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Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders

Molecular Psychiatry volume 26, pages 151–167 (2021)Cite this article

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Abstract

Cognitive dysfunctions, including impaired attention, learning, memory, planning and problem solving, occur in depressive episodes, often persist during remission, predict relapse, worsen with recurrent episodes, and are not treated by current antidepressants or other medications. Cognitive symptoms are also present in other psychiatric disorders, are a hallmark of aging, and define several late-life disorders, including Alzheimer’s disease. This pervasive occurrence suggests either a non-specific outcome of a diseased brain, or a shared underlying pathology contributing to this symptom dimension. Recent findings suggest a role for altered GABAergic inhibition in cognitive symptoms. Cellular, molecular and biochemical studies in human subjects report changes affecting the gamma-amino butyric acid (GABA) system, specifically somatostatin-expressing (SST+) GABAergic interneurons, across brain disorders and during aging. SST+ neurons gate excitatory input onto pyramidal neurons within cortical microcircuits. Experimentally reducing the function of these neurons affects excitatory signal-to-noise ratio, reduces synchronized cellular and neural activity, and leads to cognitive dysfunctions. Conversely, augmenting SST+ cell post-synaptic α5-GABA-A receptor activity has pro-cognitive efficacy in stress and aging models. Together, this suggests that reduced signaling of the SST+ neuron/α5-GABA-A receptor pathway contributes to cognitive dysfunctions, and that it represents a novel therapeutic target for remediating mood and cognitive symptoms in depression, other psychiatric disorders and during aging.

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Fig. 1: Canonical neuronal cortical microcircuit.
Fig. 2: SST+ cell-mediated “blanket of inhibition” regulates temporal and spatial signal to noise ratio: effects of depression and of α5-PAM versus α5-NAM.
Fig. 3: GABAergic inverted U-shape for optimal function: effects of disease and modulation of SST+ cell-mediated signaling through α5-GABA-A receptors.

References

  1. Semkovska M, Quinlivan L, O’Grady T, Johnson R, Collins A, O’Connor J, et al. Cognitive function following a major depressive episode: a systematic review and meta-analysis. Lancet Psychiatry. 2019;6:851–61.

    PubMed  Google Scholar 

  2. Neto FL, Borges G, Torres-Sanchez S, Mico JA, Berrocoso E. Neurotrophins role in depression neurobiology: a review of basic and clinical evidence. Curr Neuropharmacol. 2011;9:530–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008;33:73–83.

    CAS  PubMed  Google Scholar 

  4. Diehl DJ, Gershon S. The role of dopamine in mood disorders. Compr Psychiatry. 1992;33:115–20.

    CAS  PubMed  Google Scholar 

  5. Haroon E, Miller AH, Sanacora G. Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology. 2017;42:193–215.

    CAS  PubMed  Google Scholar 

  6. Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharm Ther. 2011;130:226–38.

    CAS  Google Scholar 

  7. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Murrough JW, Iacoviello B, Neumeister A, Charney DS, Iosifescu DV. Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies. Neurobiol Learn Mem. 2011;96:553–63.

    CAS  PubMed  Google Scholar 

  9. Hasselbalch BJ, Knorr U, Hasselbalch SG, Gade A, Kessing LV. Cognitive deficits in the remitted state of unipolar depressive disorder. Neuropsychology. 2012;26:642–51.

    PubMed  Google Scholar 

  10. Disner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011;12:467–77.

    CAS  PubMed  Google Scholar 

  11. Yang XH, Huang J, Zhu CY, Wang YF, Cheung EF, Chan RC, et al. Motivational deficits in effort-based decision making in individuals with subsyndromal depression, first-episode and remitted depression patients. Psychiatry Res. 2014;220:874–82.

    PubMed  Google Scholar 

  12. Marx EM, Williams JM, Claridge GC. Depression and social problem solving. J Abnorm Psychol. 1992;101:78–86.

    CAS  PubMed  Google Scholar 

  13. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. Arlington, VA, American Psychiatric Association; 2013.

  14. Cuthbert BN, Kozak MJ. Constructing constructs for psychopathology: the NIMH research domain criteria. J Abnorm Psychol. 2013;122:928–37.

    PubMed  Google Scholar 

  15. Fineberg NA, Haddad PM, Carpenter L, Gannon B, Sharpe R, Young AH, et al. The size, burden and cost of disorders of the brain in the UK. J Psychopharmacol. 2013;27:761–70.

    PubMed  PubMed Central  Google Scholar 

  16. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin psychiatry. 2015;76:155–62.

    PubMed  Google Scholar 

  17. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jonsson B, group Cs, et al. The economic cost of brain disorders in Europe. Eur J Neurol. 2012;19:155–62.

    CAS  PubMed  Google Scholar 

  18. Conradi HJ, Ormel J, De Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychological Med. 2011;41:1165–74.

    CAS  Google Scholar 

  19. Carvalho AF, Miskowiak KK, Hyphantis TN, Kohler CA, Alves GS, Bortolato B, et al. Cognitive dysfunction in depression - pathophysiology and novel targets. CNS Neurol Disord Drug Targets. 2014;13:1819–35.

    PubMed  Google Scholar 

  20. Airaksinen E, Larsson M, Lundberg I, Forsell Y. Cognitive functions in depressive disorders: evidence from a population-based study. Psychological Med. 2004;34:83–91.

    CAS  Google Scholar 

  21. Ahern E, Semkovska M. Cognitive functioning in the first-episode of major depressive disorder: a systematic review and meta-analysis. Neuropsychology. 2017;31:52–72.

    PubMed  Google Scholar 

  22. Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014;44:2029–40.

    CAS  PubMed  Google Scholar 

  23. Riddle M, Potter GG, McQuoid DR, Steffens DC, Beyer JL, Taylor WD. Longitudinal cognitive outcomes of clinical phenotypes of late-life depression. Am J Geriatr Psychiatry. 2017;25:1123–34.

    PubMed  PubMed Central  Google Scholar 

  24. McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Kudlow P, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30:515–27.

    PubMed  Google Scholar 

  25. Gorwood P, Corruble E, Falissard B, Goodwin GM. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am J psychiatry. 2008;165:731–9.

    PubMed  Google Scholar 

  26. Enabling discovery, development, and translation of treatments for cognitive dysfunction in depression: workshop summary. Washington (DC): National Academies Press (US); 2015.

  27. Roiser JP, Sahakian BJ. Hot and cold cognition in depression. CNS Spectr. 2013;18:139–49.

    PubMed  Google Scholar 

  28. Miskowiak KW, Carvalho AF. ‘Hot’ cognition in major depressive disorder: a systematic review. CNS Neurol Disord Drug Targets. 2014;13:1787–803.

    PubMed  Google Scholar 

  29. Gonda X, Pompili M, Serafini G, Carvalho AF, Rihmer Z, Dome P. The role of cognitive dysfunction in the symptoms and remission from depression. Ann General Psychiatry. 2015;14–27.

  30. Fossati P, Ergis AM, Allilaire JF. Executive functioning in unipolar depression: a review. L’Encephale. 2002;28:97–107.

    CAS  PubMed  Google Scholar 

  31. Bortolato B, Miskowiak KW, Kohler CA, Maes M, Fernandes BS, Berk M, et al. Cognitive remission: a novel objective for the treatment of major depression? BMC Med. 2016;14:9.

    PubMed  PubMed Central  Google Scholar 

  32. Lee RSC, Hermens DF, Porter MA, Redoblado-Hodge MA. A meta-analysis of cognitive deficits in first-episode major depressive disorder. J Affect Disord. 2012;140:113–24.

    PubMed  Google Scholar 

  33. Majer M, Ising M, Künzel H, Binder EB, Holsboer F, Modell S, et al. Impaired divided attention predicts delayed response and risk to relapse in subjects with depressive disorders. Psychol Med. 2004;34:1453–63.

    CAS  PubMed  Google Scholar 

  34. Panza F, Frisardi V, Capurso C, D’Introno A, Colacicco AM, Imbimbo BP, et al. Late-life depression, mild cognitive impairment, and dementia: possible continuum? Am J Geriatr Psychiatry. 2010;18:98–116.

    PubMed  Google Scholar 

  35. Gorman JM. Comorbid depression and anxiety spectrum disorders. Depression Anxiety. 1996;4:160–8.

    PubMed  Google Scholar 

  36. Wu Z, Fang Y. Comorbidity of depressive and anxiety disorders: challenges in diagnosis and assessment. Shanghai Arch Psychiatry. 2014;26:227–31.

    PubMed  PubMed Central  Google Scholar 

  37. Gulpers BJA, Oude Voshaar RC, Van Boxtel MPJ, Verhey FRJ, Köhler S. Anxiety as a risk factor for cognitive decline: a 12-year follow-up cohort study. Am J Geriatr Psychiatry. 2019;27:42–52.

    PubMed  Google Scholar 

  38. Yang Y, Zhang X, Zhu Y, Dai Y, Liu T, Wang Y. Cognitive impairment in generalized anxiety disorder revealed by event-related potential N270. Neuropsychiatr Dis Treat. 2015;11:1405–11.

    PubMed  PubMed Central  Google Scholar 

  39. Mah L, Binns MA, Steffens DC, Alzheimer’s Disease, Neuroimaging I. Anxiety symptoms in amnestic mild cognitive impairment are associated with medial temporal atrophy and predict conversion to Alzheimer disease. Am J Geriatr Psychiatry: Off J Am Assoc Geriatr Psychiatry. 2015;23:466–76.

    Google Scholar 

  40. McIntyre RS, Woldeyohannes HO, Soczynska JK, Maruschak NA, Wium-Andersen IK, Vinberg M, et al. Anhedonia and cognitive function in adults with MDD: results from the International Mood Disorders Collaborative Project. CNS Spectr. 2016;21:362–6.

    PubMed  Google Scholar 

  41. Richard-Devantoy S, Szanto K, Butters MA, Kalkus J, Dombrovski AY. Cognitive inhibition in older high-lethality suicide attempters. Int J Geriatr Psychiatry. 2015;30:274–83.

    PubMed  Google Scholar 

  42. Pu S, Setoyama S, Noda T. Association between cognitive deficits and suicidal ideation in patients with major depressive disorder. Sci Rep. 2017;7:11637.

    PubMed  PubMed Central  Google Scholar 

  43. Huang H, Movellan J, Paulus MP, Harle KM. The influence of depression on cognitive control: disambiguating approach and avoidance tendencies. PloS ONE. 2015;10:e0143714.

    PubMed  PubMed Central  Google Scholar 

  44. George MS, Raman R, Benedek DM, Pelic CG, Grammer GG, Stokes KT, et al. A two-site pilot randomized 3 day trial of high dose left prefrontal repetitive transcranial magnetic stimulation (rTMS) for suicidal inpatients. Brain Stimul. 2014;7:421–31.

    PubMed  Google Scholar 

  45. Newton DF, Fee C, Nikolova YS, Sibille E. Altered GABAergic function, cortical microcircuitry, and information processing in depression. In: Quevedo J, Carvalho AF, Zarate CA, editors. Neurobiology of depression. Academic Press; 2019, pp 315–29.

  46. Gold BI, Bowers MB, Roth RH, Sweeney DW. GABA levels in CSF of patients with psychiatric disorders. Am J Psychiatry. 1980;137:362–4.

    CAS  PubMed  Google Scholar 

  47. Gerner RH, Hare TA. CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101.

    CAS  PubMed  Google Scholar 

  48. Kasa K, Otsuki S, Yamamoto M, Sato M, Kuroda H, Ogawa N. Cerebrospinal fluid gamma-aminobutyric acid and homovanillic acid in depressive disorders. Biol Psychiatry. 1982;17:877–83.

    CAS  PubMed  Google Scholar 

  49. Gerner RH, Fairbanks L, Anderson GM, Young JG, Scheinin M, Linnoila M, et al. CSF neurochemistry in depressed, manic and schizophrenic patients compared with that of normal controls. Am J Psychiatry. 1984;141:1533–40.

    CAS  PubMed  Google Scholar 

  50. Berrettini WH, Nurnberger JI Jr, Hare TA, Simmons-Alling S, Gershon ES, Post RM. Reduced plasma and CSF gamma-aminobutyric acid in affective illness: effect of lithium carbonate. Biol Psychiatry. 1983;18:185–94.

    CAS  PubMed  Google Scholar 

  51. Petty F, Kramer GL, Dunnam D, Rush AJ. Plasma GABA in mood disorders. Psychopharmacol Bull. 1990;26:157–61.

    CAS  PubMed  Google Scholar 

  52. Petty F, Kramer GL, Fulton M, Davis L, Rush AJ. Stability of plasma GABA at four-year follow-up in patients with primary unipolar depression. Biol Psychiatry. 1995;37:806–10.

    CAS  PubMed  Google Scholar 

  53. Petty F, Kramer GL, Gullion CM, John Rush A. Low plasma γ-aminobutyric acid levels in male patients with depression. Biol Psychiatry. 1992;32:354–63.

    CAS  PubMed  Google Scholar 

  54. Petty F, Sherman AD. Plasma GABA in psychiatric illness. J Affect Disord. 1984;6:131–8.

    CAS  PubMed  Google Scholar 

  55. Petty F, Kramer GL, Fulton M, Moeller FG, Rush AJ. Low plasma GABA is a trait-like marker for bipolar illness. Neuropsychopharmacology. 1993;9:125–32.

    CAS  PubMed  Google Scholar 

  56. Lu YR, Fu XY, Shi LG, Jiang Y, Wu JL, Weng XJ, et al. Decreased plasma neuroactive amino acids and increased nitric oxide levels in melancholic major depressive disorder. BMC Psychiatry. 2014;14:123.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 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  Google Scholar 

  58. Plante DT, Jensen JE, Schoerning L, Winkelman JW. Reduced gamma-aminobutyric acid in occipital and anterior cingulate cortices in primary insomnia: a link to major depressive disorder? Neuropsychopharmacology. 2012;37:1548–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Shaw A, Brealy J, Richardson H, Muthukumaraswamy SD, Edden RA, John Evans C, et al. Marked reductions in visual evoked responses but not gamma-aminobutyric acid concentrations or gamma-band measures in remitted depression. Biol Psychiatry. 2013;73:691–8.

    CAS  PubMed  Google Scholar 

  60. Sanacora G, Gueorguieva R, Epperson CN, Wu Y-T, 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.

    CAS  PubMed  Google Scholar 

  61. Gabbay V, Mao X, Klein RG, Ely BA, Babb JS, Panzer AM, et al. Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents. Arch Gen psychiatry. 2012;69:139.

    CAS  PubMed  Google Scholar 

  62. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, M Matthews P, et al. Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol/Off Sci J Collegium Int Neuropsychopharmacologicum (CINP). 2008;11:255–60.

    CAS  Google Scholar 

  63. Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OAC, et al. Reductions in occipital cortex GABA levels in panic disorder detected with 1H-magnetic resonance spectroscopy. Arch Gen Psychiatry. 2001;58:556.

    CAS  PubMed  Google Scholar 

  64. Price RB, Shungu DC, Mao X, Nestadt P, Kelly C, Collins KA, et al. Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder. Biol Psychiatry. 2009;65:792–800.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sanacora G, Mason GF, Rothman DL, Krystal JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry. 2002;159:663–5.

    PubMed  Google Scholar 

  66. Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OAC, et al. Reduced cortical γ-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 1999;56:1043.

    CAS  PubMed  Google Scholar 

  67. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 2007;64:193–200.

    CAS  PubMed  Google Scholar 

  68. Northoff G, Walter M, Schulte RF, Beck J, Dydak U, Henning A, et al. GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nat Neurosci. 2007;10:1515–7.

    CAS  PubMed  Google Scholar 

  69. Walter M, Henning A, Grimm S, Schulte RF, Beck J, Dydak U, et al. The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Arch Gen Psychiatry. 2009;66:478–86.

    CAS  PubMed  Google Scholar 

  70. Steele JD, Glabus MF, Shajahan PM, Ebmeier KP. Increased cortical inhibition in depression: a prolonged silent period with transcranial magnetic stimulation (TMS). Psychological Med. 2000;30:565–70.

    CAS  Google Scholar 

  71. Bajbouj M, Lisanby SH, Lang UE, Danker-Hopfe H, Heuser I, Neu P. Evidence for impaired cortical inhibition in patients with unipolar major depression. Biol psychiatry. 2006;59:395–400.

    PubMed  Google Scholar 

  72. Levinson AJ, Fitzgerald PB, Favalli G, Blumberger DM, Daigle M, Daskalakis ZJ. Evidence of cortical inhibitory deficits in major depressive disorder. Biol psychiatry. 2010;67:458–64.

    CAS  PubMed  Google Scholar 

  73. Daskalakis ZJ, Christensen BK, Chen R, Fitzgerald PB, Zipursky RB, Kapur S. Evidence for impaired cortical inhibition on schizophrenia using transcranial magnetic stimulation. Arch Gen Psychiatry. 2002;59:347–54.

    PubMed  Google Scholar 

  74. Radhu N, de Jesus DR, Ravindran LN, Zanjani A, Fitzgerald PB, Daskalakis ZJ. A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders. Clin Neurophysiol. 2013;124:1309–20.

    PubMed  Google Scholar 

  75. Lissemore JI, Bhandari A, Mulsant BH, Lenze EJ, Reynolds CF 3rd, Karp JF, et al. Reduced GABAergic cortical inhibition in aging and depression. Neuropsychopharmacology. 2018;43:2277–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci. 1977;34:247–65.

    CAS  PubMed  Google Scholar 

  77. Cheetham SC, Crompton MR, Katona CL, Parker SJ, Horton RW. Brain GABAA/benzodiazepine binding sites and glutamic acid decarboxylase activity in depressed suicide victims. Brain Res. 1988;460:114–23.

    CAS  PubMed  Google Scholar 

  78. Karolewicz B, Maciag D, O’Dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G. Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol. 2010;13:411–20.

    CAS  PubMed  Google Scholar 

  79. Pabba M, Scifo E, Kapadia F, Nikolova YS, Ma T, Mechawar N, et al. Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging. Neurobiol Aging. 2017;58:180–90.

    PubMed  PubMed Central  Google Scholar 

  80. Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA. 2005;102:15653–8.

    CAS  PubMed  Google Scholar 

  81. Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, ffrench-Mullen J, et al. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry. 2009;14:175–89.

    CAS  PubMed  Google Scholar 

  82. Sequeira A, Klempan T, Canetti L, ffrench-Mullen J, Benkelfat C, Rouleau GA, et al. Patterns of gene expression in the limbic system of suicides with and without major depression. Mol Psychiatry. 2007;12:640–55.

    CAS  PubMed  Google Scholar 

  83. Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PloS one. 2009;4:e6585.

    PubMed  PubMed Central  Google Scholar 

  84. Cotter D, Landau S, Beasley C, Stevenson R, Chana G, MacMillan L, et al. The density and spatial distribution of gabaergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia. Biol Psychiatry. 2002;51:377–86.

    CAS  PubMed  Google Scholar 

  85. Khundakar A, Morris C, Thomas AJ. The immunohistochemical examination of GABAergic interneuron markers in the dorsolateral prefrontal cortex of patients with late-life depression. Int Psychogeriatr. 2011;23:644–53.

    PubMed  Google Scholar 

  86. 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. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 2007;32:471–82.

    CAS  Google Scholar 

  87. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Seney ML, Tripp A, McCune S, Lewis DA, Sibille E. Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression. Neurobiol Dis. 2015;73:213–9.

    CAS  PubMed  Google Scholar 

  89. 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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Douillard-Guilloux G, Lewis D, Seney ML, Sibille E. Decrease in somatostatin-positive cell density in the amygdala of females with major depression. Depress Anxiety. 2017;34:68–78.

    CAS  PubMed  Google Scholar 

  92. Seney ML, Chang LC, Oh H, Wang X, Tseng GC, Lewis DA, et al. The role of genetic sex in affect regulation and expression of GABA-related genes across species. Front Psychiatry. 2013;4:104.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Girgenti MJ, Wohleb ES, Mehta S, Ghosal S, Fogaca MV, Duman RS. Prefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomes. Transl Psychiatry. 2019;9:292.

    PubMed  PubMed Central  Google Scholar 

  95. Lin LC, Sibille E. Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target? Front Pharm. 2013;4:110.

    Google Scholar 

  96. Konradi C, Zimmerman EI, Yang C, et al. Hippocampal interneurons in bipolar disorder. Arch Gen psychiatry. 2011;68:340–50.

    PubMed  Google Scholar 

  97. Wang AY, Lohmann KM, Yang CK, Zimmerman EI, Pantazopoulos H, Herring N, et al. Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region. Acta Neuropathologica. 2011;122:615.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, et al. Hippocampal interneurons are abnormal in schizophrenia. Schizophrenia Res. 2011;131:165–73.

    Google Scholar 

  99. Morris HM, Hashimoto T, Lewis DA. Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia or schizoaffective disorder. Cereb Cortex. 2008;18:1575–87.

    PubMed  PubMed Central  Google Scholar 

  100. Guillozet-Bongaarts AL, Hyde TM, Dalley RA, Hawrylycz MJ, Henry A, Hof PR, et al. Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013;19:478.

    PubMed  PubMed Central  Google Scholar 

  101. Pantazopoulos H, Wiseman JT, Markota M, Ehrenfeld L, Berretta S. Decreased numbers of somatostatin-expressing neurons in the amygdala of subjects with bipolar disorder or schizophrenia: relationship to circadian rhythms. Biol Psychiatry. 2017;81:536–47.

    CAS  PubMed  Google Scholar 

  102. Erraji-Benchekroun L, Underwood MD, Arango V, Galfalvy H, Pavlidis P, Smyrniotopoulos P, et al. Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biol Psychiatry. 2005;57:549–58.

    CAS  PubMed  Google Scholar 

  103. Loerch PM, Lu T, Dakin KA, Vann JM, Isaacs A, Geula C, et al. Evolution of the aging brain transcriptome and synaptic regulation. PLoS ONE. 2008;3:e3329.

    PubMed  PubMed Central  Google Scholar 

  104. Rocco BR, Oh H, Shukla R, Mechawar N, Sibille E. Fluorescence-based cell-specific detection for laser-capture microdissection in human brain. Sci Rep. 2017;7:14213.

    PubMed  PubMed Central  Google Scholar 

  105. Davies P, Katzman R, Terry RD. Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa. Nature. 1980;288:279–80.

    CAS  PubMed  Google Scholar 

  106. Epelbaum J, Agid Y, Enjalbert A, Hamon M, Javoy-Agid F, Kordon C, et al. Somatostatin alterations and brain diseases. Adv Exp Med Biol. 1985;188:261–74.

    CAS  PubMed  Google Scholar 

  107. Morrison JH, Rogers J, Scherr S, Benoit R, Bloom FE. Somatostatin immunoreactivity in neuritic plaques of Alzheimer’s patients. Nature. 1985;314:90–2.

    CAS  PubMed  Google Scholar 

  108. Nakamura S. Qualitative and quantitative changes in normal aging and Alzheimer’s disease. Neurobiol Aging. 1987;8:578–9.

    CAS  PubMed  Google Scholar 

  109. Tamminga CA, Foster NL, Fedio P, Bird ED, Chase TN. Alzheimer’s disease: low cerebral somatostatin levels correlate with impaired cognitive function and cortical metabolism. Neurology. 1987;37:161–5.

    CAS  PubMed  Google Scholar 

  110. Epelbaum J, Guillou JL, Gastambide F, Hoyer D, Duron E, Viollet C. Somatostatin, Alzheimer’s disease and cognition: an old story coming of age? Prog Neurobiol. 2009;89:153–61.

    CAS  PubMed  Google Scholar 

  111. Chang LC, Jamain S, Lin CW, Rujescu D, Tseng GC, Sibille E. A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies. PLoS ONE. 2014;9:e90980.

    PubMed  PubMed Central  Google Scholar 

  112. 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  Google Scholar 

  113. Glorioso C, Sabatini M, Unger T, Hashimoto T, Monteggia LM, Lewis DA, et al. Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood. MolPsychiatry. 2006;11:633–48.

    CAS  Google Scholar 

  114. Oh H, Piantadosi SC, Rocco BR, Lewis DA, Watkins SC, Sibille E. The role of dendritic brain-derived neurotrophic factor transcripts on altered inhibitory circuitry in depression. Biol Psychiatry. 2019;85:517–26.

    CAS  PubMed  Google Scholar 

  115. Oh H, Lewis DA, Sibille E. The role of BDNF in age-dependent changes of excitatory and inhibitory synaptic markers in the human prefrontal cortex. Neuropsychopharmacology. 2016;41:3080–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Yu H, Chen ZY. The role of BDNF in depression on the basis of its location in the neural circuitry. Acta Pharm Sin. 2011;32:3–11.

    CAS  Google Scholar 

  117. Stengel A, Tache YF. Activation of brain somatostatin signaling suppresses CRF receptor-mediated stress response. Front Neurosci. 2017;11:231.

    PubMed  PubMed Central  Google Scholar 

  118. Prevot TD, Gastambide F, Viollet C, Henkous N, Martel G, Epelbaum J, et al. Roles of hippocampal somatostatin receptor subtypes in stress response and emotionality. Neuropsychopharmacology. 2017;42:1647–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Arancibia S, Payet O, Givalois L, Tapia-Arancibia L. Acute stress and dexamethasone rapidly increase hippocampal somatostatin synthesis and release from the dentate gyrus hilus. Hippocampus. 2001;11:469–77.

    CAS  PubMed  Google Scholar 

  120. Faron-Gorecka A, Kusmider M, Kolasa M, Zurawek D, Szafran-Pilch K, Gruca P, et al. Chronic mild stress alters the somatostatin receptors in the rat brain. Psychopharmacol (Berl). 2016;233:255–66.

    CAS  Google Scholar 

  121. Zeyda T, Diehl N, Paylor R, Brennan MB, Hochgeschwender U. Impairment in motor learning of somatostatin null mutant mice. Brain Res. 2001;906:107–14.

    CAS  PubMed  Google Scholar 

  122. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 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.

    CAS  PubMed  Google Scholar 

  124. Obermayer J, Heistek TS, Kerkhofs A, Goriounova NA, Kroon T, Baayen JC, et al. Lateral inhibition by Martinotti interneurons is facilitated by cholinergic inputs in human and mouse neocortex. Nat Commun. 2018;9:4101.

    PubMed  PubMed Central  Google Scholar 

  125. Pfeffer CK, Xue M, He M, Huang ZJ, Scanziani M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat Neurosci. 2013;16:1068–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Fino E, Yuste R. Dense inhibitory connectivity in neocortex. Neuron. 2011;69:1188–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Karnani MM, Jackson J, Ayzenshtat I, Hamzehei Sichani A, Manoocheri K, Kim S, et al. Opening holes in the blanket of inhibition: localized lateral disinhibition by VIP interneurons. J Neurosci. 2016;36:3471–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Pi HJ, Hangya B, Kvitsiani D, Sanders JI, Huang ZJ, Kepecs A. Cortical interneurons that specialize in disinhibitory control. Nature. 2013;503:521–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Gentet LJ, Kremer Y, Taniguchi H, Huang ZJ, Staiger JF, Petersen CC. Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex. Nat Neurosci. 2012;15:607–12.

    CAS  PubMed  Google Scholar 

  130. Abbas AI, Sundiang MJM, Henoch B, Morton MP, Bolkan SS, Park AJ, et al. Somatostatin interneurons facilitate hippocampal-prefrontal synchrony and prefrontal spatial encoding. Neuron. 2018;100:926–39. e923.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Stefanelli T, Bertollini C, Luscher C, Muller D, Mendez P. Hippocampal somatostatin interneurons control the size of neuronal memory ensembles. Neuron. 2016;89:1074–85.

    CAS  PubMed  Google Scholar 

  132. Sturgill JF, Isaacson JS. Somatostatin cells regulate sensory response fidelity via subtractive inhibition in olfactory cortex. Nat Neurosci. 2015;18:531–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Schmid LC, Mittag M, Poll S, Steffen J, Wagner J, Geis HR, et al. Dysfunction of somatostatin-positive interneurons associated with memory deficits in an Alzheimer’s disease model. Neuron. 2016;92:114–25.

    CAS  PubMed  Google Scholar 

  134. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama. 2010;303:47–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Raskin J, Wiltse CG, Siegal A, Sheikh J, Xu J, Dinkel JJ, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007;164:900–9.

    PubMed  Google Scholar 

  136. Shilyansky C, Williams LM, Gyurak A, Harris A, Usherwood T, Etkin A. Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study. lancet Psychiatry. 2016;3:425–35.

    PubMed  PubMed Central  Google Scholar 

  137. Sayyah M, Eslami K, AlaiShehni S, Kouti L. Cognitive function before and during treatment with selective serotonin reuptake inhibitors in patients with depression or obsessive-compulsive disorder. Psychiatry J. 2016;2016:5480391.

    PubMed  PubMed Central  Google Scholar 

  138. Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res. 2006;145:39–48.

    PubMed  Google Scholar 

  139. Baune BT, Miller R, McAfoose J, Johnson M, Quirk F, Mitchell D. The role of cognitive impairment in general functioning in major depression. Psychiatry Res. 2010;176:183–9.

    PubMed  Google Scholar 

  140. Halvorsen M, Høifødt RS, Myrbakk IN, Wang CEA, Sundet K, Eisemann M, et al. Cognitive function in unipolar major depression: a comparison of currently depressed, previously depressed, and never depressed individuals. J Clin Exp Neuropsychol. 2012;34:782–90.

    PubMed  Google Scholar 

  141. Snyder HR. Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: a meta-analysis and review. Psychol Bull. 2013;139:81–132.

    PubMed  Google Scholar 

  142. McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17:1557–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Madhoo M, Keefe RS, Roth RM, Sambunaris A, Wu J, Trivedi MH, et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 2014;39:1388–98.

    CAS  Google Scholar 

  144. Miskowiak KW, Vinberg M, Christensen EM, Bukh JD, Harmer CJ, Ehrenreich H, et al. Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. Neuropsychopharmacology. 2014;39:1399–408.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Kaser M, Zaman R, Sahakian BJ. Cognition as a treatment target in depression. Psychological Med. 2017;47:987–9.

    CAS  Google Scholar 

  146. McIntyre R, Harrison J, Loft H, Jacobson W, Olsen C. The effects of vortioxetine on cognitive function in patients with major depressive disorder: a meta-analysis of three randomized controlled trials. Int J Neuropsychopharmacol. 2016;19:pyw055.

    PubMed  PubMed Central  Google Scholar 

  147. Meltzer-Brody S, Colquhoun H, Riesenberg R, Epperson CN, Deligiannidis KM, Rubinow DR, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392:1058–70.

    CAS  PubMed  Google Scholar 

  148. Luscher B, Mohler H. Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience. F1000Res. 2019;8:F1000 Faculty Rev-751.

  149. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75:139–48.

    PubMed  Google Scholar 

  150. Sigel E, Ernst M. The benzodiazepine binding sites of GABAA receptors. Trends Pharm Sci. 2018;39:659–71.

    CAS  PubMed  Google Scholar 

  151. Nardi AE, Cosci F, Balon R, Weintraub SJ, Freire RC, Krystal JH, et al. The prescription of benzodiazepines for panic disorder: time for an evidence-based educational approach. J Clin Psychopharmacol. 2018;38:283–5.

    PubMed  Google Scholar 

  152. Gomez AF, Barthel AL, Hofmann SG. Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review. Expert Opin Pharmacother. 2018;19:883–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Vgontzas AN, Kales A, Bixler EO. Benzodiazepine side effects: role of pharmacokinetics and pharmacodynamics. Pharmacology. 1995;51:205–23.

    CAS  PubMed  Google Scholar 

  154. Gunther U, Benson J, Benke D, Fritschy JM, Reyes G, Knoflach F, et al. Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci USA. 1995;92:7749–53.

    CAS  PubMed  Google Scholar 

  155. Parker GB, Graham RK. Determinants of treatment-resistant depression: the salience of benzodiazepines. J Nerv Ment Dis. 2015;203:659–63.

    PubMed  Google Scholar 

  156. Ogawa Y, Takeshima N, Hayasaka Y, Tajika A, Watanabe N, Streiner D, et al. Antidepressants plus benzodiazepines for adults with major depression. Cochrane Database Syst Rev. 2019;6:CD001026.

    PubMed  Google Scholar 

  157. Benasi G, Guidi J, Offidani E, Balon R, Rickels K, Fava GA. Benzodiazepines as a monotherapy in depressive disorders: a systematic review. Psychother Psychosom. 2018;87:65–74.

    PubMed  Google Scholar 

  158. Rudolph U, Mohler H. GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharm. 2006;6:18–23.

    CAS  Google Scholar 

  159. Smith KS, Engin E, Meloni EG, Rudolph U. Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice. Neuropharmacology. 2012;63:250–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Behlke LM, Foster RA, Liu J, Benke D, Benham RS, Nathanson AJ, et al. A pharmacogenetic ‘restriction-of-function’ approach reveals evidence for anxiolytic-like actions mediated by alpha5-containing GABAA receptors in mice. Neuropsychopharmacology. 2016;41:2492–501.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Botta P, Demmou L, Kasugai Y, Markovic M, Xu C, Fadok JP, et al. Regulating anxiety with extrasynaptic inhibition. Nat Neurosci. 2015;18:1493–500.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Piantadosi SC, French BJ, Poe MM, Timic T, Markovic BD, Pabba M, et al. Sex-dependent anti-stress effect of an alpha5 subunit containing GABAA receptor positive allosteric modulator. Front Pharm. 2016;7:446.

    Google Scholar 

  163. Koh MT, Rosenzweig-Lipson S, Gallagher M. Selective GABA(A) alpha5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology. 2013;64:145–52.

    CAS  PubMed  Google Scholar 

  164. Prevot TD, Li G, Cook JM, Sibille E. Insight into novel treatment for cognitive dysfunctions across disorders. ACS Chem Neurosci. 2019;10:2088–90.

    CAS  PubMed  Google Scholar 

  165. Prevot TD, Li G, Vidojevic A, Misquitta KA, Fee C, Santrac A, et al. Novel benzodiazepine-like ligands with various anxiolytic, antidepressant, or pro-cognitive profiles. Mol Neuropsychiatry. 2019;5:84–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Donegan JJ, Boley AM, Yamaguchi J, Toney GM, Lodge DJ. Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner. Nat Commun. 2019;10:2819.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Sieghart W, Savic MM. International union of basic and clinical pharmacology. CVI: GABAA receptor subtype- and function-selective ligands: key issues in translation to humans. Pharm Rev. 2018;70:836–78.

    CAS  PubMed  Google Scholar 

  168. Magnin E, Francavilla R, Amalyan S, Gervais E, David LS, Luo X, et al. Input-specific synaptic location and function of the alpha5 GABAA receptor subunit in the mouse CA1 hippocampal neurons. J Neurosci. 2019;39:788–801.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Hu X, Rocco BR, Fee C, Sibille E. Cell type-specific gene expression of alpha 5 subunit-containing gamma-aminobutyric acid subtype A receptors in human and mouse frontal cortex. Mol Neuropsychiatry. 2019;4:204–15.

    PubMed  PubMed Central  Google Scholar 

  170. Mohler H, Rudolph U. Disinhibition, an emerging pharmacology of learning and memory. F1000Res 2017;6:Faculty Rev-101.

  171. Schulz JM, Knoflach F, Hernandez MC, Bischofberger J. Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear alpha5-GABAA receptors. Nat Commun. 2018;9:3576.

    PubMed  PubMed Central  Google Scholar 

  172. Bonin RP, Martin LJ, MacDonald JF, Orser BA. Alpha5GABAA receptors regulate the intrinsic excitability of mouse hippocampal pyramidal neurons. J Neurophysiol. 2007;98:2244–54.

    CAS  PubMed  Google Scholar 

  173. Schulz JM, Knoflach F, Hernandez M-C, Bischofberger J. Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABAA receptors. Nat Commun. 2018;9:3576.

    PubMed  PubMed Central  Google Scholar 

  174. Gill KM, Lodge DJ, Cook JM, Aras S, Grace AA. A novel alpha5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia. Neuropsychopharmacology. 2011;36:1903–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Milic M, Timic T, Joksimovic S, Biawat P, Rallapalli S, Divljakovic J, et al. PWZ-029, an inverse agonist selective for alpha(5) GABAA receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats. Behav Brain Res. 2013;241:206–13.

    CAS  PubMed  Google Scholar 

  176. Martinez-Cue C, Martinez P, Rueda N, Vidal R, Garcia S, Vidal V, et al. Reducing GABAA alpha5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome. J Neurosci. 2013;33:3953–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012;74:467–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. NeuroImage Clin. 2015;7:688–98.

    PubMed  PubMed Central  Google Scholar 

  179. Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM. Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of Alpha5-containing GABAA receptors. Neuropsychopharmacology. 2015;40:2499–509.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Zanos P, Nelson ME, Highland JN, Krimmel SR, Georgiou P, Gould TD, et al. A negative allosteric modulator for alpha5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro. 2017;4:ENEURO.0285–16.

    Google Scholar 

  181. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci. 2002;22:5572–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Martin LJ, Zurek AA, MacDonald JF, Roder JC, Jackson MF, Orser BA. Alpha5GABAA receptor activity sets the threshold for long-term potentiation and constrains hippocampus-dependent memory. J Neurosci. 2010;30:5269–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Zurek AA, Kemp SW, Aga Z, Walker S, Milenkovic M, Ramsey AJ, et al. alpha5GABAA receptor deficiency causes autism-like behaviors. Ann Clin Transl Neurol. 2016;3:392–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Engin E, Benham RS, Rudolph U. An emerging circuit pharmacology of GABAA receptors. Trends Pharm Sci. 2018;39:710–32.

    CAS  PubMed  Google Scholar 

  185. Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci. 2007;10:411–3.

    CAS  PubMed  Google Scholar 

  186. Zurek AA, Yu J, Wang DS, Haffey SC, Bridgwater EM, Penna A, et al. Sustained increase in alpha5GABAA receptor function impairs memory after anesthesia. J Clin Invest. 2014;124:5437–41.

    PubMed  PubMed Central  Google Scholar 

  187. Davis M. Neurobiology of fear responses: the role of the amygdala. J Neuropsychiatry Clin Neurosci. 1997;9:382–402.

    CAS  PubMed  Google Scholar 

  188. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078.

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Wang DS, Penna A, Orser BA. Ketamine increases the function of gamma-aminobutyric acid type A receptors in hippocampal and cortical neurons. Anesthesiology. 2017;126:666–77.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  192. 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.

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Campbell Family Mental Health Research Institute of CAMH.

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  1. Campbell Family Mental Health Research Institute of CAMH, Toronto, ON, Canada

    Thomas Prévot & Etienne Sibille

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Thomas Prévot & Etienne Sibille

  3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Etienne Sibille

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Prévot, T., Sibille, E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders. Mol Psychiatry 26, 151–167 (2021). https://doi.org/10.1038/s41380-020-0727-3

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