Prefrontal cortex-dependent innate behaviors are altered by selective knockdown of Gad1 in neuropeptide Y interneurons.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Interneurons/*metabolism ; Neuropeptide Y/*metabolism ; Prefrontal Cortex/*cytology ; Prefrontal Cortex/*metabolism; Animals ; Blotting, Western ; Electrophysiology ; Female ; Glutamate Decarboxylase ; Hippocampus/cytology ; Hippocampus/metabolism ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Synaptic Transmission/genetics ; Synaptic Transmission/physiology ; gamma-Aminobutyric Acid/metabolism

GABAergic dysfunction has been implicated in a variety of neurological and psychiatric disorders, including anxiety disorders. Anxiety disorders are the most common type of psychiatric disorder during adolescence. There is a deficiency of GABAergic transmission in anxiety, and enhancement of GABA transmission through pharmacological means reduces anxiety behaviors. GAD67-the enzyme responsible for GABA production-has been linked to anxiety disorders. One class of GABAergic interneurons, Neuropeptide Y (NPY) expressing cells, is abundantly found in brain regions associated with anxiety and fear learning, including prefrontal cortex, hippocampus and amygdala. Additionally, NPY itself has been shown to have anxiolytic effects, and loss of NPY+ interneurons enhances anxiety behaviors. A previous study showed that knockdown of Gad1 from NPY+ cells led to reduced anxiety behaviors in adult mice. However, the role of GABA release from NPY+ interneurons in adolescent anxiety is unclear. Here we used a transgenic mouse that reduces GAD67 in NPY+ cells (NPYGAD1-TG) through Gad1 knockdown and tested for effects on behavior in adolescent mice. Adolescent NPYGAD1-TG mice showed enhanced anxiety-like behavior and sex-dependent changes in locomotor activity. We also found enhancement in two other innate behavioral tasks, nesting construction and social dominance. In contrast, fear learning was unchanged. Because we saw changes in behavioral tasks dependent upon prefrontal cortex and hippocampus, we investigated the extent of GAD67 knockdown in these regions. Immunohistochemistry revealed a 40% decrease in GAD67 in NPY+ cells in prefrontal cortex, indicating a significant but incomplete knockdown of GAD67. In contrast, there was no decrease in GAD67 in NPY+ cells in hippocampus. Consistent with this, there was no change in inhibitory synaptic transmission in hippocampus. Our results show the behavioral impact of cell-specific interneuron dysfunction and suggest that GABA release by NPY+ cells is important for regulating innate prefrontal cortex-dependent behavior in adolescents.
Competing Interests: The authors have declared that no competing interests exist.

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R01 MH108342 United States MH NIMH NIH HHS; T32 NS061788 United States NS NINDS NIH HHS

0 (Neuropeptide Y)
56-12-2 (gamma-Aminobutyric Acid)
EC 4.1.1.15 (Glutamate Decarboxylase)
EC 4.1.1.15 (glutamate decarboxylase 1)

Date Created: 20180720 Date Completed: 20190122 Latest Revision: 20190423

20221213

PMC6053188

10.1371/journal.pone.0200809

30024942