Impairment of Inhibitory Synapse Formation and Motor Behavior in Mice Lacking the NL2 Binding Partner LHFPL4/GARLH4

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. [Display omitted] •LHFPL4 is a major NL2 binding partner enriched at inhibitory postsynaptic sites•LHFPL4 and NL2 regulate each other’s protein levels and synaptic clustering•Inhibitory synapse formation in the cerebellar granular layer depends on LHFPL4•LHFPL4 is essential for motor behaviors and postnatal survival Wu et al. identify LHFPL4/GARLH4 as a major NL2 binding partner that is specifically enriched at inhibitory postsynaptic sites and regulates inhibitory synapse formation. Deletion of LHFPL4/GARLH4 in mice results in profound impairment of inhibitory synapse formation as well as prominent motor behavioral deficits and premature death.