GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in mice

Abstract

Social novelty impairment is a hallmark feature of autism spectrum disorder associated with synaptic dysfunction. While G-protein coupled receptor 158 (GPR158) has been shown to be essential for synaptic neurotransmission, its role in modulating social novelty remains unknown. Here, we investigated the impact of GPR158 on social behavior in mice and observed that both constitutive and cell/tissue-specific knockout of Gpr158 in pyramidal neurons or the medial prefrontal cortex (mPFC) result in impaired novelty preference, but not sociability. Notably, we found a significant decline in excitatory synaptic transmission and glutamate vesicles in the mPFC synapses of global Gpr158 knockouts. Mechanistically, we identified that constitutive loss of Gpr158 led to suppressed Vglut1 distribution, possibly resulting from altered expression of vesicular V-ATPases and SNAREs by Gpr158 ablation in pyramidal neurons. Our findings suggest that GPR158 in pyramidal neurons specifically modulates social novelty and may be a potential therapeutic target for treating social disorders. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/536148v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1013ca9org.highwire.dtl.DTLVardef@359faaorg.highwire.dtl.DTLVardef@856371org.highwire.dtl.DTLVardef@143c866_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIKnockout of Gpr158 causes social novelty deficit in mice. C_LIO_LIKnockout of Gpr158 in pyramidal neurons leads to disrupted synaptic transmission and an E-I imbalance in the mPFC. C_LIO_LIDisturbed E-I homeostasis in the mPFC is likely due to reduced density of glutamate vesicles caused by Gpr158 knockout. C_LI