How does calcium mediate both E-LTP and L-LTP?
Higher calcium influx can activate PKA and lead to L-LTP
Noradrenaline lowers threshold for inducing L-LTP
- Understand how the associativity of LTP may underlie classical conditioning
- Pairing weak and strong stimuli at synaptic level → basis for associative learning
- Gives larger depolarization of weak synapse with pairing (ie gives LTP at weak synapse because of strong depol at nearby synapse)
- What is an R(AB) transgenic mouse? What conclusions were derived from studying them?
- R(AB) = mutant PKA mouse
- Mutated R subunits do not release C subunits when cAMP binds = remains inactive
- Conclusions:
- PKA mutants froze less than wildtype controls at 24 hours
- suppressing PKA activity = interfered with long term memory but left short term memory intact
- therefore, PKA is required for long-term (L-LTP) but not short-term (E-LTP) associative memory
- PKA mutants froze less than wildtype controls at 24 hours
Expression of R(AB) transgene is strong in the ______
Expression of R(AB) transgene is strong in the hippocampus
PKA activation is required for normal _____ in area _____ of the hippocampus
PKA activation is required for normal LT memory in area CO-1 Region of the hippocampus (critical for LTM)
ie PKA required for L-LTP but not E-LTP
What is bidirectional signalling? Why is it important?
- What is synaptic tagging? How does it contribute to L-LTP?
- Know the experiment suggesting that behavioral tagging may occur (rat digging for target well)
- Know the kinases and transcription factors critical for L-LTP
- What is CBP? What does it do? How does it work?
- How do histones regulate gene expression?
- Know how two distinct mutations of CBP affect transcription and long-term memory
- What is reconsolidation?
- Understand the experiment showing that extinction during reconsolidation can erase fear memories
- Synapse to nucleus
- Local signals travel back to the soma to engage transcription = L-LTP
- Soma to nucleus
- Depolarization of Soma membrane, Ca++ enters
- signals cascade → engage nucleus
- Plasticity proteins cause L-LTP
- (Proteins synthesized in the soma are shipped to activated spines where they mix in with locally synthesized proteins)
What is synaptic tagging? How does it contribute to L-LTP?
- Synaptic tagging
- activity at one set influences plasticity at another
- Model:
- A week and strong stimuli both generate local synaptic tags
- weak stimulus along produces transient memory because it cannot generate PRPs (plasticity related proteins)
- Strong stimulus alone produces tags and PRPs
- Weak paired with strong produces long-term memory because tags at weak site allow it to capture PRPs produced by the strong stimulus
Know the kinases and transcription factors critical for L-LTP
PKA, CREB. CBP
- PKA - enters nucleus where it acts on
- CREB - influences transcription (critical for L-LTP)
- CBP - Transcriptional Co-Activator
- integrates multiple signals via post-translational modification to coordinate activation of primed transcription factors
What is CBP? What does it do? How does it work?
- CBP
- CREB binding protein
- Transcriptional Co-activator
- Integrates multiple signals via post-translational modifications to coordinate activation of primed transcription factors
- Recruited by phosphorylated CREB
- Contains 2 key domains
- one binds to CREB
- one activates transcription of genes
- Activates transcription through its Histone Acetyltransferase (HAT) activity
Mutations of CBP results in:
Rubinstein-Taybi Syndrome = impaired learning/ mental retardation
How do histones regulate gene expression?
- CBP has histone acetyltransferase activity
- CBP can add acetyl groups to histones which enhances gene expression by unwinding/relaxing the chromatin
Know how two distinct mutations of CBP affect transcription and long-term memory
- CBP truncation mutant lacking the HAT domain
- Mutant lacks HAT domain = cannot activate transcription
- CBP-KIX Knock-In mice
- Blocks CREB-CBP interaction
- Mutant fails to bind to CREB
- No gene activation
- Blocks CREB-CBP interaction
What is reconsolidation?
12. Understand the experiment showing that extinction during reconsolidation can erase fear memories
Consolidation and reconsolidation each lasts about 6 hours - in which susceptible to modifications via protein synthesis
Reconsolidation allows incorporation of new information into old memories (eg new association)
Understand the experiment showing that extinction during reconsolidation can erase fear memories
- Protein synthesis inhibitor (anisomycin) blocks reconsolidation of fear memory
- Anisomycin injected into amygdala (open arrow)
- First reactivate memory with CS wait 10 minutes
- repeatedly show CS without US
- Learn CS no longer predicts US
- the next day, the memory is abolished and CS is no longer linked to US
Key Concepts
- Synaptic _____and synthesis of ________ establish L-LTP and may underlie associative learning
- _______ is needed for long-term but not short-term associative learning
- Activity can “tag” synapses so they capture PRPs to express ____
- CBP recruits transcription by ________.
- These activities are needed for ___________
- Memory reconsolidation involves updating of long-term memories through a _______ dependent process
- ________ can alleviate repeated recall of traumatic memories and may improve mental health in patients with PTSD
- Memory research is valuable for developing tx for pts with PTSD, Alzheimers disease, and addiction. It also sheds light on a fundamental brain function essential for survival and productivity in human society
Key Concepts
- Synaptic Tagging and synthesis of plasticity-related proteins (PRPs) establish L-LTP and may underlie associative learning
- PKA activation is needed for long-term but not short-term associative learning
- Activity can “tag” synapses so they capture PRPs to express L-LTP
- CBP recruits transcription by acetylating histones.
- These activities are needed for normal long-term associative memory
- Memory reconsolidation involves updating of long-term memories through a protein synthesis-dependent process
- disruption of reconsolidation can alleviate repeated recall of traumatic memories and may improve mental health in patients with PTSD
- Memory research is valuable for developing tx for pts with PTSD, Alzheimers disease, and addiction. It also sheds light on a fundamental brain function essential for survival and productivity in human society
