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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.

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Acknowledgements

We would like to thank the Vanderbilt Transgenic Mouse/Embryonic Stem Cell Shared resource for generating the transgenic animals, the Vanderbilt Murine Neurobehavioral Laboratory, especially Gregg Stanwood and John Allison, for consultation on behavioral tasks and equipment use, the Proteomics Core of the Mass Spectrometry Research Center at Vanderbilt University, especially David Anderson and Kristie Rose, for assistance with the identification of PEP19, and Andrea Varro from the University of Liverpool for her generosity in sharing the proCCK antibodies. This work was supported by National Institutes of Health R01 MH067234 and by the Vanderbilt Kennedy Center. MJS was supported by a Vanderbilt Brain Institute Scholar Award.

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Correspondence to K Mirnics.

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Schmidt, M., Horvath, S., Ebert, P. et al. Modulation of behavioral networks by selective interneuronal inactivation. Mol Psychiatry 19, 580–587 (2014). https://doi.org/10.1038/mp.2013.167

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