Differential impact of GAD67 suppression in distinct GABA-ergic interneuron populations: implications for mental illness

Abstract

GABA-ergic disturbances are hallmark features of many brain disorders. Two transgenic mouse lines were generated to suppress GAD1 in non-overlapping cell types that express cholecystokinin (CCK) or neuropeptide Y (NPY). In situ lipidomic and proteomic analyses on brain tissue sections revealed distinct, brain region specific profiles in each transgenic line. Behavioral analyses revealed that suppression of GAD1 in CCK+ interneurons resulted in locomotor and olfactory sensory changes while suppression in NPY+ interneurons affected anxiety-related behaviors and social interaction. Both transgenic mouse lines had altered sensitivity to amphetamine albeit in opposite directions. Together, these data argue that reduced GAD1 expression leads to altered molecular and behavioral profiles in a cell type-dependent manner, and that these two subpopulations of interneurons are strong and opposing modulators of dopamine system function. Furthermore, our findings also support the hypothesis that neuronal networks are differentially controlled by diverse inhibitory subnetworks.