NERVOUS SYSTEM: MOLECULAR MECHANISMS OF LEARNING AND MEMORY - PLASTICITY AND DISEASE

Question 1

What are the early and late phases of long term potentiation

Answer 1

• Early: Insertion of receptors from vesicle stores

– Late: Modification of gene expression and structural
changes

Question 2

Define: silent synapse

Answer 2

Silent synapses: synapse with only NMDArs and few or no AMPARs. Can be woken up with LTP protocols which will insert more AMPARs at postsynaptic membrane

Question 3

Describe Presynaptic LTP

Answer 3

Presynaptic LTP: Repetitive synaptic activity leads to entry of presynaptic Ca2+ → activates adenylate cyclase (AC) → activates cAMP → activates protein kinase A (PKA) → Rab3a and RIM1 → exocytosis; increased presynaptic release (release of glutamate)

Question 4

Describe mGluR LTD

Answer 4

mGluR-dependent LTD (metabotropic glutamate receptor): mGluR triggers AMPA receptors postsynaptic internalization; process requires protein synthesis

Question 5

Describe eCB-LTD (cannabinoid)

Answer 5

eCB-LTD (cannabinoid): mGluR activation → phospholipase C (PLC) and/or intracellular Ca2+ initiates the synthesis of cannabinoids. The eCB travels in a retrograde manner to bind to presynaptic cannabinoid 1 receptors (CB1R) that depresses neurotransmitter release

Question 6

Describe the late events of LTP which help with its maintenance

Answer 6

• Involve structural changes
• AMPArs are anchored by scaffolding proteins such as PSD95, cadherins, and catenins
• Expression level of structural proteins at post-synaptic density (PSD) increases
• PSD95 anchors NMDARs to cytoskeleton
• Cadherins: mediate adhesion through interactions across synaptic membrane and associate with AMPARS
• Catenins: couple AMPARs to cytoskeleton; must be removed for LTD

Question 7

Describe how short term memories are stored

Answer 7

Storing short term memories: synapses between excitatory neurons start to form new circuits within seconds of the events to be remembered and increase in the strength of even a small number of synapses create a new circuit to store new memories

Question 8

Describe how memories are lost

Answer 8

Memories are lost when the release of neurotransmitters does not produce EPSPs sufficient to reach the threshold. The synapse becomes weaker and circuit may disappear entirely

Question 9

Define: place cells

what is their function?

Answer 9

Place cells: pyramidal neurons within the hippocampus; fire only when an animal is in a particular location; through stimulus exposure, can also fire in response to associated stimuli (food, lights, and touch). This means place cells can provide a link to learning and memory

Question 10

define: cerebellum

Answer 10

important for learning

Question 11

define: purkinje cells

Answer 11

necessary for well-coordinated movement. Have the capacity to learn new targets for movement

Question 12

What kind of excitatory inputs are received by purkinje cells?

Answer 12

1. powerful synaptic contact from a single climbing fiber (inferior olive)
2. synaptic input from ~150,000 parallel fibers, from the tiny granule cells of the cerebellum itself

Question 13

When do parallel fibres synapses change their strength?

Answer 13

only if theyare active at the same time as a climbing fibre

Question 14

Describe how LTD occurs in the purkinje fibers. Why is this important?

Answer 14

When the purkinje cell’s climbing fiber and the parallel fibres are coactivated, EPSPs generated by the parallel fibre become smaller (LTD)

When motor output results in failure for motor task, inferior olive nuclei sends error signal via climbing fibre to purkinje cell which makes EPSPs from parallel fibre smaller (LTD)

on the purkinje cell where the parallel fibre meets the dendritic spine, AMPAR internalization occurs

LTD is important for motor learning

Question 15

Altered LTP and LDP has been seen in the following diseases (6)

Answer 15

Schizophrenia
Alzheimer’s disease
Depression
Anxiety
Addiction
PTSD

Question 16

How is LTD and LTP thought to be involved in alzheimer’s disease

Answer 16

Theory behind cognitive decline associated with alzheimer’s disease: LTP is blocked and LTD is triggered

It is thought that AB oligomers bind to NMDARs and/or AMPARs and lead to their internalization

Loss in plasticity

Question 17

How is LTD and LTP thought to be involved in abuse of drugs?

Answer 17

• Alters synaptic plasticity in the brain’s reward circuitry leading to changes in behaviour associated with drug addiction; associated with excessive plasticity
• Drugs modulate synaptic function and plasticity in the ventral tegmental area (VTA) which is a large part of the reward system

Cocaine, amphetamines, and ecstasy target dopamine transport, directly increasing dopamine (DA)

Other drugs (opiods, THC, GHB, and BDZ) target mainly GABAergic neurons, inhibiting their activity and indirectly increasing dopamine

Classes of drugs of abuse elicit LTP by increasing the AMPAR/NMDAR ratio at glutamatergic synapses

Increase dopamine concentration in the VTA and projection areas

Question 18

Describe how CA1 pyramidal neurons have different APs from other cells

Answer 18

• Width of action potential in CA1 pyramidal neuron is larger than other neurons
• Slower to repolarize as well; may be due to some delay in potassium channels
• Wider action potentials may be due to the flux of other ions such as calcium; this may be due to dendritic calcium channels