NEUROPLASTICITY AND NEURODEGENERATION

Adapted from Steven Stahl, MD, PHD

• Neurodevelopment• Neuronal selection• Neuronal migration• Synaptogenesis• Competitive elimination

Synaptic development and synaptic neurotransmission.

Time course of neurodevelopment

Overview of Neurodevelopment

• In adult life neurogenesis occurs in only two areas of the brain:

• in the dentate nucleus of the hyppocampus and in the olfactory bulb.

Neurogenesis also occurs in adult life

Learning, exercise,endogenous growth factors, psychotherapy and antidepressants

Adult Neurogenesis in the hippocampus

• 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.

Synapse loss and restoration

Growth Factors (promote neuronal restoration)

• 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).

Necrosis vs. Apoptosis

Neuronal death (necrosis vs. apoptosis)

• 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.

Neurodevelopment

Neuronal Selection during neurodevelopment

• 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.

Neuronal Migration

Good migration vs. defective migration

Proper migration requires recognition and adhesion molecules

• 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.

Synaptogenesis

Attractive and Repulsive neurotrophins

Axonal growth cone “docking”

• Just like the axons, dendritic growth is controlled by growth factors that promote branching of the dendritic tree.

Dendritic growth

Insufficient dendritic arborization leads to defective synaptogenesis.

• 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:

Formation of a Synapse

Stage 1 - Hemisynapse

Stage 2(obtaining supplies)

Stage 3 (extracellular scaffolding)

Stage 4 (intracellular scaffolding)

Stage 5 (adding elements)

Frequent 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

Long term potentiation

Utilization of a synapse increases its flexibility

Released neurotransmitters strengthen the synapse

Adjacent synapses form in the presynaptic and postsynaptic neurons

The 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)

Dendritic pruning

Normal pruning

Abnormal pruning(in degenerative diseases)

• Can increase the intracellular calcium which• can lead to dendritic death and• even cell death.

Out of control neurotransmission

Abnormal dendritic pruning due to increased neurotransmission

• Between birth and age 6 synapses are formed at an accelerated rate

• During adolescence competitive elimination (pruning) occurs destroying about 50% of the synapses.

Competitive Elimination

Competitive Elimination of synapses in adolescence