Synaptic Plasticity

Question 1

What is semantic memory?

Answer 1

Part of declarative memory (knowing that)

Words and their meanings, people, faces, objects, concepts - all filed into discrete categories
Conscious

Question 2

What is episodic memory?

Answer 2

Part of declarative memory (knowing that)

‘Snapshot’ of life events
Conscious

Question 3

What is procedural memory?

Answer 3

Knowing how

Information acquired and retrieved unconsciously, including motor and cognitive skills and classical conditioning

Question 4

What are the classical properties of LTP (3)?

Answer 4

Specificity - LTP is specific to tetanised pathways (fibres that have undergone HFS)

Cooperativity - LTP exhibits intensity treshold (weak stimulus can’t induce LTP)

Associativity - A weak input will potentiate provided a strong convergent input is activated at the same time (has been equated with classical conditioning - weak = conditioned stimulus, strong = non-conditioned stimulus)

Question 4

Where do connections to the hippocampus come from?

Answer 4

Parahippocampal cortex and perirhinal cortex -> synapse onto the entorhinal cortex -> synapses onto dentate gyrus (in hippocampus)

Question 4

How does signalling in the hippocampus work?

Answer 4

Dentate gyrus -> synapses onto CA3 -> synapses onto CA1 -> synapses onto subiculum -> output goes to cortex

Question 4

What are the phases of LTP?

Answer 4

• Post-tetanic potentiation
• Early LTP (0-1 hr)
• Intermediate LTP (1-2 hr)
• Late LTP (>3 hr)

Question 5

What are the stimulation protocols for patterned stimulation for inducing LTP?

Answer 5

• Tetanic stimulation (100Hz for 1s) - robust but unphysiological
• Theta burst (short burst @ 5Hz) - more physiological
• Primed burst
• Realistic stimulation protocols

Peak physiological stimulation is 20-50 Hz

Question 6

What are the postsynaptic events that induce LTP?

Answer 6

NMDARs activated -> intracellular [Ca2+] increases -> activates CaM Kinase II, PKC, Fyn kinase -> LTP induction

Question 7

What are the 3 distinct temporal phases in LTP?

Answer 7

1. Dependent on post-translational modification of existing proteins (ie phosphorylation)
2. Dependent on synthesis of new protein from existing mRNA (ie mRNA translation)
3. Dependent on synthesis of new protein and new mRNA (ie gene transcription)

Question 8

Inhibition of which kinases inhibits the early phase of LTP?

Answer 8

PKA, PKC, PKG, ERK, CamKII, CamKIV, PYK2, Fyn

Implies multiple parallel pathways, all necessary for full expression of plasticity response

Question 9

How can it be tested whether kinases are involved in early phase LTP?

Answer 9

By inhibiting the function of a specific protein. Done through:

• Receptor antagonists
• Enzyme inhibitors
• Knockout mice
• Use of inactive/dominant negative forms

Question 10

CamKII alpha subunit knockout mice

Answer 10

Wild type -> displays robust LTP
Knockout -> magnitude of LTP reduced
NMDAR antagonist -> block LTP

Question 11

How are naive GluA1 subunits affected by HFS and LFS?

Answer 11

Naive GluA1 = phosphorylated at S845, not phosphorylated at S831

HSF: thanks to CamKII S831 becomes phosphorylated
-> S845 & S831 phosphorylated
-> LTP

LFS: thanks to PKA S845 dephosphorylated
-> neither S845 or S831 are phosphorylated
-> LTD

Question 12

Evidence that GluA receptors traffick during LTP?

Answer 12

Indirect - studies that block post-synaptic interactions with regulatory/trafficking proteins (ie PICK/GRIP) + evidence from silent synapses

Direct - immunohistochemical detection of surface GluA receptors (culture) & from imaging fluorescent GluA chimeras (ie SEP-GluA1)
Ie green-fluorescent tag is pH senstive -> fluoresces at surface (pH 7) and not inside (pH 4)

Question 13

What are TARPs?

Answer 13

Transmembrane AMPA receptor regulatory proteins (TARPs)
Ie stargazin

Control AMPA receptor trafficking & lateral surface diffusion of AMPA receptors
Also modulate electrophysiological (biophysical) properties of AMPA receptors

Question 14

Evidence for changes in AMPA receptor subunit composition during LTP

Answer 14

Lacking GluA2 -> show inward rectification (of I/V curve) due to voltage-dependent block of channel by polyamines (ie serine) at positive membrane potential
Ca2+ permeable

Containing GluA2 -> Ca2+ impermeable (blocked by R residue)
Linear I/V curve

Question 15

What are examples of proteins synthesised in phase 2 of synaptic plasticity?

Answer 15

Likely to involve mRNA present in dendrites

Could be mRNA encoding:
- MAP2 - microtubule associated protein 2, modulates microtubule dynamics, promotes outgrowth processes
- CamKII - subunit involved in NMDAR-dependent signalling

Question 16

What are possible mechanisms for local protein synthesis in phase 2 of synaptic plasticity?

Answer 16

Inhbition of mRNA degradation -> increased mRNA levels, increased synthesis of corresponding protein (if mRNA levels is rate limiting)

Phosphorylation of ribosomal proteins (triggered by ERK) - near synapse -> more efficient translation of mRNA

Question 17

How to alter GlutamateR number on the post-synaptic membrane

Answer 17

Same phases as LTP

Phase 1 - increase protein delivery
- Membrane insertion/trafficking
- Via lateral mobility

Phase 2 & 3 - increase protein synthesis
- Local protein synthesis
- Somatic synthesis (general protein traffickin)

Question 18

What is involved in phase 3 of synaptic plasticity?

Answer 18

Transcription factors (TFs) -> bind to target sites in genome -> regulate transcription of target gene (increase = activator, decrease = repressor)

Question 19

What are the 2 types of transcription factors involved in phase 3 of synaptic plasticity? Examples?

Answer 19

Consititutive TFs - present in inactive form in cytoplasm, activated following stimulus
- cAMP-response element binding protein (CREB)
- Elk1
- Nuclear factor for kappa B light chains (NFkappaB)

Inducible TFs - activated as targets genes of constitutive TFs -> then stimulate transcription of their own target ‘late response genes’
(Inducible TFs seen as immediate-early genes (IEGs) due to rapid transient transcription after stimulus)
- zig268 (early growth response1 - egr1)
- junB (component of AP1)

Question 20

Is zif268 a causal step in LTP?

Answer 20

• High frequency stimulation induces zif/268: appears about 15 min after stimulus, peaks at 30-60 min
• MK801 blocks LTP and blocks zif/268 induction​
• Stimulating an inhibitory pathway blocks LTP and blocks zif/268 induction​
• Sub-threshold stimulation which does not induce LTP, does not induce zif/268

Question 21

What are examples of late response genes?

Answer 21

CREB target LRG:
BDNF (brain derived neurotrophic factor) - promotes neuronal survival, neurite outgrowth, further platicity

NFkB target LRG:
NCAM (neuronal cell adhesion molecule) - promotes neurite outgrowth, maintenance of synaptic architecture

zif268 target LRG:
- Proteasome genes
- Agrin/gephyrin (cluster receptors and stabilise synapses - key adaptor proteins)

Question 22

What is the composition of different types of synapses after LTP induction?

Answer 22

Control: 70% simple, 20% perforated, 10% mushroom body (MSB)

30 min after LTP induction: 45% simple + perforated each, 10% MSB

45-120 min after LTP induction: 65% simple, 20% perforated, 15% MSB