UCSF

The magnitude and timing of neural activity precisely determines adaptive responses to stimuli. Neural activity is subject to extensive transformation between sensation and motor execution, and this transformation itself is subject to change due to the rewiring of the nervous system during development and learning. In this thesis I present data exploring how synapses between neural circuit elements might be homeostatically regulated, such that activity levels are maintained to ensure effective functioning of the nervous system.

Inhibition of postsynaptic glutamate receptors at the Drosophila neuromuscular junction (NMJ) initiates a compensatory increase in presynaptic release termed synaptic homeostasis. This ensures that muscle depolarization stays constant despite diminished postsynaptic function, and this process of synaptic homeostasis may be important for maintaining proper NMJ function throughout development. While BMP signaling has been proposed to mediate the retrograde signal that controls synaptic homeostasis at this synapse, BMP signaling is also necessary for normal synaptic growth and stability. It remains unknown whether BMPs function as instructive retrograde signals that directly modulate presynaptic transmitter release. Here we demonstrate that the BMP receptor (Wit) and ligand (Gbb) are necessary for the induction of synaptic homeostasis, but that Gbb does not function as an instructive retrograde signal. Rather our data indicate that Wit and Gbb function via the downstream transcription factor Mad, and that Mad-mediated signaling is continuously required to gate the expression of synaptic homeostasis in motoneurons.

Forms of synaptic plasticity in the central nervous system such as long-term potentiation (LTP) increase synaptic activity in a synapse- and cell-specific fashion. Although network-wide excitation triggers compensatory homeostatic changes, whether vertebrate neurons initiate homeostatic synaptic changes in response to cell-autonomous increases in excitation has not been examined. We cell-autonomously excited rodent CA1 pyramidal neurons and find that a compensatory postsynaptic depression of both AMPAR and NMDAR function results. Elevated calcium influx through L-type calcium channels leads to activation of a pathway involving CaM kinase kinase and CaM kinase 4 that induces synaptic depression of AMPAR and NMDAR responses. The synaptic depression of AMPARs but not of NMDARs requires protein synthesis and the GluA2 AMPAR subunit.