Lecture 3 - Spatial Learning & LTP 2

Question 1

Recap

Answer 1

• how are AMPA and NMDA different?
  > both are glutamate receptor but only NMDA is permeable to calcium (via voltage gated channel)
  > NMDA is our coincidence detector
• Magnesium is released when the cell is partially depolarised (-20mv to -40mv) near the AP threshold (-55mv)
• deficiency in magnesium or calcium cause issues with LTP
  > magnesium deficiency = calcium more able to enter cell which can be bad for cells & LTP. linked to impaired memory, depression, neurodegenerative disorders, depression
  > calcium deficiency = reduced LTP but would experience hypocalcemia more broadly
• is the glutamate being released by the presynaptic cell as the post-synaptic cell is more receptive a form of positive feedback?
  > cycle of repeated activity & LTP - pos feedback
  > but pre-synaptic cell is also releasing glutamate independently of the activity of post-synaptic cell (may be enhanced through retrograde messengers)

Question 2

The discovery of LTP

Answer 2

• in 1973 Bliss & Lomo used pre-synaptic stimulation recording post-synaptic cell to the mammalian hippocampus
• found larger spike in EPSP after tetanic stimulation
• LTP is long-term (over a week or month later still high)
  phase 1: weak stimulation of pre synaptic neuron = weak response of post synaptic neuron
  phase 2: strong stimulation = strong response
  phase 3: weak stimulation = strong response

Question 3

hebbian basis of memory

Answer 3

• if the synapse is active at same time as post-synaptic cell fires (gluatamate released) synapse becomes stronger (glutamate strengthens)
• when axon of cell A is near enough to excite cell B and repeatedly or persistently take part in firing it (both active) some growth process or metabolic change takes place in one or both cells where A’s efficiency as one of the cells firing B is increased
• puff of air and tone (strong input = motor response, but tone is weak). repeated pairing = synapse strengthens so playing tone is responsive enough to glutamate and will trigger a motor response
• associative mechanism

Question 4

induction of LTP

Answer 4

• LTP most widely studied at synapses in hippocampus with many NMDA receptors (glutamate)
• NMDA works maximally when post-synaptic neuron is partially depolarised as well as glutamate binding to it

Question 5

NMDA receptor-linked channels: coincidence detectors

Answer 5

• only open in presence of nt and when post synaptic membrane is depolarised (so are both pre and post synaptic activity coincidence detector as only when post-synaptic cell depolarised through stimulation AND glutamate has been released from pre-synapse)
• they are a channel that allows ions into cells, when MG blocks channel glutamate cannot enter

1. at -70mv Mg blcoks channel
2. when cell depolarises (-40mv) Mg leaves gate and glutamate can enter and will bind to the channel
3. calcium then able to enter cell which allows changes to take place where proteins are being generated
4. NMDA receptor channel allows an influx of calcium

Question 6

How is the synapse more efficient?

Answer 6

• the induction mechanisms (NMDA receptor) is post synaptic - calcium
  > inc in AMPA receptor no. AMPAR tracking
  > protein synthesis & LT structural changes
• pre synaptic effect
  > retrograde transmitters (NO). when calcium enters and triggers caclium cascades, NO may get released and trigger the presynaptic cell to generate more glutamate
  > enhanced glutamate production & release. post-synaptic cell more able to pick this up (more sensitive to glutamate)

Question 7

summary of LTP

Answer 7

• glutamate released - binds to AMPA receptors
• pos charged ions enter
• post-synaptic depolarised (-55mv) and AP triggered
• MG+ block released from NMDA receptor
• calcium enters post-synaptic cell
• LTP:
  > inc AMPA receptors
  > structural changes (protein synthesis)
• retrograde transmitter (NO) acts on pre synaptic cell = enhanced glutamate release
• post-synaptic cell enhanced responsiveness to glutamate and easier to depolarise post synaptic cell

Question 8

Is LTP necessary for spatial learning?

Answer 8

• prediction that LTP in hipp is necessary for spatial learning
• Morris et al (1982) - water maze task is hipp dependent
• Morris (1989) - AP5 (NMDA receptor antagonist) infused into rat brains who did water maze task.
  > rats given control drug showed preference for training quadrant but AP5 rats no preference = LTP reduced in AP5 rats & not able to learn task

Question 9

AP5 and spatial learning (confounding effects to Morris 1989)

Answer 9

• Bannerman et al (1995) - AP5 led rats to become ‘wobbly’. used 2 mazes with unique extra maze cues where learning in one would not help navigate the other
  > AP5 impaired performance where there was no pretraining
  > AP5 did not impair performance when rats had pretraining
  > hippocampal lesions impaired performance even when rats had pretraining
• conc: when rats had pretraining on water maze task AP5 failed to impair hipp-dependent spatial learning. this suggests LTP in hipp may not be necessary for spatial learning

Question 10

Newer tools - genetic manipulation

Answer 10

• genetic manipulators can knock out and knock in genes
• function of NMDA receptor can be directly manipulated: deleting the gene responsible for receptor subunits
• genetic manipulations can be targeted to particular brain areas with greater accuracy than drug manipulations

Question 11

doogie mice - Nr2B overexpression

Answer 11

• Tang et al (1999) - used different approach to assess if LTP needed for learning by assessing if enhancing LTP would enhance learning
• LTP can be enhanced by inc expression of NR2B subunit of NMDA receptor (Tsien 2000) = learn faster & remember for longer
  > better MWM (faster and in correct location more
  > better object recognition & prefernece for newer object (Tang et al 1999)
  > also looked at fear conditioning: better fear member and for longer both in context and on cue
• shows overexpressing Nr2B gene enhances learning
• however knockout mice are impaired on lots of behavioural tasks that assess learning so it is not possible to see if there is selective deficit in learning

Question 12

more selective knockout

Answer 12

• what happens when NMDA recepors are knocked out in the hippocampus?
• NR1 subunit is obligatory for NMDA receptors. If NR1 subunit is knocked out there is no NMDA receptor
• Grin1ΔDGCA1 mice: dentate gyrus & CA1.

Question 13

Bannerman et al (2012) selective knockout

Answer 13

• mice trained on water maze task
• two identical beacons placed in pool. one signalled location of platform. could distinguish beacons using extramaze cues
• over trials of training mice placed in locations near incorrect beacon, correct beacon or equidistant
  > when released from point that was equidistant the knockout mice were not impaired = normal spatial learning
  > when released near incorrect beacon knockout mice made more errors = could not inhibit the response to approach the incorrect beacon
  > at end the beacons were removed and the control and knockout mice preferred quadrant of maze where platform was located
• conclusion: NMDA receptors in hippocampus are important for inhibiting responses to ambiguous cues.
• NMDA receptor dependent LTP not essential for spatial learning but play important role in spatial behaviour

Question 14

LTP and learning

Answer 14

• Gallistel and Matzel (2012) - LTP and learning are not similar
  > timing of events: LTP milliseconds, associative learning is seconds, minutes or hours
  > perisistence: LTP is long lasting but not long term, associative learning is long term
  > reacquisition: associative learning is reacquired more rapidly than initial acquisition and neural mechanisms do not match this