THESIS
2019
xi, 135 pages : illustrations ; 30 cm
Abstract
Neuroligin2, a type of postsynaptic adhesion protein exclusively located at
inhibitory synapses, is a critical component in synapse formation and functions, while its
dysfunction is thought to participate in several brain disorders. Previous work has shown
that neuronal activity is a major determinant of synapse development and plasticity by
regulating protein post-translational modifications, proteolytic processing and trafficking.
However, the interplay between neuronal activity and NL2 is poorly understood. Here,
we addressed the role of neuronal activity in controlling NL2 synaptic levels by
promoting NL2 ubiquitination at K749 and thereby regulating inhibitory synapse density.
Using NL2 K749R mutant that is unable to be ubiquitinated, we found that the
ubiquitination state...[
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Neuroligin2, a type of postsynaptic adhesion protein exclusively located at
inhibitory synapses, is a critical component in synapse formation and functions, while its
dysfunction is thought to participate in several brain disorders. Previous work has shown
that neuronal activity is a major determinant of synapse development and plasticity by
regulating protein post-translational modifications, proteolytic processing and trafficking.
However, the interplay between neuronal activity and NL2 is poorly understood. Here,
we addressed the role of neuronal activity in controlling NL2 synaptic levels by
promoting NL2 ubiquitination at K749 and thereby regulating inhibitory synapse density.
Using NL2 K749R mutant that is unable to be ubiquitinated, we found that the
ubiquitination state of NL2 is important for its synaptic stability in response to TTX-mediated
chronical neuronal activity blockade. By immunoprecipitation-mass
spectrometry (IP-MS) screening, we identified that USP8, an ubiquitin specific protease,
is involved in this process. In addition, USP8 is shown to mediate inhibitory synapse
density by deubiquitinating NL2 in vivo and in vitro. These results provide novel insights
into how neuronal activity regulates inhibitory synapse density and underscores the
significance of NL2 ubiquitination in synapse formation.
Keywords: neuroligin2, ubiquitination, USP8, inhibitory synapse
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