Chapter 8 11/1/2012. Synaptic Components are Ancient. Syncytium or Synapses? Synapse Formation and Function. Early Calcium Spikes

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1 Chapter 8 Synaptic Components are Ancient Synapse Formation and Function Fig 8.1 Syncytium or Synapses? Electrical Development Synapses Improve in Function with Time Fig 8.2 Fig 8.3 Early Calcium Spikes Ca++ Decline of low threshold T Ca++ currents, increase of high threshold L and N Ca++ currents Na+ /Ca++ Na+ Fig 8.4 Fig 8.5 1

2 Morphological Development Morphological Development Fig 8.7 Fig 8.8 Development of Isolated Terminals Decreasing Cell Density Corresponds to Increasing Synaptic Density Fig 8.9 Fig 8.10 Sniffing for Synaptic Function: Spontaneous Ach release Vesicle release in growth cones Fig 8.11 Fig

3 Ca ++ -sensitive dye ratiometric imaging Contact-mediated ACh release increases with time Myoball of Sema3A and Netrin-1 have opposing effects on growth cone membrane potential Contact-mediated increases in Ca ++ likely affect actin polymerization and maturation Fig 8.13 Fig 8.14 Intracellular Extracellular Intracellular Adhesion between growth cones and target cells mediated by SynCAMs Cadherins connect indirectly to actin filaments and may mediate synaptic specificity Fig 8.15 Fig 8.16 Stop signal on contact Post-contact changes: recruitment of active zones (presynaptic release site proteins) and postsynaptic sites. Either side can initiate synaptogenesis New release site Molecular components at synapses Nlgn-Nrxn binding initiates presynaptic differentiation Synaptobrevin = Fig 8.17 Fig

4 Synaptogenesis in C. elegans AChR clustering at the NMJ: Partially input-dependent Induction of presynaptic site by epithelial cells (SYG-2 to SYG- 1) or glial cells (netrin/unc-6 to netrin receptor unc-40) Fig 8.19 Fig 8.20 Contact between nerve fibers and muscle cells induces AChR clustering The clustering signal is secreted by the neuron into the ECM and survives degeneration of the muscle following nerve damage. Fig 8.21 Fig 8.22 Agrin-MuSK signaling is necessary to align AChRs with the motor neuron terminals EphB receptor function is necessary and sufficient for GluR clustering Fig 8.23 Fig

5 Assay for GluR clusters: Even if action potentials are blocked with TTX or if glutamate receptors are pharmacologically blocked for 10 days of culturing in vitro, clustering of AMPAR occurs Synaptic Scaffold Components Fig 8.25 Fig 8.26 Scaffold components at inhibitory synapses Innervation triggers insertion of new AChRs Fig 8.27 Fig 8.28 AMPARs are synthesized locally Clustering is activity-dependent Fig 8.29 Fig

6 Competition between Agrin-MuSK signaling and ACh-AChR signaling may regulate clustering Old View Two Models New View Fig 8.31 Previous (a) and new (b) views of neuromuscular synaptogenesis. (a)(i) Numerous in vitro and in vivo observations suggested that nerves initiate postsynaptic development, rather than innervating spontaneously formed AChR clusters (red). The central location of the intramuscular nerve thus explained the localization of NMJs to the central endplate band. (ii) In this model, spontaneous AChR clusters subsequently disappear and (iii) nerveinduced clusters grow and (iv) topologically mature as directed by the developing nerve terminal arbor, thus ensuring pre- and post-synaptic matching. (b)(v) New observations reviewed here suggest that muscles pre-pattern AChRs independently of the ingrowing nerve. (vi) At least in some cases the nerve incorporates initially aneural clusters into NMJs, (iii) dispersing uninnervated clusters and remodeling innervated clusters to refine pre- and postsynaptic alignment. (iv) Formation of pretzel-shaped postsynaptic sites can occur nerve-independently in vitro, suggesting that some aspects of synaptic maturation might also be muscle-driven. (Kummer et al., Current Opinion in Neurobiology 2006, 16:74 82) Activity regulates AMPAR distribution GluR activity increases Arc, leading to AMPAR internalization Fig 8.32 Fig 8.33 PSPs get shorter with time Receptor subunit composition can change Fig 8.34 Gradual maturation Fig

7 GlyR are immature at birth, and subunit substitution leads to maturation GABAR subunit distribution changes with development Fig 8.36 Fig 8.37 Mature NMDARs have shorter open times Plasticity is more easily evoked in young animals Fig 8.38 Fig 8.39 GABA currents are depolarizing early in development Fig

8 Maturation of Currents Fig 8.6 8