Synaptic Plasticity

Question 1

What is synaptic plasticity?

Answer 1

• ability of the brain to re-organise and/or create new neural pathways
• new neural pathways are adaptations to what the brains needs

Question 2

The images labelled 1-4 in the image below is a good way to visualise synaptic plasticity, why?

Answer 2

• image 1 - current neuronal pathways
• image 2 - a potential new neuronal path has developed
• image 3 and 4 - more and more use of the new path are used and the new pathway becomes embedded

Question 3

Trauma can lead to adaptive synaptic plasticity and result in changes in synaptic connectivity. What will this then go on to affect?

1. behaviour
2. emotions
3. sensory
4. co-ordination

Answer 3

1. behaviour

Question 4

What is Hebbs rule? (think hypertrophy and atrophy)

Answer 4

• if you don’t use it you will lose it
• synapses not used can be removed as not needed
• persistence/repetition is required to induce lasting cellular changes and add to its stability

Question 5

What is Hebbs cell assembly hypothesis?

Answer 5

• cells are reciprocally interconnected
• activation of the interconnected cell for long enough would provide consolidation
• these activated reciprocal connections will be more effective and neurons that fire together are wired together
• future activations requires only a small activation, but still capable of causing the whole cell to become active

Question 6

What are the 2 key rules of synaptic modification, that also rhyme?

Answer 6

1 - neurons that fire together are wired together

2 - neurons that fire out of sync lose their link

Question 7

When we consider Hebbs rule, do synaptic modifications always get stronger?

Answer 7

• no they can become weaker if not used
• neurons that fire out of sync lose their link

Question 8

When we look at rules of synaptic modification, are all individual stimulations sufficient to create an excitatory post synaptic potential?

Answer 8

• sometimes, but sometimes insufficient
• synaptic integration MUST be positive and larger than threshold

Question 9

When we look at rules of synaptic modification, if the signal to cell A and cell B fire in isolation or together what could be the possible outcomes, in relation to excitatory post synaptic potential (EPSP)?

Answer 9

• A alone - may or may not provide EPSP
• B alone - may or may not provide EPSP
• A+B together - more likely to cause EPSP than A or B alone

Question 10

When we look at rules of synaptic modification, if the signal to cell A and cell B fire together repeatably these synapse will be strengthened, what can this cause to cells A and B firing in isolation or together, in relation to excitatory post synaptic potential (EPSP)?

Answer 10

• A alone = may cause EPSP in A and B
• B alone = may cause EPSP in A and B
• essentially the strength of A+B together has trained A and B so that if either is excited they can activate the other (neurons that fire together are wired together)

Question 11

What is the connectome?

Answer 11

• complete description of the structural connectivity (the physical wiring, i.e. nerves) of an organism’s nervous system.

Question 12

Long term potentiation (LTP) (think long term weight training for synapses) is one of the key mechanisms underlying synaptic strengthening. What is LTP?

Answer 12

• a process involving persistent high frequency stimulation that strengthens synapses
• persistent strengthening leads to a long-lasting increase in signal transmission between neurons

Question 13

Synaptic plasticity and long term potentiation have been heavily linked with what 2 processes that make us human and allow us to develop that are inherently linked. The 2 key parts of the brain involved are the hippocampus and cerebral cortex. What are these 2 processes?

1. emotion and learning
2. memory and pain
3. memory and addiction
4. memory and learning

Answer 13

4. memory and learning

Question 14

Synaptic plasticity and long term potentiation have been heavily linked with learning and memory. How can long term changes be measured in humans that can confirm plasticity?

1. increased IQ
2. better memory
3. modified gene expression and peptide turnover
4. modified expression of EMG

Answer 14

3. modified gene expression and peptide turnover

Question 15

What is a tetanic stimulus?

1. low frequency sequence of individual stimulation of a neuron
2. low frequency sequence stimulation of multiple neurons
3. high frequency stimulation of a neuron
4. high frequency sequence stimulation of multiple neurons

Answer 15

3. high frequency stimulation of a neuron

Question 16

A tetanic stimulus is a high-frequency stimulation (HFS) of an individual neuron. How long can one and multiple HFS last for?

1. one = seconds to minutes, multiple = minutes to hours
2. one = hours, multiple = days
3. one = days, multiple = days to months
4. one = weeks, multiple = months to years

Answer 16

3. one = days, multiple = days to months

Question 17

In an inactive cell, what is the activation pathway of the ionotropic ligand gated glutamate receptors AMPA and NMDA?

Answer 17

Inactive cell (resting membrane potential)

• glutamate binds to AMPA receptor, creating an excitatory postsynaptic potential (EPSP)
• NMDA receptor remains blocked by Mg²⁺ ion

Question 18

Once the ionotropic ligand gated AMPA receptor has caused depolarisation through binding with glutamate, what is the activation pathway of the glutamate receptor NMDA?

Answer 18

• AMPA receptor activated by glutamate causing depolarisation
• glutamate and glycine bind to NMDA receptor
• Mg²⁺ blockage of NMDA is removed
• Na⁺ passes through AMPA and NMDA channels causing depolarisation
• Ca²⁺ passes through NMDA receptor causing depolarisation

Question 19

What is a key cation that is involved in the glutamate pathway, that is able to pass through NMDA receptors in the ‘wind up’ phase following continued and strengthening of glutamate binding with AMPA receptors that ultimately will remove the Mg²⁺ blockage on the NMDA receptor has been suggested to be involved in learning and memory?

1. Na+
2. K+
3. Mg+
4. Ca2+

Answer 19

4 . Ca2+

Question 20

Once Ca²⁺ enters the cell through the NMDA receptor during ‘wind up’ (neuronal responses to repetitive electrical stimulation), what are the 2 key secondary messengers that become activated in the glutamate pathway? (think Gaq GPCR)

Answer 20

1. protein kinase C
2. calcium calmodulin-dependent protein kinase II (CaMKII)

Question 21

Once Ca2+ enters the cell through the NMDA receptor during ‘wind up’ (neuronal responses to repetitive electrical stimulation), the Gaq intracellular pathway begins with increased levels of secondary messengers protein kinase C (PKc) and Calcium calmodulin-dependent protein kinase II (CaMKII). These 2 key secondary messengers PKc and CaMKII are then able to perform 2 key functions in relation to AMPA receptors, what are these?

Note:

• kinases remove phosphate from high energy yielding molecule and add phosphate to another molecule and is called phosphorylation (on/off switch for intracellular proteins)

Answer 21

1 - phosphorylates existing AMPA receptors, increasing effectiveness

2 - stimulates insertion of new AMPA receptors into the membrane

INCREASED AMPA RECEPTOR EFFICACY AND NUMBER OF AMPA RECEPTORS CAUSES FURTHER EXCITATORY POST SYNAPTIC POTENTIAL

Question 22

What does autocatalytic activity mean?

Answer 22

• a molecule that once it becomes activated becomes free from Ca²⁺ and can continue phosphorylation alone

Question 23

Calcium calmodulin-dependent protein kinase II (CaMKII) has autocatalytic activity, which means that once it has been phosphorylated by Ca²⁺ it becomes constitutively active (no longer needs Ca²⁺). What 2 things can this do to glutamate AMPA receptors and excitability of neurons?

Answer 23

1 - maintain phosphorylation of AMPA receptors even after depolarisation has ended

2 - molecular switch that is able to maintain excitability of neurons for minutes or hours, essentially a form of long term potentiation

Question 24

What does molecular switch mean?

1. ability of a molecule able to turn other molecules on or off
2. a molecules that shares similarity to another molecule
3. molecule that can be reversibly shifted between two or more stable states
4. molecule that cannot be turned off once activated

Answer 24

3. molecule that can be reversibly shifted between two or more stable states

• • Calcium calmodulin-dependent protein kinase II (CaMKII) is inactive, but once Ca²⁺ causes CaMKII to become phosphorylated it is switched on regardless of Ca²⁺
• demonstration of how CaMKII can switch between 2 stable states

Question 25

Long term potentiation (LTP) can be categorised into 2 categories that are associated with memory, what are they? 1. acute and chronic LTP 2. early and late phase LTP 3. cytotoxic and adaptive LTP 4. enhanced and dangerous LTP

Answer 25

2. early and late phase LTP * early phase LTP = minutes to hours ( short term/working memory) * long phase LTP = hours, days or months (long term memory)

Question 26

Long term potentiation (LTP) can be categorised into 2 categories, early or late phase. Early phase LTP can last minutes to hours. What drives this LTP? 1. Ca²⁺ binding to AMPA 2. Na+ binding to AMPA 3. K+ binding to NMDA 4. higher concentrations of glutamate

Answer 26

1. Ca²⁺ binding to AMPA - Ca²⁺ binds AMPA causing subsequent events - involved in working memory, but continued potentiation can develop into long term memory

Question 27

Long term potentiation (LTP) can be categorised into 2 categories, early or late phase. Late phase LTP can last hours, days or even months. What 2 secondary messengers that have autocatalytic activity and flip the molecular switch that drives the late phase LTP? 1. PKa and cAMP 2. PKa and CaMKII 3. PKc and CaMKII 4. PKc and cAMP * PKc = protein kinase C * PKa = protein kinase A * CaMKII = Calcium calmodulin-dependent protein kinase II

Answer 27

3. PKc and CaMKII

Question 28

Long term potentiation (LTP) can be categorised into 2 categories, early or late phase. Late phase LTP can last hours, days or even months and is driven by PKc and CaMKII that once activated by Ca2+ flip the molecular switch that drives the late phase LTP. In order for the neurone to sustain the LTP, what is needed in the neuron? 1. increased number of AMPA and NMDA receptors 2. new protein synthesis and morphological changes forming new synapses 3. increased sensitivity of AMPA and NMDA receptors 4. new AMPA receptors that are able to bind with more glutamate * PKc = protein kinase C * CaMKII = Calcium calmodulin-dependent protein kinase II

Answer 28

2. new protein synthesis and morphological changes forming new synapses

Question 29

Once Protein kinase C and Calcium calmodulin-dependent protein kinase II (CaMKII) have been phosphorylated, CaMKII is able to activate a precursor that is involved in the pre-synaptic feedback. What is this precursor? 1. arganine 2. glutamine 3. dopamine 4. serotonin

Answer 29

1. arganine - arganine is turned into nitric oxide (NO) which influences glutamate release at the pre-synapse

Question 30

Once Protein kinase C and Calcium calmodulin-dependent protein kinase II (CaMKII) have been phosphorylated due to the release of Ca²⁺, CaMKII is able to activate arganine, which is then turned into nitric oxide (NO). What role does NO have on glutamate pathway at the pre-synapse? 1. binds directly with vesicles containing glutamate, increases pre-synaptic release 2. NO becomes a second messenger, travels to pre-synapse increasing pre-synaptic release 3. binds to Ca2+ channels in pre-synapse, increasing glutamate vesicles fusing with membrane 4. NO inhibits glutamate release

Answer 30

2. NO becomes a second messenger, travels to pre-synapse increasing pre-synaptic release

Question 31

What is excitotoxicity?

Answer 31

- toxic effects of excitatory neurotransmitters - can cause neuronal dysfunction or cell death - this can happen in chronic stress where cortisol stimulate hippocampus releasing Ca2+ and damaging the hippocampus

Question 32

The activation pathway for NMDA glutamate receptors is activated by increased long term potentiation (LTP) of AMPA and the binding of glutamate and glycine at the NMDA receptors. Ultimately this leads to Na+ passing through AMPA and NMDA channels and then Ca2+ passes through NMDA receptor, which ultimately leads to phosphorylation of protein kinase C and Calcium calmodulin-dependent protein kinase II (CaMKII). In addition to causing synaptic plasticity, this may have detrimental effects?

Answer 32

- can be dangerous - overstimulation of neurotransmitters causes excitotoxicity - caused by Ca²⁺ overload

Question 33

Long term depression (LTD) relates to an activity dependent reduction in the efficacy of neuronal synapses that can last hours or longer. This can be beneficial in learning a new skill and form implicit, non-declarative memories. For example when we learn a new skill like riding a bike, the cerebellum constantly modifies the movements until we get the skill correct. Synapses that lead to errors will undergo LTD as they are not useful. How can lLTD affect AMPA receptors?

Answer 33

* - pre-synapse receives low frequency stimulation (LFS), meaning low glutamate release * - LFS leads to decreased glutamate release and reduced excitatory postsynaptic potential through AMPA receptors * - AMPA receptors undergo de-phosphorylation and reduced efficacy or they can be removed from the membranes as they are not needed * NEURONS THAT FIRE OUT OF SYNC WILL LOSE THEIR LINK

Question 34

Which part of the brain has been linked with long term potentiation (LTP) and spatial learning, and which receptor has this been associated with? 1. glutamate (NMDA receptor) in thalamus 2. glutamine (AMPA receptor) in hippocampus 3. glutamate (NMDA receptor) in hippocampus 4. glutamate (AMPA receptor) in hippocampus

Answer 34

3. glutamate (NMDA receptor) in hippocampus - drug AP5 has been shown to inhibit NMDA and impair learning through reduced LTP - rat study in image show how important LTP of NMDA receptors in the hippocampus is

Question 35

Glutamate in the hippocampus is important for long term potentiation of NMDA receptors in the hippocampus and contributes to learning and memory. What effect does alcohol have on the NMDA pathway? 1. acts as a partial antagonist and increases the sensitivity of the pathway 2. acts as an antagonist, inhibiting NMDA receptors 3. acts as an antagonist causing long term depression of AMPA receptors 4. inhibits AMPA receptors

Answer 35

2. acts as an antagonist and inhibition of NMDA receptors - linked with blackouts and amnesia

Question 36

What are Benzodiazepines?

Answer 36

- are a type of sedative medication (calm, drowsiness and sleep) - facilitating the binding of the inhibitory neurotransmitter GABA at various GABA receptors throughout the CNS

Question 37

Benzodiazepines have been linked with anterograde amnesia (difficulty remembering new information), how could this occur?

Answer 37

- Benzodiazepines facilitate the binding of the inhibitory neurotransmitter GABA at various GABA receptors throughout the CNS - GABA increases Cl- and reduces action potentials which slows neuronal activity down - short term/working memories may not get stored in long term memories

Question 38

Cholinergic / Anti-cholinergics are drugs that act on the nicotinic and muscarinic receptors in the body or inhibit them, respectively. What effect may these drugs have on learning?

Answer 38

- muscarinic antagonist seems to impair spatial learning - acetylcholinesterase inhibitors increase levels of ACh and have been linked with improvements in alzheimers

Question 39

Smoking has been linked with synaptic plasticity, how?

Answer 39

- smokers have been shown to have increased levels of nicotinic receptors in the brain - effects of smoking appears to activate nicotinic receptors - smoking activates nicotinic receptors causing LTP that can last hours, days or months, which could be good just when you are about to learn something