Long Term Potentiation (LTP) Flashcards
What is procedural memory?
Information acquired and retrieved unconsciously, including motor and cognitive skills and classical conditioning
What is episodic memory?
Snapshots of life events. Conscious
What is semantic memory?
- Words and their meanings, people, faces, objects, concepts - all filed into discrete categories.
- Conscious
When does synaptic plasticity occur?
Development, learning and memory, ageing, response to trauma/disease
Which pathways are LTP specific to?
- LTP is specific to the tetanised pathways.
- Non-tetanized inputs, even convergent on the same dendritic region are not poteniated
Explain what cooperativity means in terms of LTP
LTP exhibits an intensity threshold whereby a weak stimulus is unable to induce LTP whereas a strong stimulus can
Explain what associativity means in terms of LTP
- A weak input will potentiate provided a strong convergent input is activated at the same time.
- This feature has been equated with classical conditioning, with the weak and strong inputs corresponding to the conditioned and non-conditioned stimuli respectively
How many stages does LTP have and what are these?
4 stages - post-titanic potentiation, early LTP, intermediate LTP, late LTP
What is the key regulator of NMDA receptor activation?
Calcium
In all models of LTP there are 3 distinct temporal phases, what are these?
- Dependent on post-translational modification of existing proteins i.e. phosphorylation
- Dependent on synthesis of new protein from existing mRNA i.e. mRNA translation
- Dependent on synthesis of new protein and new mRNA i.e. gene transcription
Describe phase I of LTP
- Inhibition of a variety of kinases inhibits the early phase of LTP - PKA, PKC, ERK, CamKII, PYK2 etc.
- This implies there are multiple parallel pathways, all of them essential for the full expression of the plasticity response
Calcium dependent kinases are involved in LTD and phosphatases are involved in LTP. T/F?
False - calcium dependent kinases are involved in LTP and phosphatases are involved in LTD
How can early phase synaptic plasticity be maintained?
Phosphorylation of receptors and receptor trafficking
What effect does phosphorylation of GluA1 at s831 and s845 have?
Both increase conductance (in different ways) and effect receptor trafficking
Describe LTP in terms of activity, calcium level, conductance and AMPA receptor number
- Fast, strong activity
- High calcium
- Increased conductance
- Increased AMPAR number
Describe LTD in terms of activity, calcium level, conductance and AMPA receptor number
- Lower. sustained activity
- Moderate calcium
- Decreased conductance
- Decreased AMPAR number
What indirect evidence is there that GluA receptors traffic during LTP?
- From studies that block post-synaptic interactions with regulatory/trafficking proteins e.g. PICK/GRIP
- Also, evidence from silent synapses
What direct evidence is there that GluA receptors traffic during LTP?
From immunohistochemical detection of surface GluA receptors (culture) and from imaging fluorescent GluA chimeras
What do TARPs do?
- Transmembrane AMPA receptor recegulatory proteins (TARPs) control AMPA receptor trafficking and lateral surface diffusion of AMPA receptors
- TARPs also modulate the electrophysiological properties of AMPA receptors
What do AMPARs lacking GluA2 subunits show?
Pronounced inward rectification due to voltage-dependent block of the channel by polyamines at positive membrane potentials
How can postsynaptic receptor numbers be increased?
- Increase of receptor delivery
- Lateral diffusion
- Reduce removal of receptor
What is MAP2?
Microtubule associated protein 2 - modulates microtubule dynamics and so promotes outgrowth of dendritic processes
What is CamKII?
A subunit involved in NMDAR dependent signalling
What could stimulation of protein synthesis from mRNAs present in dendrites involve?
- Inhibition of mRNA degradation, leading to elevated mRNA levels and increased synthesis of the corresponding protein
- Phosphorylation of ribosomal proteins near the synapse, leading to more efficient translation of the mRNA
- Phosphorylation of ribosomal proteins is triggered by ERK
How can glutamate R number on the post-synaptic membrane be altered?
- Phase 1 - increase protein delivery - membrane insertion/trafficking via lateral mobility
- Phases 2 and 3 - increase protein synthesis - local protein synthesis and somatic synthesis
Gene transcription is activated by transcription factors (TFs). These TFs bind to specific target sites in the genome to regulate transcription of a target gene. What are the 2 types of TF?
- Constitutive TFs - present in an inactive form in the cytoplasm, to be activated following the stimulus
- Inducible TFs - activated as target genes of constitutive TFs and themselves then stimulating transcription of their own target ‘late response genes’
What are inducible TFs often known as?
Considered a type of immediate-early gene (IEG) due to their rapid, transient transcription after a stimulus
Name the constitutive transcription factors involved in synaptic plasticity
- cAMP-response element binding protein (CREB)
- Elk1
- Nuclear factor for kappa B light chains (NFkappaB)
Name the inducible TFs involve in synaptic plasticity
- zif268
- junB
How does CREB activation work?
CREB protein binds to DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing transcription of a downstream gene
How are immediate-early genes (IEGs) involved in LTP?
- Calcium activates kinase -> short term effects
- Kinase also enters the nucleus which causes phosphorylation of a transcription factor TF binds to IEG DNA and initiates transcription
- (or alternatively phosphorylation of a repressor protein e.g. EF-2, initiates transcription)
- IEG product is itself a TF
- This initiates synthesis of other proteins
Is zif268 induction a causal step in LTP?
- High frequency stimulation induces zif268 MK801 blocks LTP and blocks zif268 induction
- Stimulating an inhibitory pathway blocks LTP and blocks zif268 induction
- Sub-threshold stimulation which does not induce LTP, does not induce zif268
What morphological changes are thought to occur during LTP?
Synapse splitting and enlarged postsynaptic density
