...is the formation of synapses. It involves axon guidance, topographic mapping, synapse formation, and synapse refinement.
Axon Guidance - As previously discussed on this blog in two parts, axon guidance involves long distance, intrinsic programs interacting with extrinsic cues. See Axon Guidance - Part One and Axon Guidance - Part Two if you want to learn some more.
Topographic Mapping - medium distance, attractive and repellent gradients. Topographic connections match behavior to the outside world. Again, we can look at Sperry's Chemoaffinity Hypothesis...each target cell carries an id tag, the growing terminals of (RGC) cells have complementary tags, and the net effect is to permit RGC axons to seek out a specific location in the target region.
Synapse Formation - short distance, contact mediated. Let's look at a specific molecule, Agrin. Agrin is a proteoglycan that plays an integral role in the development of the NMJ during embryogenesis. It also aids in the aggregation of ACh receptors during synaptogenesis. Researchers found that pre- and post-synaptic elements at the NMJ are disrupted in agrin-deficient mice. They found the exact same result in MuSK-deficient mice. Agrin does not bind directly to MuSK but it does require MuSK to cluster AChRs. Below is a figure detailing the multiple receptor signaling cascades that coordinate NMJ formation.
Synapse Refinement - near distance, activity-dependent. Let's get into the specificity. The brain favors molecular diversity; this requires synaptic elimination. Connections that are not crucial or entirely necessarily will atrophy; crucial connections will strengthen. If it's not required, it will be eliminated. Synaptic refinement is a delicate and important process. Again, it is obviously activity-dependent, and it occurs in the CNS as well. Disrupting sensory activity perturbs refinement of synaptic connections.
And like most everything in the NS, when something goes wrong, we end up with disorders. Angelman's, autism, and Fragile X are all implicated in dysregulation of synapse elimination.
Summary:
1. Synaptogenesis involves multiple steps - axon guidance, topo mapping, synapse formation, synapse refinement.
2. Maps are established by attractive and repulsive cues.
3. Synapse formation involves both adhesive and inductive signaling events.
4. Protein families involved in synaptogenesis include receptor tyrosine kinases (eg the EphRs and their ephrin ligands) and cell adhesion proteins (eg the Neuroligins and their neurexin ligands).
5. Synapse specificity arises in part from molecular diversity (intrinsic) and then is refined by activity-dependent processes (extrinsic).
6. Dysregulation of activity-dependent synapse refinement may contribute to neurodevelopmental disorders.
Axon Guidance - As previously discussed on this blog in two parts, axon guidance involves long distance, intrinsic programs interacting with extrinsic cues. See Axon Guidance - Part One and Axon Guidance - Part Two if you want to learn some more.
Topographic Mapping - medium distance, attractive and repellent gradients. Topographic connections match behavior to the outside world. Again, we can look at Sperry's Chemoaffinity Hypothesis...each target cell carries an id tag, the growing terminals of (RGC) cells have complementary tags, and the net effect is to permit RGC axons to seek out a specific location in the target region.
Synapse Formation - short distance, contact mediated. Let's look at a specific molecule, Agrin. Agrin is a proteoglycan that plays an integral role in the development of the NMJ during embryogenesis. It also aids in the aggregation of ACh receptors during synaptogenesis. Researchers found that pre- and post-synaptic elements at the NMJ are disrupted in agrin-deficient mice. They found the exact same result in MuSK-deficient mice. Agrin does not bind directly to MuSK but it does require MuSK to cluster AChRs. Below is a figure detailing the multiple receptor signaling cascades that coordinate NMJ formation. Synapse Refinement - near distance, activity-dependent. Let's get into the specificity. The brain favors molecular diversity; this requires synaptic elimination. Connections that are not crucial or entirely necessarily will atrophy; crucial connections will strengthen. If it's not required, it will be eliminated. Synaptic refinement is a delicate and important process. Again, it is obviously activity-dependent, and it occurs in the CNS as well. Disrupting sensory activity perturbs refinement of synaptic connections. And like most everything in the NS, when something goes wrong, we end up with disorders. Angelman's, autism, and Fragile X are all implicated in dysregulation of synapse elimination.
Summary:
1. Synaptogenesis involves multiple steps - axon guidance, topo mapping, synapse formation, synapse refinement.
2. Maps are established by attractive and repulsive cues.
3. Synapse formation involves both adhesive and inductive signaling events.
4. Protein families involved in synaptogenesis include receptor tyrosine kinases (eg the EphRs and their ephrin ligands) and cell adhesion proteins (eg the Neuroligins and their neurexin ligands).
5. Synapse specificity arises in part from molecular diversity (intrinsic) and then is refined by activity-dependent processes (extrinsic).
6. Dysregulation of activity-dependent synapse refinement may contribute to neurodevelopmental disorders.
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