Neurotrophic Factors and Cell Death

Neurotrophic Factors and Regulation of Cell Death

• Lecture 13 focuses on neurotrophic factors, their mechanisms, and programmed cell death (PCD).

The Neurotrophin Family

• The neurotrophin family in mammals includes NGF, BDNF, NT-3, and NT-4.
• NGF supports the survival of sympathetic ganglia, certain dorsal root ganglia (DRG) neurons involved in nociception, and cholinergic neurons in the basal forebrain.
• BDNF (Brain-Derived Neurotrophic Factor) plays a role in the survival and function of various CNS neurons, vestibular ganglion neurons, and DRG mechanoreceptors.
• NT-3 (Neurotrophin-3) is important for the survival of many CNS neurons, cochlear ganglion neurons, and DRG proprioceptive neurons.
• NT-4 (Neurotrophin-4) supports the survival of various CNS neurons and other ganglia.
• Each neurotrophin interacts with receptor tyrosine kinases (Trks).
  • TrkA has a high affinity for NGF.
  • TrkB has a high affinity for BDNF and NT-4.
  • TrkC has a high affinity for NT-3.
• Neurotrophin-Trk interactions are crucial for the selective survival of distinct neuronal populations during development.
• P75NTR low affinity can promote cell death; removal of p75 may result in survival or cell death.

Beyond Neurotrophins

• Cytokines and GDNF are other factors that contribute to neuronal survival.
• CNTF (ciliary neurotrophic factor) supports motoneuron survival, autonomic neurons, DRG neurons, and hippocampal neurons.
• GDNF (glial cell line-derived neurotrophic factor) is crucial for midbrain dopaminergic neuron survival, which are affected in Parkinson's disease

Neurotrophic Factors - More Than Just Survival

• Target-derived NGF is necessary for the formation of postsynaptic specializations on the dendrites of sympathetic neurons.
• Retrograde NGF signaling regulates the connectivity of sympathetic neurons by promoting the selective maintenance of appropriate synapses.

p75NTR: A Receptor with Dual Roles

• Neurotrophins interact with p75NTR which has a lower affinity than Trks.
• P75NTR can mediate both cell survival and cell death.
• The ratio of TrkA to p75NTR determines whether NGF promotes survival or death in a neuron i.e. high ratios favor survival, low ratios favor death.

Punishment Signals: Accelerating Cell Death

• Punishment signals intensify competition for neurotrophic factors and accelerate the death of neurons lacking trophic support.

Apoptosis: A Closer Look

• Caspases dismantle cellular components during apoptosis where activated extrinsic/intrinsic trigger initiation caspase, Casp8 and casp9, lead to execution caspases 3,6,7..
• Apoptosis is regulated by both extrinsic (external signals) and intrinsic (internal stress) pathways

Microglia: The Cleanup Crew

• Microglia are the brain's resident immune cells that clear cellular debris after apoptosis to prevent inflammation and damage.

Beyond Target-Derived Survival Cues

• Afferent innervation, synaptic activity, and hormones influence neuronal survival in the CNS.
• Ablating the cochlea (removing auditory input) leads to cell death in the auditory brainstem.
• Neuronal activity, particularly NMDA receptor activation, promotes neuronal survival.
• Hormones like testosterone regulate neuronal survival, contributing to sex differences in brain structure and function.

Reasons For Cell Death: Revisited

• Woodworker Assumption: Eliminating excess neurons is more efficient than generating the exact required number.
• Removal of Non-Functional Cells: Neurons with incorrect connections or those failing to integrate into functional circuits are eliminated.
• Systems Matching: Programmed cell death (PCD) ensures appropriate size ratios between interconnected neuronal populations.
• Removal of Transient Structures: Some neurons are necessary only transiently during development and are then removed.
• Removal of Harmful Cells: Damaged or dysfunctional neurons are eliminated to prevent further harm.

Summary: A Complex Interplay of Life and Death

• The neurotrophin family consists of multiple factors supporting specific neuronal populations.
• Neurotrophins act through Trk receptors and p75NTR, with the latter mediating both survival and death.
• Neurotrophins influence not only survival but also synapse formation and connectivity.
• Apoptosis is executed by caspases and regulated by complex signaling pathways.
• Microglia clear apoptotic cells, preventing inflammation.
• Neuronal survival is influenced by afferent input, synaptic activity, and hormones.
• PCD is crucial for various aspects of nervous system development, ensuring the formation of functional circuits.

Chemical Synapses

• Chemical synapses can be inhibitory or excitatory.
• The growth cone becomes the synaptic terminal and identifies the target to mature to the presynaptic side.