Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?

The processing of excitatory synaptic inputs involves compartmentalized dendritic Ca2+ oscillations. The downstream signaling evoked by these local Ca2+ transients and their impact on local synaptic development and remodeling are unknown. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an important decoder of Ca2+ signals and mediator of synaptic plasticity. In addition to its known accumulation at spines, we observed with live imaging the dynamic recruitment of CaMKII to dendritic subdomains adjacent to activated synapses in cultured hippocampal neurons. This localized and transient enrichment of CaMKII to dendritic sites coincided spatially and temporally with dendritic Ca2+ transients. We show that it involved an interaction with microtubular elements, required activation of the kinase, and led to localized dendritic CaMKII autophosphorylation. This process was accompanied by the adjacent remodeling of spines and synaptic AMPA receptor insertion. Replacement of endogenous CaMKII with a mutant that cannot translocate within dendrites lessened this activity-dependent synaptic plasticity. Thus, CaMKII could decode compartmental dendritic Ca2+ transients to support remodeling of local synapses.

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The postsynaptic t-SNARE Syntaxin 4 controls traffic of Neuroligin 1 and Synaptotagmin 4 to regulate retrograde signaling

eLife ◽

10.7554/elife.13881 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 17

Author(s):

Kathryn P Harris ◽

Yao V Zhang ◽

Zachary D Piccioli ◽

Norbert Perrimon ◽

J Troy Littleton

Keyword(s):

Synaptic Plasticity ◽

Neuromuscular Junctions ◽

Genetic Interaction ◽

Retrograde Signaling ◽

Synaptic Development ◽

Synaptic Growth ◽

Adhesion Protein ◽

Neuronal Stimulation ◽

Syntaxin 4 ◽

Activity Dependent

Postsynaptic cells can induce synaptic plasticity through the release of activity-dependent retrograde signals. We previously described a Ca2+-dependent retrograde signaling pathway mediated by postsynaptic Synaptotagmin 4 (Syt4). To identify proteins involved in postsynaptic exocytosis, we conducted a screen for candidates that disrupted trafficking of a pHluorin-tagged Syt4 at Drosophila neuromuscular junctions (NMJs). Here we characterize one candidate, the postsynaptic t-SNARE Syntaxin 4 (Syx4). Analysis of Syx4 mutants reveals that Syx4 mediates retrograde signaling, modulating the membrane levels of Syt4 and the transsynaptic adhesion protein Neuroligin 1 (Nlg1). Syx4-dependent trafficking regulates synaptic development, including controlling synaptic bouton number and the ability to bud new varicosities in response to acute neuronal stimulation. Genetic interaction experiments demonstrate Syx4, Syt4, and Nlg1 regulate synaptic growth and plasticity through both shared and parallel signaling pathways. Our findings suggest a conserved postsynaptic SNARE machinery controls multiple aspects of retrograde signaling and cargo trafficking within the postsynaptic compartment.

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