Activity Dependence of Synapse Assembly and Growth

Synaptic activity plays a crucial role in shaping the Drosophila NMJ and has recently been implicated in shaping the C. elegans NMJ as well. In Drosophila, synaptic activity influences synaptic connectivity, size, and functional homeostasis3. Hyperexcitable and hypoexcitable mutants display abnormal axon and synapse morphology. For example, hyperexcitable Shaker (Sh) and ether a gogo (eag) mutants synthetically interact to cause an increase in the number of higher-order axonal branches and synaptic swellings on the neurites93. This effect is mediated by presynaptic changes in excitability. Drosophila glutamate receptors preferentially cluster opposite the largest and most physiologically active sites94. Elevated expression of muscle glutamate receptors leads to significant NMJ

expansion94'95. These results suggest retrograde control of motor neuron growth is influenced by synaptic receptor activation. Presynaptic effects on postsynaptic glutamate receptor activity require the activity of Wit, mediated through Ca2+/calmodulin-dependent protein kinase II (CaMKII)96. CaMKII is regulated by activity-dependent calcium changes, and thus may provide an additional mechanism for activity-dependent NMJ changes. Localization of DLG and Fas II to the NMJ is regulated by the activity of CaMKII97. Whether synaptic excitability affects the NMJ via these signaling molecules has yet to be examined.

Fas II and the cAMP Response Element-Binding Protein (CREB) modulate activity-dependent NMJ changes98. Increased activity causes an increase in cAMP levels that leads to a reduction of Fas II and a concurrent increase of CREB activity. Decreased Fas II levels promote expansion of the NMJ. Transcription of CREB responsive genes ultimately increases neurotransmitter release. In the fly NMJ, the Ras MAPK cascade functions through Fas II cell adhesion to control synapse growth99.

In C. elegans, mutants with reduced cholinergic synaptic transmission show abnormal synapse sprouting in a set of cholinergic motor neurons100. These effects are mediated by an unknown retrograde signal from the postsynaptic cell that affects formation of synaptic connections. UNC-122 is a postsynaptic transmembrane protein that affects neuromuscular signaling101. In unc-122 mutants, impaired synaptic transmission causes axon-sprouting defects in a subset of GABAergic neurons. Although synaptic activity is implicated in invertebrate synapse assembly and growth, the mechanism is poorly understood.

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