6. Gunther U, Benson J, Benke D, Fritschy J-M, Reyes G, et al. (1995) Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci U S A 92: 7749–7753. 7. Crestani F, Lorez M, Baer K, Essrich C, Benke D, et al. (1999) Decreased GABA(A)-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci 2: 833–839. 8. Earnheart JC, Schweizer C, Crestani F, Iwasato T, Itohara S, et al. (2007) GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J Neurosci 27: 3845–3854. 9. Shen Q, Lal R, Luellen BA, Earnheart JC, Andrews AM, et al. (2010) Gamma- aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry 68: 512–520. 10. Dixon CI, Rosahl TW, Stephens DN (2008) Targeted deletion of the GABRA2 gene encoding alpha2-subunits of GABA(A) receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiaz- epines and barbiturates. Pharmacol Biochem Behav 90: 1–8. 11. Vollenweider I, Smith KS, Keist R, Rudolph U (2011) Antidepressant-like properties of alpha2-containing GABA(A) receptors. Behav Brain Res 217: 77– 80. 12. Smith KS, Rudolph U (2012) Anxiety and depression: mouse genetics and pharmacological approaches to the role of GABA(A) receptor subtypes. Neuropharmacology 62: 54–62. 13. Mohler H (2012) The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 62: 42–53. 14. Carlson GA, Cantwell DP (1980) Unmasking masked depression in children and adolescents. Am J Psychiatry 137: 445–449. 15. Weissman MM, Warner V, Wickramaratne P, Moreau D, Olfson M (1997) Offspring of depressed parents. 10 Years later. Arch Gen Psychiatry 54: 932– 940. 16. Phillips NK, Hammen CL, Brennan PA, Najman JM, Bor W (2005) Early adversity and the prospective prediction of depressive and anxiety disorders in adolescents. J Abnorm Child Psychol 33: 13–24. 17. Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA (2011) Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476: 458–461. 18. Vollmayr B, Simonis C, Weber S, Gass P, Henn F (2003) Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol Psychiatry 54: 1035–1040. 19. Holick KA, Lee DC, Hen R, Dulawa SC (2008) Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology 33: 406–417. 20. Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, et al. (2008) Drug- Dependent Requirement of Hippocampal Neurogenesis in a Model of Depression and of Antidepressant Reversal. Biol Psychiatry 64: 293–301. 21. Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, et al. (2008) TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 59: 399–412. 22. Samuels BA, Hen R (2011) Neurogenesis and affective disorders. Eur J Neurosci 33: 1152–1159. 23. Hanson ND, Owens MJ, Nemeroff CB (2011) Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal. Neuropsychopharmacology. 24. Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci. 25. Song J, Zhong C, Bonaguidi MA, Sun GJ, Hsu D, et al. (2012) Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature 489: 150–154. 26. Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, et al. (2006) GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439: 589–593. 27. Jagasia R, Steib K, Englberger E, Herold S, Faus-Kessler T, et al. (2009) GABA- cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci 29: 7966–7977. 28. Sernagor E, Chabrol F, Bony G, Cancedda L (2010) GABAergic control of neurite outgrowth and remodeling during development and adult neurogenesis: general rules and differences in diverse systems. Front Cell Neurosci 4: 11. 29. Ge S, Pradhan DA, Ming Gl, Song H (2007) GABA sets the tempo for activity- dependent adult neurogenesis. Trends Neurosci 30: 1–8. 30. Purves D (1988) Body and brain: a trophic theory of neural connections. Cambridge, MA: Harvard University Press. 31. Akerman CJ, Cline HT (2007) Refining the roles of GABAergic signaling during neural circuit formation. Trends Neurosci 30: 382–389. 32. Hensch TK (2005) Critical period plasticity in local cortical circuits. Nat Rev Neurosci 6: 877–888. 33. Fagiolini M, Hensch TK (2000) Inhibitory threshold for critical-period activation in primary visual cortex. Nature 404: 183–186. 34. Harauzov A, Spolidoro M, DiCristo G, De Pasquale R, Cancedda L, et al. (2010) Reducing intracortical inhibition in the adult visual cortex promotes ocular dominance plasticity. J Neurosci 30: 361–371. Development of Anxious-Depression-Related Behavior 35. Hayashi S, McMahon AP (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 244: 305–318. 36. Schweizer C, Balsiger S, Bluethmann H, Mansuy M, Fritschy JM, et al. (2003) The gamma2 subunit of GABA(A) receptors is required for maintenance of receptors at mature synapses. Mol Cell Neurosci 24: 442–450. 37. Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, et al. (2001) Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1: 4. 38. Low K, Crestani F, Keist R, Benke D, Brunig I, et al. (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290: 131–134. 39. Depino AM, Tsetsenis T, Gross C (2008) GABA homeostasis contributes to the developmental programming of anxiety-related behavior. Brain Res 1210: 189– 199. 40. Weissman MM, Leaf PJ, Holzer CE 3rd, Myers JK, Tischler GL (1984) The epidemiology of depression. An update on sex differences in rates. Journal of affective disorders 7: 179–188. 41. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU (2012) Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. International journal of methods in psychiatric research. 42. Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92: 180–185. 43. Lucki I (1997) The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 8: 523–532. 44. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85: 367– 370. 45. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266: 730–732. 46. Castagne V, Moser P, Roux S, Porsolt RD (2011) Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci Chapter 8: Unit 8 10A. 47. Bilkei-Gorzo A, Racz I, Michel K, Zimmer A (2002) Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. J Neurosci 22: 10046–10052. 48. Clancy B, Kersh B, Hyde J, Darlington RB, Anand KJ, et al. (2007) Web-based method for translating neurodevelopment from laboratory species to humans. Neuroinformatics 5: 79–94. 49. Silver DP, Livingston DM (2001) Self-excising retroviral vectors encoding the Cre recombinase overcome Cre-mediated cellular toxicity. Mol Cell 8: 233–243. 50. Schmidt-Supprian M, Rajewsky K (2007) Vagaries of conditional gene targeting. Nat Immunol 8: 665–668. 51. Kim JJ, Clark RE, Thompson RF (1995) Hippocampectomy impairs the memory of recently, but not remotely acquired trace eyeblink conditioned responses. Behav Neurosci 109: 195–203. 52. Tsetsenis T, Ma XH, Lo Iacono L, Beck SG, Gross C (2007) Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nat Neurosci 10: 896–902. 53. Bergami M, Rimondini R, Santi S, Blum R, Gotz M, et al. (2008) Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proc Natl Acad Sci USA 105: 15570–15575. 54. Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, et al. (2009) Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry 14: 959–967W. 55. Koob GF (2012) Animal models of psychiatric disorders. Handb Clin Neurol 106: 137–166. 56. Duman CH (2010) Models of depression. Vitamins and hormones 82: 1–21. 57. Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47: 379– 391. 58. Hasler G, Drevets WC, Manji HK, Charney DS (2004) Discovering endophenotypes for major depression. Neuropsychopharmacology 29: 1765– 1781. 59. Leussis MP, Andersen SL (2008) Is adolescence a sensitive period for depression? Behavioral and neuroanatomical findings from a social stress model. Synapse 62: 22–30. 60. Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, et al. (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416: 396–400. 61. Ansorge MS, Hen R, Gingrich JA (2007) Neurodevelopmental origins of depressive disorders. Curr Opin Pharmacol 7: 8–17. 62. Sibille E, Pavlides C, Benke D, Toth M (2000) Genetic inactivation of the Serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. J Neurosci 20: 2758–2765. 63. Vinkers CH, Oosting RS, van Bogaert MJ, Olivier B, Groenink L (2010) Early- life blockade of 5-HT(1A) receptors alters adult anxiety behavior and benzodiazepine sensitivity. Biol Psychiatry 67: 309–316. 64. Yoo JH, Lee HK, Kim HC, Lee SY, Jang CG (2010) GABA(A) receptors mediate the attenuating effects of a 5-HT(3) receptor antagonist on methamphetamine-induced behavioral sensitization in mice. Synapse 64: 274– 279. PLOS ONE | www.plosone.org 11 October 2012 | Volume 7 | Issue 10 | e47441