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MSRC Mass Spectrometry Research and Development

Modulation of behavioral networks by selective interneuronal inactivation.

AUTHORS

Schmidt MJM J , Horvath S S , Ebert P P , Norris JL J L , Seeley EH E H , Brown J J , Gellert L L , Everheart M M , Garbett KA K A , Grice TW T W , Caprioli RM R M , Mirnics K K . Molecular psychiatry. 2014 5 ; 19(5). 580-7

ABSTRACT

Gamma-aminobutyric acid (GABA)-ergic disturbances are hallmark features of schizophrenia and other neuropsychiatric disorders and encompass multiple interneuronal cell types. Using bacterial artificial chromosome-driven, miRNA silencing technology we generated transgenic mouse lines that suppress glutamic acid decarboxylase 1 (GAD1) in either cholecystokinin (CCK)- or neuropeptide Y (NPY)-expressing interneurons. 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, whereas 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 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.

Gamma-aminobutyric acid (GABA)-ergic disturbances are hallmark features of schizophrenia and other neuropsychiatric disorders and encompass multiple interneuronal cell types. Using bacterial artificial chromosome-driven, miRNA silencing technology we generated transgenic mouse lines that suppress glutamic acid decarboxylase 1 (GAD1) in either cholecystokinin (CCK)- or neuropeptide Y (NPY)-expressing interneurons. 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, whereas 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 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.