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

Katelynn M Corder,Samantha A Lear,Farah D Lubin,Mariana A Cortes,Lynn E Dobrunz,Aundrea F Bartley,Uwe Rudolph

doi:10.1371/journal.pone.0200809

Abstract

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.

Highlights

Anxiety disorders are the most prevalent group of psychiatric disorders found in adolescents [1]
The NPYGAD1-TG mouse line was shown to have reduced anxiety-like behavior in adult mice [34], here different results were observed in adolescent mice
We found a decrease in the percent of distance traveled in the central zone in both male and female NPYGAD1-TG mice (Fig 1D; NPYGAD1-WT n = 21; NPYGAD1-TG n = 19; F(1,39) = 22.69; p < 0.001), as well as a reduction in percent of ambulatory time in the center (Fig 1E; NPYGAD1-WT n = 21; NPYGAD1-TG n = 19; F(1,39) = 24.94; p < 0.001)

Summary

Introduction

Anxiety disorders are the most prevalent group of psychiatric disorders found in adolescents [1]. Several studies have determined that manifestation and coping of anxiety disorders differ between children, adolescents, and adults [2,3,4]. Abnormalities in the GABAergic system are associated with a variety of neurological and psychiatric disorders including anxiety and mood disorders [5,6,7,8,9], schizophrenia [5,10,11], autism [7,12], Rett syndrome [13], and epilepsy [14]. Deficits in GABAergic transmission are thought to underlie anxiety and depression in adults [8]. Many medications used to treat anxiety in adults—such as benzodiazepines —function by enhancing GABAergic synaptic transmission. The GABAergic system is still developing [17], and the role of reduced GABA release in adolescent anxiety is not fully understood

Methods

Results

Conclusion