1. NEUROPLASTICITY AND NEURODEGENERATIONAdapted from Steven Stahl, MD, PHD
2. Synaptic development and synaptic neurotransmission.• Neurodevelopment• Neuronal selection• Neuronal migration• Synaptogenesis• Competitive elimination
3. Time course of neurodevelopment
4. Overview of Neurodevelopment
5. Neurogenesis also occurs in adult life• In adult life neurogenesis occurs in only two areas of the brain:• in the dentate nucleus of the hyppocampus and in the olfactory bulb.
6. Adult Neurogenesis in the hippocampus
7. Synapse loss and restoration• Stress, aging and neurodegeneration can cause loss of the synapse with or without neuronal loss.• Learning, exercise, growth factors, antidepressants and psychotherapy cause restoration of the synapse and of neurons.• Transplantation of stem cells is another way to restore the neurons or the synapses.
8. Growth Factors (promote neuronal restoration)
9. Necrosis vs. Apoptosis• In necrosis neurons are being destroyed by suffocation or toxins/poisons(neuronal assassination).• In apoptosis neurons are being destroyed by the activation of a gene inside the cell’s DNA(neuronal suicide).
10. Neuronal death(necrosis vs. apoptosis)
11. Neurodevelopment• During neurodevelopment, neurons are formed in excess (some are normal and some are defective) then they are selected for performing their duties.• The defective neurons are eliminated.• In developmental disorders the defective neurons may be selected leading to a neurologic or psychiatric condition.
12. Neuronal Selection during neurodevelopment
13. Neuronal Migration• After neurons are selected, they must migrate to the right parts of the brain.• In order to migrate, neurons trace either glial cells or the neurons that already migrated.• Migration is helped by adhesion molecules on the neuronal surfaces and complementary molecules on the glia.• If migration is successful, the neurons are properly aligned to grow, develop and form synapses.
14. Good migration vs. defective migration
15. Proper migration requires recognition and adhesion molecules
16. Synaptogenesis• Synaptogenesis is directed by neurotrophins.• Neurotrophins are molecules that cause neurons to sprout an axonal growth cone.• Once the growth cone is formed the neurons and glia in the area make recognition molecules that can be ATTRACTIVE or REPULSIVE.• Repulsive neurotrophins cause the neurons to grow away from them, while attractive neurotrophins cause the neurons to grow towards them.
17. Attractive and Repulsive neurotrophins
18. Axonal growth cone “docking”
19. Dendritic growth• Just like the axons, dendritic growth is controlled by growth factors that promote branching of the dendritic tree.
20. Insufficient dendritic arborizationleads to defective synaptogenesis.
21. Formation of a Synapse• Presynaptic axons contain some of the molecular components necessary to form a synaptic connection even before making contact with a postsynaptic site.• A synapse is formed in stages:
22. Stage 1 - Hemisynapse
23. Stage 2(obtaining supplies)
24. Stage 3 (extracellular scaffolding)
25. Stage 4 (intracellular scaffolding)
26. Stage 5 (adding elements)
27. Long term potentiationFrequent utilization of synapse leads to:• increased flexibility of the postsynaptic site,• Increased neurotransmitter release• postsynaptic receptors increase in number• surface area of the postsynaptic neuron increases• adjacent postsynaptic sites form
28. Utilization of a synapse increases its flexibility
29. Released neurotransmitters strengthen the synapse
30. Adjacent synapses form in thepresynaptic and postsynaptic neurons
31. Dendritic pruningThe dendritic tree is constantly changing throughout life, it can:• sprout new branches, grow and establish synaptic connections when necessary• trims, alter or destroy synaptic connections when necessary (pruning)
32. Normal pruning
33. Abnormal pruning(in degenerative diseases)
34. Out of control neurotransmission• Can increase the intracellular calcium which• can lead to dendritic death and• even cell death.
35. Abnormal dendritic pruning due to increased neurotransmission
36. Competitive Elimination• Between birth and age 6 synapses are formed at an accelerated rate• During adolescence competitive elimination (pruning) occurs destroying about 50% of the synapses.
37. Competitive Elimination of synapses in adolescence