!! Increase BDNF BAD  Decrease BDNF

  6. Chronic Stress Affective Disorders BDNF Exercise Learning BDNF Relaxation

  7. Dendritic Branching… Control BDNF added

  8. Cycle (Unlikely that synaptic activity is the only catalyst) Synaptic firing NMDA + L-VSCC (number of non-Ca2+ mechanisms involved) Ca+ enters cell BDNF produced and released Sustained BDNF activity strengthens synapses and promotes neuronal growth

  9. BDNF signaling • Activates genes that turn on LTP systems • Enhance trafficking and cytoskeletal structure • Actin polymerazation • Results in the increased branching and spine density • Brings in new AMPA subunits to existing synapses

  10. The Gene – Many mRNAs, One protein • Promoters, alternative splicing, polyadenylation sites • 18 mRNAs • Different strands go different places – regulation @ the mRNA level Greer & Greenberg 08’ Aid et al. 07’

  11. Pruunsild et al. 07’

  12. Don’t drown in promoters! • Just remember I & IV • (activity dependent)

  13. Epigenetics • ‘the study of heritable changes in genome function that occur without a change in DNA sequence‘ • “DNA is just a tape carrying information, and a tape is no good without a player. Epigenetics is about the tape player.” • http://epigenome.eu/en/1,1,0

  14. Histone Acetyltransferase (HAT) Histone Deacetylase (HDAC) Acetyl groups Gene Activated Histone Gene Repressed Methyl groups Histone Methyltransferase (HMT) Histone Demethylase (HDM)

  15. NMDA receptor activation induces differential epigenetic modification of BDNF promoters in hippocampal neurons Feng Tian, Ann M. Marini, Robert H. Lipsky

  16. Methods • Hippocampal cell cultures monitored for gene expression of BDNF promoters I & IV (mRNA and DNA) • Primary sources of activating Ca2+ for BDNF gene are NMDA + L-type Voltage Sensitive Calcium Channels • This work uses NMDA activity to induce BDNF transcription NOT L-VSCC

  17. Two repressors of BDNF translation • Anchors other repressor enzymes to histone HDAC1 • Removes acetyl groups from histone • MEF2 recruits MeCP2

  18. HDAC1 MeCP2

  19. Cells treated with NMDA over time • NMDA = exon 1 L-VSCC = exon 4

  20. Histone Deacetylase (HDAC) Acetyl groups Gene Activated • Peaked @ 250 nM Cells treated with different HDAC inhibitor concentrations

  21. DNA Antibody BOOM!!! Segment on interest TF Amplify & run on gel Glass Bead

  22. Time Post NMDA treatment Exon I HDAC1 • 2 sites @ Exon I • 1 site @ Exon IV Exon IV

  23. MeCP2 Slow action at Exon 1 Exon 2 acted faster. Start with less?

  24. Conclusions • Promoters I + IV respond differentially to signals affecting chromatin structure • Same signal may act differently • MeCP2 is temporally different • While NMDA strongly activates Exon 1 realitive to Exon 4, L-VSCC activation would have been interesting

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