BIPN 148 Lecture 15

Calcium regulation of gene expression

Spatial learning defects in dnCKIV mice

Impaired hippocampal LTP in CKIV null mice

Impaired amygdala and cortical LTP in CKIV null mice

Impaired fear conditioning in CKIV null mice

Calcium regulation of gene expression

Reduced CREB phosphorylation in CKIV null mice

Reduced CREB phosphorylation in CKIV null mice

Reduced CREB phosphorylation in fear conditioning

Fear conditioning induces CRE-mediated gene expression

Reduced Fear Conditioning after inhibition of CREB

CRE SRE zif268

C/EBP krox20

AMPARHOMER

BDNF (Brain-derived Neurotrophic Factor)NT-3

Arc

CBP/CREB

CaMKIV + ERK

Elk-1

RSK2

Transcriptional targets of CREB

BDNF increases synaptic efficacy

Reduction in LTP in BDNF null mice

Kandel et al.

Rescue of LTP defect by infusion of BDNF

Kandel et al.

Reduced LTP in conditional TrkB (BDNF receptor) null mice

Klein et al.

Impaired spatial learning in BDNF mutants

WT BDNF mutant

New gene products or

proteins

Signal to

nucleus

New gene products or

proteins

Synaptic Potentiation

Locally generated tag captures new gene product

Synaptictag

NMDAR

Synaptic Tagging and LTP

CREB and taste aversion

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 KOsBlock of L-LTP with Arc antisense 

Loss of L-LTP with CaMKIV KO Loss of L-LTP with zif268 KO  

THE CASE FOR GENE EXPRESSION IN L-LTP

EXPERIMENT TYPE and FINDING

MeasureIncreased zif268/krox24 mRNA Increased krox20 Increased expression of fos, jun IEG mRNAs 

Increased CREB phosphorylation 

Increased CRE read-outIncreased elk-1 phosphorylation Increased Arc/Arg3.1 mRNA expression 

Increased AMPA receptor protein Increased BDNF (Brain-derived neurotrophic factor) message