Molecular mechanisms underlying excitatory shaft-synapse formation and homeostatic synaptic scaling

In order for a neuron to sustain normal synaptic activity, it is necessary for synapses to form and function properly. Here, I present my work investigating the signaling mechanisms underlying the formation of an uncharacterized type of excitatory synapse and the mechanisms regulating a form of homeostatic plasticity that stabilizes overall synaptic activity.;Excitatory synapses in the CNS are formed on both dendritic shafts and spines. Recent evidence suggests that shaft synapses may be independently regulated by behavioral learning and by the induction of synaptic plasticity. While the molecular mechanisms underlying spinogenesis have been extensively explored, those regulating shaft synapses are still unknown. Here, I demonstrate that postsynaptic ephrinB3 promotes the formation of glutamategric synapses specifically on dendritic shafts and not spines. Glutamate receptor-interacting protein 1 (GRIP1) functions downstream of ephrinB3 reverse signaling. Together, I propose a novel mechanism for the independent modulation of shaft synapse formation.;Synaptic scaling, a form of homeostatic plasticity, has been proposed to maintain constant overall synaptic activity levels. The molecular mechanisms involved in transcription-independent synaptic scaling remain unknown. I will present data demonstrating that all-trans retinoic acid (RA), a potent developmental morphogen, surprisingly mediates synaptic scaling in response to chronic activity blockade. I show that activity blockade increases RA synthesis and secretion and that acute RA treatment enhances synaptic transmission. This form of activity-dependent synaptic scaling operates via a translation-dependent but transcription-independent mechanism that results in increased postsynaptic glutamate receptor levels and is mediated by dendritically localized retinoic acid receptor-alpha (RARalpha). In hippocampal neurons, RARalpha, a well-characterized nuclear transcription factor, directly binds mRNA in a sequence-specific manner in the dendrite and represses translation through its uncharacterized C-terminus domain. Together, our data suggest that RA/RARalpha are the crucial signaling molecules that enhance synaptic transmission by activating dendritic translation following activity blockade.