Reduced gene expression levels of Munc13-1 and additional components of the presynaptic exocytosis machinery upon conditional targeting of Vglut2 in the adolescent mouse

Abstract

Presynaptic proteins orchestrate an intricate interplay of dynamic interactions in order to regulate quantal exocytosis of transmitter-filled vesicles, and their dysregulation might cause neurological and neuropsychiatric dysfunction. Mice carrying a spatiotemporal restriction in the expression of the Vesicular glutamate transporter 2 (Vglut2; aka Slc17a6) in the cortex, amygdala and hippocampal subiculum from the third postnatal week show a strong anxiolytic phenotype and certain behavioral correlates of schizophrenia. To further understand the molecular consequences of this targeted deletion of Vglut2, we performed an unbiased microarray analysis comparing gene expression levels in the subiculum of these conditional Vglut2 knockout mice (Vglut2f/f;CamKII cKO) to those in control littermates. Expression of Unc13C (Munc13-3), a member of the Unc/Munc family, previously shown to be important for glutamatergic transmission, was identified to be significantly down-regulated. Subsequent analysis by quantitative RT-PCR revealed a 50% down-regulation of Munc 13-1, the gene encoding the Unc/Munc subtype described as an essential component in the majority of glutamtergic synapses in the hippocampus. Genes encoding additional components of the presynaptic machinery were also found regulated, including Rab3A, RIM1α, as well as Syntaxin1 and Synaptobrevin. Altered expression levels of these genes were further found in the amygdala and in the retrosplenial group of the cortex, additional regions in which Vglut2 was conditionally targeted. These findings suggest that expression levels of Vglut2 might be important for the maintenance of gene expression in the presynaptic machinery in the adult mouse brain. Synapse 68:624-633, 2014.