title: Modulation of behavioral networks by selective interneuronal inactivation.
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.
authors: 1] Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA [2] Department of Psychiatry, Vanderbilt University, Nashville, TN, USA.
authors: M J
authors: MJ
authors: Schmidt
authors: 1] Department of Psychiatry, Vanderbilt University, Nashville, TN, USA [2] Department of Psychiatry, University of Szeged, Szeged, Hungary.
authors: S
authors: S
authors: Horvath
authors: Department of Psychiatry, Vanderbilt University, Nashville, TN, USA.
authors: P
authors: P
authors: Ebert
authors: Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.
authors: J L
authors: JL
authors: Norris
authors: Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.
authors: E H
authors: EH
authors: Seeley
authors: Department of Psychiatry, Vanderbilt University, Nashville, TN, USA.
authors: J
authors: J
authors: Brown
authors: Department of Psychiatry, University of Szeged, Szeged, Hungary.
authors: L
authors: L
authors: Gellert
authors: Department of Psychiatry, Vanderbilt University, Nashville, TN, USA.
authors: M
authors: M
authors: Everheart
authors: Department of Psychiatry, Vanderbilt University, Nashville, TN, USA.
authors: K A
authors: KA
authors: Garbett
authors: Department of Psychiatry, Vanderbilt University, Nashville, TN, USA.
authors: T W
authors: TW
authors: Grice
authors: Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.
authors: R M
authors: RM
authors: Caprioli
authors: 1] Department of Psychiatry, Vanderbilt University, Nashville, TN, USA [2] Department of Psychiatry, University of Szeged, Szeged, Hungary [3] Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA.
authors: K
authors: K
authors: Mirnics
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001519:Behavior / Q000502:physiology*; D001921:Brain / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002766:Cholecystokinin / Q000235:genetics / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism*; D007395:Interneurons / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D055696:Olfactory Perception / Q000502:physiology; D040901:Proteomics / Q000379:methods; D012919:Social Behavior; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D009478:Neuropeptide Y; D005680:gamma-Aminobutyric Acid; D002766:Cholecystokinin; D000661:Amphetamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1