Abstract
Normal brain functions depend on the balanced development of excitatory and inhibitory synapses. Our knowledge of the molecular mechanisms underlying inhibitory synapse formation is limited. 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 identify LHFPL4/GARLH4 as a major NL2 binding partner that is specifically enriched at inhibitory postsynaptic sites. LHFPL4/GARLH4 and NL2 regulate the protein levels and synaptic clustering of each other in the cerebellum. Lhfpl4/Garlh4-/- mice display profound impairment of inhibitory synapse formation as well as prominent motor behavioral deficits and premature death. Our findings highlight the essential role of LHFPL4/GARLH4 in brain functions by regulating inhibitory synapse formation as a major NL2 binding partner.
Highlights
Neurons in the central nervous system (CNS) process and transmit information predominantly through two distinct categories of synapses: glutamatergic excitatory synapses and g-aminobutyric acid (GABA)ergic inhibitory synapses. a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission, whereas ionotropic type A GABA receptors (GABAARs) mediate most of the fast inhibitory synaptic transmission in the CNS (Olsen and Sieghart, 2008; Traynelis et al, 2010)
Identification of lipoma HMGIC fusion partner-like 4 (LHFPL4)/GABAAR regulatory Lhfpl4 (GARLH4) as a Major NL2 Binding Partner by Immunoprecipitation-Mass Spectrometry To identify inhibitory synaptic proteins that interact with NL2, mouse brain homogenates were subjected to immunoprecipitation using an anti-NL2 antibody followed by mass spectrometry analysis
We identified LHFPL4/GARLH4 as a major NL2 binding partner that is associated with GABAARs
Summary
Neurons in the central nervous system (CNS) process and transmit information predominantly through two distinct categories of synapses: glutamatergic excitatory synapses and g-aminobutyric acid (GABA)ergic inhibitory synapses. a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission, whereas ionotropic type A GABA receptors (GABAARs) mediate most of the fast inhibitory synaptic transmission in the CNS (Olsen and Sieghart, 2008; Traynelis et al, 2010). Neurons in the central nervous system (CNS) process and transmit information predominantly through two distinct categories of synapses: glutamatergic excitatory synapses and g-aminobutyric acid (GABA)ergic inhibitory synapses. A-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission, whereas ionotropic type A GABA receptors (GABAARs) mediate most of the fast inhibitory synaptic transmission in the CNS (Olsen and Sieghart, 2008; Traynelis et al, 2010). To explore the molecular mechanisms of synapse formation, extensive studies have been conducted to identify protein components of the excitatory glutamatergic postsynaptic density (PSD) using either yeast two-hybrid (Y2H) screening or purification coupled with mass spectrometry analysis (Greger et al, 2017; Sheng and Kim, 2011). Given the diversity of GABAAR subtypes and the complexity of interneurons (Kepecs and Fishell, 2014; Olsen and Sieghart, 2008), a large number of inhibitory synaptic proteins likely remain to be identified
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