Summary

1. In unicellular organisms, calcium regulators like calmodulin, and transmembrane proteins such as kinases and G proteins that serve as environmental sensors, provided evolutionary precursors for components of postsynaptic responses in metazoans. Primitive metazoans like sponges use adhesive molecules such as cadherins, which were exploited by later-arising species for selective formation of synapses. See Figure 6.1
2. The basic machinery of neurotransmitter release and reception, including GABA and glutamate receptors, is found in all species with a nervous system, including jellyfish. A great leap in nervous system complexity after our common ancestor with insects was the duplication of neurotransmitter receptor genes, followed by divergence that led to a greater variety of receptors for a given transmitter. See Figure 6.2
3. Synapses consist of (1) a presynaptic terminal with synaptic vesicles near an active zone to fuse vesicles with the membrane to release neurotransmitter into (2) the synaptic cleft, filled with extracellular matrix (ECM) of long-chain molecules to retain chemical signals, and (3) the postsynaptic region, including postsynaptic densities (PSDs) to detect neurotransmitter and trigger changes in the postsynaptic cell.
4. Synapses mature in stages, including (1) the initial contact where adhesive molecules favor certain connections and discourage others, (2) the assembly of synaptic machinery to increase the magnitude of synaptic transmission, and (3) the stabilization and maturation of synapses to provide more rapid, crisp synaptic transmission. See Figure 6.3
5. Many adhesive molecules, including cadherins, NCAM, and the ephrins, maintain some initial synaptic connections while discouraging others. There are over 100 different protocadherins, which preferentially adhere to each other (homophilic binding), enabling a very specific range of synaptic preferences. Nonpreferred connections tend to detach rather than mature further. When the extracellular domain of a cadherin molecule is bound, the intracellular domain binds to β-catenin, which also binds to actin in the cell’s cytoskeleton, anchoring the assembly in place. Neighboring postsynaptic regions may compete for β-catenin, and therefore for survival. See Figures 6.4 and 6.5
6. Fragile X syndrome is caused by an excess of trinucleotide repeats, which reduces the ability of the protein product to suppress transcription. Thus overall production of brain proteins is increased and an excess of synapses is seen, which seems to cause mental impairment. See Figure 6.6
7. Once appropriate pre- and postsynaptic partners are in contact, presynaptic neurexins bind to postsynaptic neuroligins to induce assembly of synaptic machinery in each. Activation of neurexin in the presynaptic terminal triggers construction of an active zone of vesicles and synaptic release proteins, including SNAREs and synaptotagmin. See Figures 6.7 and 6.9
8. Activation of neuroligin in the target cell triggers construction of a PSD of scaffolding proteins linked to neurotransmitter receptors and cytoskeletal elements, anchoring the region on the cell’s surface. See Figure 6.8
9. Neuromuscular junctions (NMJs) in vertebrates form when motor neuronal growth cones releasing acetylcholine (ACh) contact myotubes that are already producing ACh receptors (AChRs) in random clumps. See Figures 6.10 and 6.11
10. Motor neuronally released agrin induces existing AChRs in the muscle to aggregate under the nerve terminal. Agrin binds together molecules of muscle-specific kinase (MuSK) and LRP4 in the muscle fiber, resulting in autophosphorylation of MuSK. The phosphorylated intracellular domain of MuSK activates the intracellular protein rapsyn, which also binds the internal portion of AChRs, lashing many receptors together. Rapsyn also binds the muscle cytoskeleton to hold the flotilla of receptors in place. See Figure 6.12
11. Muscle AChRs that are not stabilized by the agrin-induced complex of rapsyn are quickly internalized, a process facilitated when the muscle is electrically active, thereby reducing the half-life of extrajunctional receptors. See Figure 6.13
12. Motor neuronally released neuregulins bind to ErbB receptors in muscle to boost expression of AChR subunits in the target, specifically in the muscle’s subsynaptic nuclei. Motor neuronal neuregulins also contact terminal Schwann cells to promote their differentiation and survival. See Figure 6.13
The basal lamina in the region of the NMJ retains long-chain molecules such as synapse-specific laminin (β2-laminin), which serve to guide regenerating axon terminals and muscle AChRs back to the original synaptic site. See Figure 6.14
13. Both voltage-gated and ligand-gated ion channels change subunit composition, and therefore physiological function, during development. Generally this results in slow, sluggish synaptic responses becoming more rapid and brief. See Figures 6.15, 6.16, and 6.18
14. GABA and glycine receptors that are almost always inhibitory in adult neurons are usually excitatory in the developing brain because the potassium-chloride cotransporter to reduce intracellular Cl^– levels is not yet fully expressed. See Figure 6.17
15. Axonal expression of neuregulin induces Schwann cells to form myelin sheaths in a dose-dependent manner, so axons expressing high neuregulin receive a thick sheath while those expressing less neuregulin receive a thinner sheath. Something similar is probably at work inducing oligodendrocytes to form myelin in the CNS. See Figure 6.19
16. Surviving oligodendrocytes repel growth cones, which may contribute to the limited ability for axons to regenerate in the adult CNS. Multiple sclerosis is caused by autoimmune attack of myelin components in the CNS. See Figures 6.20 and 6.21