07. Learning & Memory - Part 2 Flashcards
What is the role of NMDA in learning (LTPs)?
- Morris Water Maze task attempted with NMDA antagonist (AP5) administered in hippocampus
- No evidence of learning (or LTP)
(Morris et al., 1986)
What’s happening at the synapse (at resting potential)?
- AMPA receptor activated to create EPSP
- NMDA receptor blocked by Mg2+ ion
- Depolarisation from AMPA not sufficient to expel Mg2+
What’s happening at the synapse (depolarisation)?
- AMPA receptor activated
- Mg2+ block on NMDA relieved due to voltage increase
- Na+ moves through both channels
- Ca2+ influx through NMDA
What happens at the synapse after Ca2+ influx?
Activation of CaMKII (Yasuda et al., 2022), which…
- phosphorylates AMPA receptors (increasing their effectiveness)
- stimulates insertion of new AMPA receptors into the membrane
EPSPs therefore increase in size (long-term potentiation)
What is CaMKII?
- Calcium calmodulin-dependent protein kinase II
- A molecular switch (maintaining excitability of neurons for mins-hours)
How does it work?
- it has sustained activity after repolarisation
- it becomes phosphorylated, then no longer requires Ca2+ to stay activated
- it can then keep inserting AMPA receptors
Can presynaptic events affect LTPs?
- the postsynaptic neuron can feed back to the presynaptic neuron using Nitric Oxide (anterograde transmitter)
How does NO affect the LTP?
- Ca2+ through the NMDA channel activates Nitric oxide synthase
- NO diffuses from site of production and activates guanylyl cyclase in the presynaptic terminal
- Guanylyl cyclase produces the second messenger cGMP
- Signal transduction cascade leads to increased glutamate release from the synaptic bouton
This results in LTP being maintained (minutes - hours)
LTPs and Protein Synthesis
- protein synthesis makes an LTP last from days-months
- protein synthesis inhibitors prevent LTPs
- protein synthesis inhibitor injected just post-acquisition (of a memory) inhibits recall
What does tetanic stimulation cause?
- development of new synapses
- formation of new dendritic spines
LTP in the lab
- Uses High Frequency Stimulation (HFS) (1 sec of 100Hz = 100 stimulations per second)
- Causes increase in EPSP amplitude, strengthens synapse, and causes an AP
LTD in the lab
- Uses Low Frequency Stimulation (LFS) (100 sec of 1 Hz)
- Causes a decrease in EPSP upon further stimulation
Long Term Depression is similar to Long Term Potentiation because…
…the same receptors are involved:
- NMDA
- AMPA (but it is phosphorylated & removed from the membrane)
Long Term Depression is different to Long Term Potentiation because…
- Ca2+ activate phosphatase rather than kinase
Do we see LTP in humans?
Yes (Chen 1996)
- a human inferotemporal cortex was removed during surgery
- when stimulated it showed LTP (HFS) and LTD (LFS)
But is tetanic stimulation a good research technique?
- Potentially no
- It is an artificially high level of stimulation
What is the psychological equivalent of tetanic stimulation?
Theta rhythms (Nuñez & Buño., 2021)
- A neural oscillation (4-12 Hz)
- Roles: memory, spatial nav, coordinating neuronal networks in brain, esp. in REM sleep
When do theta rhythms occur?
- Occurs when rats run, swim, or move their heads (therefore, they affect coordination)
- Involved in arousal, alertness (they fire during exploration)
- Disruption in theta waves causes deficits in learning tasks similar to hippocampal lesions
How do theta rhythms relate to LTP and LTD?
- Depolarizing stimulation coincident with peak of theta wave generates LTP
- Depolarizing stimulation coincident with trough of theta wave generates LTD
Enhancing LTP genetically
- Increased amounts of a particular type of the NMDA receptor (NR2B receptor) leads to enhanced LTP (Tang et al., 1999)
LTP diminishing with age
- Age negatively affects LTP in rats (Clayton et al. 2002) - they have decreased acquisition in Morris Water Maze and decreased expression of NMDA receptors
Enhancing LTP with enrichment
- learning and memory deficits (Alzheimer’s disease) can be reduced by enrichment (transgenic mouse model) (Jankowsky et al., 2005)
- increases acquisition in Morris water maze
Reversal of aging effects on LTP
- Use enrichment
- Aged mice in impoverished environment (IE) show greater deficits than those in normal (SE) or enriched environment (EE)(Winocur G. 1998)
- Reintroducing to enriched environment will improve
