THESIS
2018
x, 146 pages : illustrations (some color) ; 30 cm
Abstract
Normal brain functions depend on the balanced development of excitatory and inhibitory
synapses. Our current understanding of the molecular mechanisms underlying
synaptogenesis remains poor, especially for inhibitory synapses, as exemplified by the
meager list of inhibitory synaptic proteins. Given the diversity of inhibitory synapses, a
large number of inhibitory synaptic proteins likely remain to be identified. Neuroligin-2
(NL2), a transmembrane protein at inhibitory postsynaptic sites, is capable of initiating
inhibitory synapse formation. In an effort to search for NL2 binding proteins and the
downstream mechanisms responsible for inhibitory synapse development, we identified
LHFPL4/GARLH4, a four-transmembrane-domain protein, as a major NL2 binding partner.
LHFPL4/GARLH4...[
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Normal brain functions depend on the balanced development of excitatory and inhibitory
synapses. Our current understanding of the molecular mechanisms underlying
synaptogenesis remains poor, especially for inhibitory synapses, as exemplified by the
meager list of inhibitory synaptic proteins. Given the diversity of inhibitory synapses, a
large number of inhibitory synaptic proteins likely remain to be identified. Neuroligin-2
(NL2), a transmembrane protein at inhibitory postsynaptic sites, is capable of initiating
inhibitory synapse formation. In an effort to search for NL2 binding proteins and the
downstream mechanisms responsible for inhibitory synapse development, we identified
LHFPL4/GARLH4, a four-transmembrane-domain protein, as a major NL2 binding partner.
LHFPL4/GARLH4 was exclusively expressed in the nervous system and specifically
enriched at inhibitory postsynaptic sites. Significant proportions of LHFPL4/GARLH4 and
NL2 were associated with each other in the brain, and they regulated the protein levels and
synaptic clustering of each other in the cerebellum. Moreover, deficiency of
LHFPL4/GARLH4 resulted in profound impairment of inhibitory synapse formation as well
as prominent motor behavioral deficits, increased pentylenetetrazole (PTZ)-induced seizure
susceptibility and premature death in LHFPL4/GARLH4 KO mice. Thus, these findings
highlight the essential role of LHFPL4/GARLH4 in brain functions by regulating inhibitory
synapse formation as a major NL2 binding partner.
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