Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The Rap1 small GTPase is a critical mediator of the effects of stress on prefrontal cortical dysfunction

Abstract

The neural molecular and biochemical response to stress is a distinct physiological process, and multiple lines of evidence indicate that the prefrontal cortex (PFC) is particularly sensitive to, and afflicted by, exposure to stress. Largely through this PFC dysfunction, stress has a characterized role in facilitating cognitive impairment, which is often dissociable from its effects on non-cognitive behaviors. The Rap1 small GTPase pathway has emerged as a commonly disrupted intracellular target in neuropsychiatric conditions, whether it be via alterations in Rap1 expression or through alterations in the expression of direct and specific upstream Rap1 activators and inhibitors. Here we demonstrate that escalating, intermittent stress increases Rap1 in mouse PFC synapses, results in cognitive impairments, and reduces the preponderance of mature dendritic spines in PFC neurons. Using viral-mediated gene transfer, we reveal that the hyper-induction of Rap1 in the PFC is sufficient to drive stress-relevant cognitive and synaptic phenotypes. These findings point to Rap1 as a critical mediator of stress-driven neuronal and behavioral pathology and highlight a previously unrecognized involvement for Rap1 in novelty-driven PFC engagement.

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: Restraint stress alters Rap1 levels and produces cognitive and synaptic aberrations.
Fig. 2: mPFC Rap1 adversely impacts Y-maze spontaneous alternation behavior.
Fig. 3: mPFC Rap1 impairs object-in-place recognition memory.
Fig. 4: Rap1 reduces dendritic spine subtype density in the mPFC.
Fig. 5: Rap1 reduces novelty-mediated induction of IEGs in the mPFC.

References

  1. 1.

    Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9:690–701.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 2002;16:1587–609.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Penzes P, Cahill ME. Deconstructing signal transduction pathways that regulate the actin cytoskeleton in dendritic spines. Cytoskeleton (Hoboken). 2012;69:426–41.

    CAS  Article  Google Scholar 

  4. 4.

    Woolfrey KM, Srivastava DP. Control of dendritic spine morphological and functional plasticity by small GTPases. Neural Plast. 2016;2016:3025948.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5.

    Woolfrey KM, Srivastava DP, Photowala H, Yamashita M, Barbolina MV, Cahill ME, et al. Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat Neurosci. 2009;12:1275–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Bos JL. Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci. 2006;31:680–6.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Jossin Y, Cooper JA. Reelin, Rap1 and N-cadherin orient the migration of multipolar neurons in the developing neocortex. Nat Neurosci. 2011;14:697–703.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Lilja J, Zacharchenko T, Georgiadou M, Jacquemet G, De Franceschi N, Peuhu E, et al. SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. Nat Cell Biol. 2017;19:292–305.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Takahashi M, Li Y, Dillon TJ, Stork PJ. Phosphorylation of Rap1 by cAMP-dependent protein kinase (PKA) creates a binding site for KSR to sustain ERK activation by cAMP. J Biol Chem. 2017;292:1449–61.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    York RD, Yao H, Dillon T, Ellig CL, Eckert SP, McCleskey EW, et al. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature. 1998;392:622–6.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Kortholt A, Bolourani P, Rehmann H, Keizer-Gunnink I, Weeks G, Wittinghofer A, et al. A Rap/phosphatidylinositol 3-kinase pathway controls pseudopod formation [corrected]. Mol Biol Cell. 2010;21:936–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Xie Z, Huganir RL, Penzes P. Activity-dependent dendritic spine structural plasticity is regulated by small GTPase Rap1 and its target AF-6. Neuron. 2005;48:605–18.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham DE. SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron. 2004;43:563–74.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009;360:599–605.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Funk AJ, Rumbaugh G, Harotunian V, McCullumsmith RE, Meador-Woodruff JH. Decreased expression of NMDA receptor-associated proteins in frontal cortex of elderly patients with schizophrenia. Neuroreport. 2009;20:1019–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008;40:880–5.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Chen X, Wang X, Hossain S, O’Neill FA, Walsh D, Pless L, et al. Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia. Hum Mol Genet. 2006;15:3329–42.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Xu B, Woodroffe A, Rodriguez-Murillo L, Roos JL, van Rensburg EJ, Abecasis GR, et al. Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans. Proc Natl Acad Sci USA. 2009;106:16746–51.

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Bacchelli E, Blasi F, Biondolillo M, Lamb JA, Bonora E, Barnby G, et al. Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Mol Psychiatry. 2003;8:916–24.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Middeldorp CM, Vink JM, Hettema JM, de Geus EJ, Kendler KS, Willemsen G, et al. An association between Epac-1 gene variants and anxiety and depression in two independent samples. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:214–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Dwivedi Y, Mondal AC, Rizavi HS, Faludi G, Palkovits M, Sarosi A, et al. Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Arch Gen Psychiatry. 2006;63:639–48.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Yuan P, Zhou R, Wang Y, Li X, Li J, Chen G, et al. Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord. 2010;124:164–9.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Hains AB, Arnsten AF. Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness. Learn Mem. 2008;15:551–64.

    PubMed  Article  Google Scholar 

  24. 24.

    Compas BE. Psychobiological processes of stress and coping: implications for resilience in children and adolescents-comments on the papers of Romeo & McEwen and Fisher et al. Ann NY Acad Sci. 2006;1094:226–34.

    PubMed  Article  Google Scholar 

  25. 25.

    Tsuchiya KJ, Byrne M, Mortensen PB. Risk factors in relation to an emergence of bipolar disorder: a systematic review. Bipolar Disord 2003;5:231–42.

    PubMed  Article  Google Scholar 

  26. 26.

    Corcoran C, Mujica-Parodi L, Yale S, Leitman D, Malaspina D. Could stress cause psychosis in individuals vulnerable to schizophrenia? CNS Spectr. 2002;7:41–2.

    Article  Google Scholar 

  27. 27.

    Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Mika A, Mazur GJ, Hoffman AN, Talboom JS, Bimonte-Nelson HA, Sanabria F, et al. Chronic stress impairs prefrontal cortex-dependent response inhibition and spatial working memory. Behav Neurosci. 2012;126:605–19.

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    McEwen BS, Morrison JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron. 2013;79:16–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10:410–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Bogdanov M, Schwabe L. Transcranial stimulation of the dorsolateral prefrontal cortex prevents stress-induced working memory deficits. J Neurosci. 2016;36:1429–37.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Qin S, Hermans EJ, van Marle HJ, Luo J, Fernandez G. Acute psychological stress reduces working memory-related activity in the dorsolateral prefrontal cortex. Biol Psychiatry. 2009;66:25–32.

    PubMed  Article  Google Scholar 

  33. 33.

    Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8:365–71.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6:603–21.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 2006;8:383–95.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Pan BX, Vautier F, Ito W, Bolshakov VY, Morozov A. Enhanced cortico-amygdala efficacy and suppressed fear in absence of Rap1. J Neurosci. 2008;28:2089–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Barker GR, Bird F, Alexander V, Warburton EC. Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J Neurosci. 2007;27:2948–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Cahill ME, Xie Z, Day M, Photowala H, Barbolina MV, Miller CA, et al. Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes. Proc Natl Acad Sci USA. 2009;106:13058–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Kraeuter AK, Guest PC, Sarnyai Z. The Y-Maze for assessment of spatial working and reference memory in mice. Methods Mol Biol. 2019;1916:105–11.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Seibenhener ML, Wooten MC. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp. 2015;e52434.

  41. 41.

    Miller MM, McEwen BS. Establishing an agenda for translational research on PTSD. Ann NY Acad Sci. 2006;1071:294–312.

    PubMed  Article  Google Scholar 

  42. 42.

    Torok B, Sipos E, Pivac N, Zelena D. Modelling posttraumatic stress disorders in animals. Prog Neuropsychopharmacol Biol Psychiatry. 2019;90:117–33.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Cahill ME, Walker DM, Gancarz AM, Wang ZJ, Lardner CK, Bagot RC, et al. The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. Mol Psychiatry. 2018;23:1474–86.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Sadler AM, Bailey SJ. Repeated daily restraint stress induces adaptive behavioural changes in both adult and juvenile mice. Physiol Behav. 2016;167:313–23.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Farovik A, Dupont LM, Arce M, Eichenbaum H. Medial prefrontal cortex supports recollection, but not familiarity, in the rat. J Neurosci. 2008;28:13428–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Uylings HB, Groenewegen HJ, Kolb B. Do rats have a prefrontal cortex? Behav Brain Res. 2003;146:3–17.

    PubMed  Article  Google Scholar 

  47. 47.

    Cahill ME, Bagot RC, Gancarz AM, Walker DM, Sun H, Wang ZJ, et al. Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through rap1 small GTPase signaling. Neuron. 2016;89:566–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Jeong JY, Lee DH, Kang SS. Effects of chronic restraint stress on body weight, food intake, and hypothalamic gene expressions in mice. Endocrinol Metab (Seoul). 2013;28:288–96.

    Article  Google Scholar 

  49. 49.

    Arnsten AF, Raskind MA, Taylor FB, Connor DF. The effects of stress exposure on prefrontal cortex: translating basic research into successful treatments for post-traumatic stress disorder. Neurobiol Stress. 2015;1:89–99.

    PubMed  Article  Google Scholar 

  50. 50.

    Barker GR, Warburton EC. NMDA receptor plasticity in the perirhinal and prefrontal cortices is crucial for the acquisition of long-term object-in-place associative memory. J Neurosci. 2008;28:2837–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Cahill ME, Browne CJ, Wang J, Hamilton PJ, Dong Y, Nestler EJ. Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure. J Neurochem. 2018;147:84–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Neve RL, Neve KA, Nestler EJ, Carlezon WA Jr. Use of herpes virus amplicon vectors to study brain disorders. Biotechniques. 2005;39:381–91.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Penrod RD, Wells AM, Carlezon WA Jr., Cowan CW. Use of adeno-associated and herpes simplex viral vectors for in vivo neuronal expression in mice. Curr Protoc Neurosci. 2015;73:4.37.1–31.

    Article  Google Scholar 

  54. 54.

    Gallo FT, Katche C, Morici JF, Medina JH, Weisstaub NV. Immediate early genes, memory and psychiatric disorders: focus on c-Fos, Egr1 and Arc. Front Behav Neurosci. 2018;12:79.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. 55.

    Kubik S, Miyashita T, Guzowski JF. Using immediate-early genes to map hippocampal subregional functions. Learn Mem. 2007;14:758–70.

    PubMed  Article  Google Scholar 

  56. 56.

    Minatohara K, Akiyoshi M, Okuno H. Role of immediate-early genes in synaptic plasticity and neuronal ensembles underlying the memory trace. Front Mol Neurosci. 2015;8:78.

    PubMed  Google Scholar 

  57. 57.

    McAvoy T, Zhou MM, Greengard P, Nairn AC. Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology. Proc Natl Acad Sci USA. 2009;106:3531–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Lee E, Lee J, Kim E. Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biol Psychiatry. 2017;81:838–47.

    PubMed  Article  Google Scholar 

  59. 59.

    Apicelli AJ, Uhlmann EJ, Baldwin RL, Ding H, Nagy A, Guha A, et al. Role of the Rap1 GTPase in astrocyte growth regulation. Glia. 2003;42:225–34.

    PubMed  Article  Google Scholar 

  60. 60.

    Sinha R, Lacadie C, Skudlarski P, Wexler BE. Neural circuits underlying emotional distress in humans. Ann NY Acad Sci. 2004;1032:254–7.

    PubMed  Article  Google Scholar 

  61. 61.

    Lalonde R. The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev. 2002;26:91–104.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Yang ST, Shi Y, Wang Q, Peng JY, Li BM. Neuronal representation of working memory in the medial prefrontal cortex of rats. Mol Brain. 2014;7:61.

    PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Tada T, Sheng M. Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol. 2006;16:95–101.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci. 2001;4:1086–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20.

    PubMed  Article  Google Scholar 

  66. 66.

    Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, et al. Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol. 2008;507:1141–50.

    PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Holtmaat AJ, Trachtenberg JT, Wilbrecht L, Shepherd GM, Zhang X, Knott GW, et al. Transient and persistent dendritic spines in the neocortex in vivo. Neuron. 2005;45:279–91.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Bourne J, Harris KM. Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol. 2007;17:381–6.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Miyashita T, Kubik S, Haghighi N, Steward O, Guzowski JF. Rapid activation of plasticity-associated gene transcription in hippocampal neurons provides a mechanism for encoding of one-trial experience. J Neurosci. 2009;29:898–906.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    DeNardo L, Luo L. Genetic strategies to access activated neurons. Curr Opin Neurobiol. 2017;45:121–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, et al. Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J Neurosci. 2001;21:5484–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Tanimizu T, Kono K, Kida S. Brain networks activated to form object recognition memory. Brain Res Bull. 2018;141:27–34.

    PubMed  Article  Google Scholar 

  74. 74.

    Barbosa FF, Santos JR, Meurer YS, Macedo PT, Ferreira LM, Pontes IM, et al. Differential cortical c-Fos and Zif-268 expression after object and spatial memory processing in a standard or episodic-like object recognition task. Front Behav Neurosci. 2013;7:112.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Bland ST, Schmid MJ, Der-Avakian A, Watkins LR, Spencer RL, Maier SF. Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress. Brain Res. 2005;1051:90–9.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010;30:16082–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Goldstein JM, Jerram M, Abbs B, Whitfield-Gabrieli S, Makris N. Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci. 2010;30:431–8.

    PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Goldfarb EV, Seo D, Sinha R. Sex differences in neural stress responses and correlation with subjective stress and stress regulation. Neurobiol Stress. 2019;11:100177.

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Sood A, Chaudhari K, Vaidya VA. Acute stress evokes sexually dimorphic, stressor-specific patterns of neural activation across multiple limbic brain regions in adult rats. Stress. 2018;21:136–50.

    PubMed  Article  Google Scholar 

  80. 80.

    Wall VL, Fischer EK, Bland ST. Isolation rearing attenuates social interaction-induced expression of immediate early gene protein products in the medial prefrontal cortex of male and female rats. Physiol Behav. 2012;107:440–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Belzung C, Griebel G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav Brain Res. 2001;125:141–9.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Mizoguchi K, Shoji H, Ikeda R, Tanaka Y, Tabira T. Persistent depressive state after chronic stress in rats is accompanied by HPA axis dysregulation and reduced prefrontal dopaminergic neurotransmission. Pharm Biochem Behav. 2008;91:170–5.

    CAS  Article  Google Scholar 

  83. 83.

    Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T. Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J Neurosci. 2000;20:1568–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Mokler DJ, Torres OI, Galler JR, Morgane PJ. Stress-induced changes in extracellular dopamine and serotonin in the medial prefrontal cortex and dorsal hippocampus of prenatally malnourished rats. Brain Res. 2007;1148:226–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Shinohara R, Taniguchi M, Ehrlich AT, Yokogawa K, Deguchi Y, Cherasse Y, et al. Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice. Mol Psychiatry. 2018;23:1717–30.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Nagai T, Nakamuta S, Kuroda K, Nakauchi S, Nishioka T, Takano T, et al. Phosphoproteomics of the dopamine pathway enables discovery of Rap1 activation as a reward signal in vivo. Neuron. 2016;89:550–65.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the Brain & Behavior Research Foundation NARSAD Young Investigator Award, grant 23711 (to MEC).

Author information

Affiliations

Authors

Corresponding author

Correspondence to M. E. Cahill.

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

Kermath, B.A., Vanderplow, A.M., Bjornson, K.J. et al. The Rap1 small GTPase is a critical mediator of the effects of stress on prefrontal cortical dysfunction. Mol Psychiatry 26, 3223–3239 (2021). https://doi.org/10.1038/s41380-020-0835-0

Download citation

Search

Quick links