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Calcium Regulation of Gene Expression and Impaired Learning in ckIV Null Mice

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This lecture explores the role of calcium in gene expression regulation and its impact on spatial learning. We focus on deficits observed in ckIV null mice, including impaired long-term potentiation (LTP) in the hippocampus, amygdala, and cortex, alongside difficulties in fear conditioning. Reduced phosphorylation of CREB and impaired expression of CRE-mediated genes suggest a significant link between calcium signaling, synaptic plasticity, and learning processes. We also discuss the implications of BDNF in synaptic efficacy and its potential in rescuing LTP defects.

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Calcium Regulation of Gene Expression and Impaired Learning in ckIV Null Mice

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Presentation Transcript

  1. BIPN 148 Lecture 15

  2. Calcium regulation of gene expression

  3. Spatial learning defects in dnCKIV mice

  4. Impaired hippocampal LTP in CKIV null mice

  5. Impaired amygdala and cortical LTP in CKIV null mice

  6. Impaired fear conditioning in CKIV null mice

  7. Calcium regulation of gene expression

  8. Reduced CREB phosphorylation in CKIV null mice

  9. Reduced CREB phosphorylation in CKIV null mice

  10. Reduced CREB phosphorylation in fear conditioning

  11. Fear conditioning induces CRE-mediated gene expression

  12. Reduced Fear Conditioning after inhibition of CREB

  13. Transcriptional targets of CREB CaMKIV + ERK RSK2 Elk-1 CBP/CREB zif268 CRE SRE C/EBP krox20 Arc AMPAR HOMER BDNF (Brain-derived Neurotrophic Factor) NT-3

  14. BDNF increases synaptic efficacy

  15. Reduction in LTP in BDNF null mice Kandel et al.

  16. Rescue of LTP defect by infusion of BDNF Kandel et al.

  17. Reduced LTP in conditional TrkB (BDNF receptor) null mice Klein et al.

  18. Impaired spatial learning in BDNF mutants WT BDNF mutant

  19. Synaptic Tagging and LTP New gene products or proteins New gene products or proteins Synaptic tag NMDAR Signal to nucleus Synaptic Potentiation Locally generated tag captures new gene product

  20. CREB and taste aversion

  21. THE CASE FOR GENE EXPRESSION IN L-LTP EXPERIMENT TYPE and FINDING Block Block of L-LTP with protein/RNA synthesis inhibitors  Block of L-LTP with RNA synthesis inhibitors Loss of L-LTP with CREB KOs Block of L-LTP with Arc antisense Loss of L-LTP with CaMKIV KO  Loss of L-LTP with zif268 KO

  22. THE CASE FOR GENE EXPRESSION IN L-LTP EXPERIMENT TYPE and FINDING Measure Increased zif268/krox24 mRNA  Increased krox20  Increased expression of fos, jun IEG mRNAs Increased CREB phosphorylation Increased CRE read-out Increased elk-1 phosphorylation  Increased Arc/Arg3.1 mRNA expression Increased AMPA receptor protein  Increased BDNF (Brain-derived neurotrophic factor) message

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