Whole-brain spatial distribution of serine incorporator 2 mRNA in adult C57BL/6 J mice

Abstract

Serine Incorporator 2(SERINC2), a highly conserved eukaryotic membrane lipid regulator, promotes critical membrane lipid biosynthesis to maintain neuronal metabolic homeostasis by assembling serine synthase complexes. Our team previously identified SERINC2 as a bipolar disorder (BD) risk gene in Chinese Han familial BD cases, with mutations affecting cerebral white matter volume. Despite established clinical relevance, brain expression patterns of SERINC2 remains poorly characterized experimentally. We used RNAscope® in situ hybridization to comprehensively map SERINC2 mRNA distribution across mouse coronal brain sections, and quantified positive cells across regions. Given BD's potential association with excitatory/inhibitory imbalance, multiplex fluorescence in situ hybridization examined SERINC2 co-expression patterns with vesicular glutamate transporter 2 (VGLUT2, marker for glutamatergic neurons) and glutamic acid decarboxylase 2 (GAD2, marker for GABAergic neurons) in SERINC2-positive regions. Widespread SERINC2 expression was observed in in the telencephalon and diencephalon, including cortical areas (neocortex and limbic cortex), hippocampal subregions (CA1 - CA3, dentate gyrus, and subiculum), thalamic nuclei, and basolateral amygdala. High-intensity signals were detected in hindbrain regions, particularly the pontine nuclei (PN) and reticulotegmental nucleus of the pons (RtTg). Cerebellar Purkinje and granular layers also exhibited significant expression. Notably, multiplex fluorescence in situ hybridization revealed SERINC2 + /VGLUT2 + co-expression in cortical layers III-IV, dorsal subiculum, thalamus, PN, and RtTg. Co-expression of SERINC2 + /GAD2 + was identified in the cerebellar Purkinje cell layer. These findings delineate the brain-wide expression landscape of SERINC2 in mice and provide a neuroanatomical basis for studying its role in excitation/inhibition imbalance in the pathogenesis of BD.