Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses

Abstract

Major depressive disorder (MDD) is associated with alterations of GABAergic interneurons, notably somatostatin (Sst) as well as parvalbumin (Pvalb), in cortical brain areas. In addition, the antidepressant effects of rapid-acting drugs are thought to occur via inhibition of GABA interneurons. However, the impact of these interneuron subtypes in affective behaviors as well as in the effects of rapid-acting antidepressants remains to be determined. Here, we used a Cre-dependent DREADD-chemogenetic approach to determine if inhibition of GABA interneurons in the mPFC of male mice is sufficient to produce antidepressant actions, and conversely if activation of these interneurons blocks the rapid and sustained antidepressant effects of scopolamine, a nonselective acetylcholine muscarinic receptor antagonist. Chemogenetic inhibition of all GABA interneurons (Gad1+), as well as Sst+ and Pvalb+ subtypes in the mPFC produced dose and time-dependent antidepressant effects in the forced swim and novelty suppressed feeding tests, and increased synaptic plasticity. In contrast, stimulation of Gad1, Sst, or Pvalb interneurons in mPFC abolished the effects of scopolamine and prevented scopolamine induction of synaptic plasticity. The results demonstrate that transient inhibition of GABA interneurons promotes synaptic plasticity that underlies rapid antidepressant responses.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Chemogenetic activation of Gad1 interneurons in the mPFC produces time- and dosing-dependent rapid antidepressant-like effects.
Fig. 2: Chemogenetic inhibition of Sst or Pvalb interneurons in the mPFC produces fast antidepressant-like effects and increases c-Fos expression.
Fig. 3: Chemogenetic inhibition of Sst or Pvalb interneurons in the mPFC increases VGLUT1 expression.
Fig. 4: Chemogenetic activation of Gad1, Pvalb, or Sst interneurons in the mPFC abolishes the rapid antidepressant-like effects of scopolamine.
Fig. 5: Chemogenetic activation of Sst or Pvalb interneurons abolishes scopolamine induction of VGLUT1 in the mPFC.

References

  1. 1.

    Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617–27.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Reddy MS. Depression: the disorder and the burden. Indian J Psychol Med. 2010;32:1–2.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. 3.

    Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67–104.

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  6. 6.

    Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63:1121–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Drevets WC, Zarate CA Jr, Furey ML. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review. Biol Psychiatry. 2013;73:1156–63.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Furey ML, Zarate CA Jr. Pulsed intravenous administration of scopolamine produces rapid antidepressant effects and modest side effects. J Clin Psychiatry. 2013;74:850–1.

    PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP, et al. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci. 1999;2:833–9.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Vollenweider I, Smith KS, Keist R, Rudolph U. Antidepressant-like properties of alpha2-containing GABA(A) receptors. Behav Brain Res. 2011;217:77–80.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Shalaby A, Kamal S. Effect of Escitalopram on GABA level and anti-oxidant markers in prefrontal cortex and nucleus accumbens of chronic mild stress-exposed albino rats. Int J Physiol Pathophysiol Pharm. 2009;1:154–61.

    CAS  Google Scholar 

  13. 13.

    Drugan RC, Morrow AL, Weizman R, Weizman A, Deutsch SI, Crawley JN, et al. Stress-induced behavioral depression in the rat is associated with a decrease in GABA receptor-mediated chloride ion flux and brain benzodiazepine receptor occupancy. Brain Res. 1989;487:45–51.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Banasr M, Lepack A, Fee C, Duric V, Maldonado-Aviles J, DiLeone R, et al. Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression. Chronic Stress (Thousand Oaks). 2017;1:2470547017720459.

    Google Scholar 

  15. 15.

    Tripp A, Kota RS, Lewis DA, Sibille E. Reduced somatostatin in subgenual anterior cingulate cortex in major depression. Neurobiol Dis. 2011;42:116–24.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

    Godfrey KEM, Gardner AC, Kwon S, Chea W, Muthukumaraswamy SD. Differences in excitatory and inhibitory neurotransmitter levels between depressed patients and healthy controls: a systematic review and meta-analysis. J Psychiatr Res. 2018;105:33–44.

    PubMed  Article  Google Scholar 

  17. 17.

    Hasler G, van der Veen JW, Grillon C, Drevets WC, Shen J. Effect of acute psychological stress on prefrontal GABA concentration determined by proton magnetic resonance spectroscopy. Am J Psychiatry. 2010;167:1226–31.

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry. 2004;61:705–13.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    DeFelipe J, Lopez-Cruz PL, Benavides-Piccione R, Bielza C, Larranaga P, Anderson S, et al. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat Rev Neurosci. 2013;14:202–16.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Rudy B, Fishell G, Lee S, Hjerling-Leffler J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol. 2011;71:45–61.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. Interneurons of the neocortical inhibitory system. Nat Rev Neurosci. 2004;5:793–807.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Tremblay R, Lee S, Rudy B. GABAergic interneurons in the neocortex: from cellular properties to circuits. Neuron. 2016;91:260–92.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Sibille E, Morris HM, Kota RS, Lewis DA. GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders. Int J Neuropsychopharmacol. 2011;14:721–34.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Rajkowska G, O’Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ. GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology. 2007;32:471–82.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Todorovic N, Micic B, Schwirtlich M, Stevanovic M, Filipovic D. Subregion-specific protective effects of fluoxetine and clozapine on parvalbumin expression in medial prefrontal cortex of chronically isolated rats. Neuroscience. 2019;396:24–35.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Czeh B, Vardya I, Varga Z, Febbraro F, Csabai D, Martis LS, et al. Long-term stress disrupts the structural and functional integrity of GABAergic neuronal networks in the medial prefrontal cortex of rats. Front Cell Neurosci. 2018;12:148.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Urban-Ciecko J, Barth AL. Somatostatin-expressing neurons in cortical networks. Nat Rev Neurosci. 2016;17:401–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Ferguson BR, Gao WJ. PV interneurons: critical regulators of E/I balance for prefrontal cortex-dependent behavior and psychiatric disorders. Front Neural Circuits. 2018;12:37.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Wohleb ES, Gerhard D, Thomas A, Duman RS. Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine. Curr Neuropharmacol. 2017;15:11–20.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Duman RS, Shinohara R, Fogaca MV, Hare B. Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function. Mol Psychiatry. 2019;24:1816–32.

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Miller OH, Moran JT, Hall BJ. Two cellular hypotheses explaining the initiation of ketamine’s antidepressant actions: direct inhibition and disinhibition. Neuropharmacology. 2016;100:17–26.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  32. 32.

    Tripp A, Oh H, Guilloux JP, Martinowich K, Lewis DA, Sibille E. Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. Am J Psychiatry. 2012;169:1194–202.

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Lin LC, Sibille E. Somatostatin, neuronal vulnerability and behavioral emotionality. Mol Psychiatry. 2015;20:377–87.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Fee C, Banasr M, Sibille E. Somatostatin-positive gamma-aminobutyric acid interneuron deficits in depression: cortical microcircuit and therapeutic perspectives. Biol Psychiatry. 2017;82:549–59.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Soumier A, Sibille E. Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice. Neuropsychopharmacology. 2014;39:2252–62.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Fogaca MV, Duman RS. Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions. Front Cell Neurosci. 2019;13:87.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR, Alreja M, et al. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Invest. 2016;126:2482–94.

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Jendryka M, Palchaudhuri M, Ursu D, van der Veen B, Liss B, Katzel D, et al. Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice. Sci Rep. 2019;9:4522.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Manvich DF, Webster KA, Foster SL, Farrell MS, Ritchie JC, Porter JH, et al. The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice. Sci Rep. 2018;8:3840.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Ghosal S, Bang E, Yue W, Hare BD, Lepack AE, Girgenti MJ, et al. Activity-dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine. Biol Psychiatry. 2018;83:29–37.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Fogaca MV, Fukumoto K, Franklin T, Liu RJ, Duman CH, Vitolo OV, et al. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology. 2019;44:2230–8.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Ghosal S, Duman CH, Liu RJ, Wu M, Terwilliger R, Girgenti MJ, et al. Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents. Neurobiol Dis. 2019;134:104669.

  43. 43.

    Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Elsayed M, Banasr M, Duric V, Fournier NM, Licznerski P, Duman RS. Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression. Biol Psychiatry. 2012;72:258–65.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Pothula S, Kato T, Liu RJ, Wu M, Gerhard D, Shinohara R, et al. Cell-type specific modulation of NMDA receptors triggers antidepressant actions. Mol Psychiatry. 2020.

  46. 46.

    Lepack AE, Bang E, Lee B, Dwyer JM, Duman RS. Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures. Neuropharmacology. 2016;111:242–52.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J Clin Invest. 2020;130:1336–49.

  48. 48.

    Guettier JM, Gautam D, Scarselli M, Ruiz de Azua I, Li JH, Rosemond E, et al. A chemical-genetic approach to study G protein regulation of beta cell function in vivo. Proc Natl Acad Sci USA. 2009;106:19197–202.

    PubMed  Article  Google Scholar 

  49. 49.

    Navarria A, Wohleb ES, Voleti B, Ota KT, Dutheil S, Lepack AE, et al. Rapid antidepressant actions of scopolamine: role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiol Dis. 2015;82:254–61.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Natl Acad Sci USA. 2015;112:8106–11.

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Yu H, Li M, Zhou D, Lv D, Liao Q, Lou Z, et al. Vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release and membrane GluA1 activation is involved in the rapid antidepressant-like effects of scopolamine in mice. Neuropharmacology. 2018;131:209–22.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R, et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry. 2013;74:742–9.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Guilloux JP, Douillard-Guilloux G, Kota R, Wang X, Gardier AM, Martinowich K, et al. Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression. Mol Psychiatry. 2012;17:1130–42.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Fuchs T, Jefferson SJ, Hooper A, Yee PH, Maguire J, Luscher B. Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state. Mol Psychiatry. 2017;22:920–30.

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Perova Z, Delevich K, Li B. Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress. J Neurosci. 2015;35:3201–6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Delgado MR, Beer JS, Fellows LK, Huettel SA, Platt ML, Quirk GJ, et al. Viewpoints: dialogues on the functional role of the ventromedial prefrontal cortex. Nat Neurosci. 2016;19:1545–52.

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Vertes RP. Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse. 2004;51:32–58.

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Fukumoto K, Fogaca MV, Liu RJ, Duman C, Kato T, Li XY, et al. Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine. Proc Natl Acad Sci USA. 2019;116:297–302.

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Kawaguchi Y. Selective cholinergic modulation of cortical GABAergic cell subtypes. J Neurophysiol. 1997;78:1743–7.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Gulledge AT, Park SB, Kawaguchi Y, Stuart GJ. Heterogeneity of phasic cholinergic signaling in neocortical neurons. J Neurophysiol. 2007;97:2215–29.

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Page CE, Shepard R, Heslin K, Coutellier L. Prefrontal parvalbumin cells are sensitive to stress and mediate anxiety-related behaviors in female mice. Sci Rep. 2019;9:19772.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

RSD passed away on February 1st, 2020. This article is dedicated to RSD in memory of his great mentorship and scientific leadership.

Funding

This study was supported by a grant from MH093897 and MH105910. RSD has received consulting, speaking fees, and/or grant support from Psychogenics, Aptynx, Taisho, Johnson & Johnson, Lilly, Lundbeck, Relmada, Sumitomo Dianippon, Navitor, and Allergan.

Author information

Affiliations

Authors

Contributions

MVF designed the study, performed the experiments, analyzed the data, and wrote the manuscript. MW performed the electrophysiological experiments and analyzed the data. X-YL performed the genotyping of the animals. CL helped to perform the CUS experiments. MRP provided scientific input for experiments added in revision and contributed to editing and revising the manuscript. RSD designed the study, revised, and contributed to writing the manuscript.

Corresponding author

Correspondence to Manoela V. Fogaça.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fogaça, M.V., Wu, M., Li, C. et al. Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-00916-y

Download citation

Search