1. Long term potentiation and depression
Domina Petric, MD 1

2. Plasticity It is capacity of the nervous system to change.
Plasticity can be short term (seconds to minutes) or long term (minutes to day to life-time).

3. Plasticity occurs at: within the structure and function of neuron
synapses
within the structure and function of neuron
within glial cells (astrocytes)

4. Plasticity
Plasticity affects the structure and function of neural circuits and systems.
Plasticity affects the organization of functional representations (cortical maps).

5. Plasticity is the basis of:
memory
acquisition of motor skills
acquisition of cognitive skills (learning, language...)
adaptation and recovery from injury or disability

6. Cellular mechanisms of synaptic plasticity
Neural activity triggers the activation of postsynaptic, second messenger systems.
Trigger is usually an alteration in the level of intracellular calcium in the postsynaptic neuron.

7. Cellular mechanisms of synaptic plasticity
Calcium-dependent second messenger systems alter the activity of :
protein kinases (phosphorylate target proteins)
phosphatases (dephosphorylate target proteins)

8. Plasticity
Alterations in protein phosphorylation mediate the early stages of long-term synaptic plasticity.

9. LTP (long term potentiation)
Specificity
Associativity
In order for a pathway to be potentiated, it must be active.
If the weak pathway is concurrently activated with a strong pathway then the weak pathway is strengthened (the weak synapse can be potentiated).

10. LTP and silent synapses
Silent synapse is a synapse that might be capable of function, but it lacks AMPA glutamate receptors.
In developing brain there are silent synapses with NMDA glutamate receptors and not enough AMPA receptors for normal function of synapse.

11. LTP and silent synapses
In the presence of stimulations that can induce LTP there is insertion of AMPA receptors close to the NMDA receptors.
LTP awakens silent synapse that turns to functional synapse that contains both AMPA glutamate and NMDA glutamate receptors.

12. AMPA and NMDA receptors
AMPA glutamate receptors can respond to a milder postsynaptic depolarisation, but NMDA glutamate receptors respond only to significant depolarisation, strong enough to evacuate magnesium ions that block the opening of the channel.

13. LTP

14. LTD (long term depression)
When there is a period of low frequency stimulation, there is a 50% decrease in synaptic strength and even more decrease during a long period of time.

15. LTD
When there is slower and lower level increase in postsynaptic calcium, protein phosphatases are activated.
Protein phosphatases dephosphorylate target proteins.
(In LTP higher level increase in postsynaptic calcium activates protein kinases that phosphorylate target proteins.)

16. LTD
Activation of protein phosphatases leads to the internalisation of AMPA receptors (AMPA receptors are removed).
Activation of protein kinases in LTP leads to the mobilisation of new AMPA receptors.

17. LTD in the cerebellum Brittanica.com
The principal cell in the cerebellum is the Purkinje cell.

18. LTD in the cerebellum
Main synapse in the cerebellum is the synapse between the parallel fiber and Purkinje cell.
Climbing fibres (axons) from Inferior olivary nucleus make also a very important and strong synaptic connection with the dendrites of the Purkinje cell.
The strongest known synapse in the human CNS.

19. LTD in the cerebellum
The pairing of the activity between the climbing fiber and the parallel fiber is what causes the depression in the strength of the connection between the parallel fiber and Purkinje cell.

20. LTD in the cerebellum
In the synapse between parallel fiber and Purkinje cell there are AMPA glutamate receptors and metabotropic glutamate receptors (mGluR).
Climbing fibers open voltage gated calcium channels in the Purkinje cells dendrites.

21. LTD in the cerebellum
Because of a sudden and high-level rise of intracellular calcium in dendrites there is internalisation of AMPA receptors.
In the cerebellum protein kinase C phosphorylates target proteins that leads to the internalisation of AMPA glutamate receptors and LTD.

22. Role of calcium levels
In the cerebral cortex high levels of calcium lead to long term potentiation, BUT in the cerebellar cortex high levels of calcium lead to long term depression.

23. Literature
Leonard E. White, PhD, Duke University
Brittanica.com