Systemic administration of ML297, a selective activator of G protein-gated inwardly rectifying K + (GIRK) channels, decreases innate avoidance behavior in male C57BL/6J mice. The cellular mechanisms mediating the ML297-induced suppression of avoidance behavior are unknown. Here, we show that systemic ML297 administration suppresses elevated plus maze (EPM)-induced neuronal activation in the ventral hippocampus (vHPC) and basolateral amygdala (BLA), and that ML297 activates GIRK1-containing GIRK channels in these limbic structures. While intracranial infusion of ML297 into the vHPC suppressed avoidance behavior in the EPM test, mirroring the effect of systemic ML297, intra-BLA administration of ML297 provoked the opposite effect. Using neuron-specific viral genetic and chemogenetic approaches, we found that the combined inhibition of excitatory neurons in CA3 and dentate gyrus (DG) sub-regions of the vHPC was sufficient to decrease innate avoidance behavior in the EPM, open-field, and light-dark tests in male C57BL/6J mice, while performance in the marble-burying test was not impacted. Furthermore, genetic ablation of GIRK channels in CA3/DG excitatory neurons precluded the suppression of avoidance behavior evoked by systemic ML297 in the EPM test. Thus, acute inhibition of excitatory neurons in the ventral CA3 and DG sub-regions of the vHPC is necessary for the apparent anxiolytic efficacy of systemic ML297 and is sufficient to decrease innate avoidance behavior in male C57BL/6J mice. SIGNIFICANT STATEMENTWe interrogated the cellular mechanisms underlying the apparent anxiolytic efficacy of ML297, a selective activator of GIRK channels and promising lead compound. Intracranial infusion of ML297 into the vHPC and BLA complex exerted opposing influence on innate avoidance behavior in male C57BL/6J mice, the former recapitulating the suppression of avoidance behavior evoked by systemic ML297. Using viral genetic and chemogenetic approaches, we showed that combined inhibition of excitatory neurons in CA3 and dentate gyrus sub-regions of the ventral hippocampus is sufficient to decrease innate avoidance behavior in male mice and mediates the decrease in avoidance behavior evoked by systemic ML297. These findings establish a foundation for future investigations into the therapeutic potential of GIRK channel modulation in anxiety disorders.
Bibliographical noteFunding Information:
Acknowledgements: We thank Zhilian Xia, Nicholas Carlblom, Mehrsa Zahiremami, and Courtney Wright for taking care of the mouse colony; Janna Moen, Jenna Robinson, and Margot DeBaker for assisting with c-Fos immunohistochemistry; Dr. Yasushi Nakagawa for providing support for the viral fidelity validation experiments; Dr. Megan Tipps and Dr. Nora McCall for providing valuable feedback on the manuscript; and Dr. C. David Weaver for providing some of the ML297 used for this study. This work was supported by National Institutes of Health Grants DA034696 (to K.W.), AA027544 (to K.W.), MH107399 (to K.W., C.R.H.), and DA007234 (to T.R.R.); a Wallin Neuroscience Discovery Fund Award (K.W.); and a Doctoral Dissertation Fellowship from the University of Minnesota (B.N.V.). The authors declare no competing financial interests. Correspondence should be addressed to Kevin Wickman at email@example.com. https://doi.org/10.1523/JNEUROSCI.2787-20.2021 Copyright © 2021 the authors
Copyright © 2021 the authors.
- Basolateral amygdala
- Elevated plus maze
- Ventral hippocampus
PubMed: MeSH publication types
- Journal Article