Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency



Overconsumption of high-fat diets (HFDs) can critically affect synaptic and cognitive functions within telencephalic structures such as the medial prefrontal cortex (mPFC). The underlying mechanisms, however, remain largely unknown. Here we show that adolescence is a sensitive period for the emergence of prefrontal cognitive deficits in response to HFD. We establish that the synaptic modulator reelin (RELN) is a critical mediator of this vulnerability because (1) periadolescent HFD (pHFD) selectively downregulates prefrontal RELN+ cells and (2) augmenting mPFC RELN levels using transgenesis or prefrontal pharmacology prevents the pHFD-induced prefrontal cognitive deficits. We further identify N-methyl-d-aspartate-dependent long-term depression (NMDA-LTD) at prefrontal excitatory synapses as a synaptic signature of this association because pHFD abolishes NMDA-LTD, a function that is restored by RELN overexpression. We believe this study provides the first mechanistic insight into the vulnerability of the adolescent mPFC towards nutritional stress, such as HFDs. Our findings have primary relevance to obese individuals who are at an increased risk of developing neurological cognitive comorbidities, and may extend to multiple neuropsychiatric and neurological disorders in which RELN deficiency is a common feature.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5


  1. 1

    Haggarty P . Epigenetic consequences of a changing human diet. Proc Nutr Soc 2013; 72: 363–371.

    Article  PubMed  Google Scholar 

  2. 2

    Simopoulos AP . Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999; 70: 560S–569S.

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Wilson MM, Reedy J, Krebs-Smith SM . American Diet Quality: where it is, where it is heading, and what it could be. J Acad Nutr Diet 2016; 116: e1.

    Article  Google Scholar 

  4. 4

    Mozaffarian D, Ludwig DS . The 2015 US Dietary Guidelines: lifting the ban on total dietary fat. JAMA 2015; 313: 2421–2422.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Vickers SP, Jackson HC, Cheetham SC . The utility of animal models to evaluate novel anti-obesity agents. Br J Pharmacol 2011; 164: 1248–1262.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Francis H, Stevenson R . The longer-term impacts of Western diet on human cognition and the brain. Appetite 2013; 63: 119–128.

    Article  PubMed  Google Scholar 

  7. 7

    Sarnyai Z, Jashar C, Olivier B . Modeling combined schizophrenia-related behavioral and metabolic phenotypes in rodents. Behav Brain Res 2015; 276: 130–142.

    Article  PubMed  Google Scholar 

  8. 8

    Morris MC, Tangney CC . Dietary fat composition and dementia risk. Neurobiol Aging 2014; 35 (Suppl 2): S59–S64.

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Heyward FD, Gilliam D, Coleman MA, Gavin CF, Wang J, Kaas G et al. Obesity weighs down memory through a mechanism involving the neuroepigenetic dysregulation of Sirt1. J Neurosci 2016; 36: 1324–1335.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Boitard C, Etchamendy N, Sauvant J, Aubert A, Tronel S, Marighetto A et al. Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice. Hippocampus 2012; 22: 2095–2100.

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Reichelt AC, Maniam J, Westbrook RF, Morris MJ . Dietary-induced obesity disrupts trace fear conditioning and decreases hippocampal reelin expression. Brain Behav Immun 2015; 43: 68–75.

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Edwards LM, Murray AJ, Holloway CJ, Carter EE, Kemp GJ, Codreanu I et al. Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men. Faseb J 2011; 25: 1088–1096.

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Holloway CJ, Cochlin LE, Emmanuel Y, Murray A, Codreanu I, Edwards LM et al. A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects. Am J Clin Nutr 2011; 93: 748–755.

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Bocarsly ME, Fasolino M, Kane GA, LaMarca EA, Kirschen GW, Karatsoreos IN et al. Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. Proc Natl Acad Sci USA 2015; 112: 15731–15736.

    CAS  PubMed  Google Scholar 

  15. 15

    Kanoski SE, Meisel RL, Mullins AJ, Davidson TL . The effects of energy-rich diets on discrimination reversal learning and on BDNF in the hippocampus and prefrontal cortex of the rat. Behav Brain Res 2007; 182: 57–66.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA 2004; 101: 8174–8179.

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Spear LP . The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 2000; 24: 417–463.

    CAS  Article  Google Scholar 

  18. 18

    Hensch TK . Critical period plasticity in local cortical circuits. Nat Rev Neurosci 2005; 6: 877–888.

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Andersen SL . Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 2003; 27: 3–18.

    Article  Google Scholar 

  20. 20

    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  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Yates KF, Sweat V, Yau PL, Turchiano MM, Convit A . Impact of metabolic syndrome on cognition and brain: a selected review of the literature. Arterioscler Thromb Vasc Biol 2012; 32: 2060–2067.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Øverby NC, Lüdemann E, Høigaard R . Self-reported learning difficulties and dietary intake in Norwegian adolescents. Scand J Public Health 2013; 41: 754–760.

    Article  PubMed  Google Scholar 

  23. 23

    Maayan L, Hoogendoorn C, Sweat V, Convit A . Disinhibited eating in obese adolescents is associated with orbitofrontal volume reductions and executive dysfunction. Obesity (Silver Spring, MD) 2011; 19: 1382–1387.

    Article  Google Scholar 

  24. 24

    Yau PL, Javier DC, Ryan CM, Tsui WH, Ardekani BA, Ten S et al. Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus. Diabetologia 2010; 53: 2298–2306.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Nyaradi A, Foster JK, Hickling S, Li J, Ambrosini GL, Jacques A et al. Prospective associations between dietary patterns and cognitive performance during adolescence. J Child Psychol Psychiatry 2014; 55: 1017–1024.

    Article  PubMed  Google Scholar 

  26. 26

    Moreno-Lopez L, Contreras-Rodriguez O, Soriano-Mas C, Stamatakis EA, Verdejo-Garcia A . Disrupted functional connectivity in adolescent obesity. NeuroImage Clin 2016; 12: 262–268.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Gidding SS, Dennison BA, Birch LL, Daniels SR, Gillman MW, Gilman MW et al. Dietary recommendations for children and adolescents: a guide for practitioners. Pediatrics 2006; 117: 544–559.

    Article  PubMed  Google Scholar 

  28. 28

    Chen Y, Beffert U, Ertunc M, Tang T-S, Kavalali ET, Bezprozvanny I et al. Reelin modulates NMDA receptor activity in cortical neurons. J Neurosci 2005; 25: 8209–8216.

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Iafrati J, Orejarena MJ, Lassalle O, Bouamrane L, Gonzalez-Campo C, Chavis P . Reelin an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway. Mol Psychiatry 2014; 19: 417–426.

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Brosda J, Dietz F, Koch M . Impairment of cognitive performance after reelin knockdown in the medial prefrontal cortex of pubertal or adult rats. Neurobiol Dis 2011; 44: 239–247.

    Article  PubMed  Google Scholar 

  31. 31

    Iafrati J, Malvache A, Gonzalez Campo C, Orejarena M, Lassalle O, Bouamrane L et al. Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex. Sci Rep 2016; 6: 35504.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P . NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin. J Neurosci 2007; 27: 10165–10175.

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Beffert U, Weeber EJ, Durudas A, Qiu S, Masiulis I, Sweatt JD et al. Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron 2005; 47: 567–579.

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Qiu S, Korwek KM, Pratt-Davis AR, Peters M, Bergman MY, Weeber EJ . Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice. Neurobiol Learn Mem 2006; 85: 228–242.

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Qiu S, Zhao LF, Korwek KM, Weeber EJ . Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus. J Neurosci 2006; 26: 12943–12955.

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J . Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun 2008; 22: 469–486.

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Matrisciano F, Tueting P, Dalal I, Kadriu B, Grayson DR, Davis JM et al. Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice. Neuropharmacology 2013; 68: 184–194.

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Buret L, van den Buuse M . Corticosterone treatment during adolescence induces down-regulation of reelin and NMDA receptor subunit GLUN2C expression only in male mice: implications for schizophrenia. Int J Neuropsychopharmacol 2014; 17: 1221–1232.

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Pujadas L, Rossi D, Andrés R, Teixeira CM, Serra-Vidal B, Parcerisas A et al. Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer’s disease. Nat Commun 2014; 5: 3443.

    Article  PubMed  Google Scholar 

  40. 40

    Lane-Donovan C, Philips GT, Wasser CR, Durakoglugil MS, Masiulis I, Upadhaya A et al. Reelin protects against amyloid β toxicity in vivo. Sci Signal 2015; 8: ra67.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Teixeira CM, Martín ED, Sahún I, Masachs N, Pujadas L, Corvelo A et al. Overexpression of Reelin prevents the manifestation of behavioral phenotypes related to schizophrenia and bipolar disorder. Neuropsychopharmacology 2011; 36: 2395–2405.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Fatemi SH . Reelin, a Marker of Stress Resilience in Depression and Psychosis. Neuropsychopharmacology 2011; 36: 2371–2372.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Pujadas L, Gruart A, Bosch C, Delgado L, Teixeira CM, Rossi D et al. Reelin regulates postnatal neurogenesis and enhances spine hypertrophy and long-term potentiation. J Neurosci 2010; 30: 4636–4649.

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Kasanetz F, Manzoni OJ . Maturation of excitatory synaptic transmission of the rat nucleus accumbens from juvenile to adult. J Neurophysiol 2009; 101: 2516–2527.

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Rebustini IT, Hayashi T, Reynolds AD, Dillard ML, Carpenter EM, Hoffman MP . miR-200c regulates FGFR-dependent epithelial proliferation via Vldlr during submandibular gland branching morphogenesis. Development 2012; 139: 191–202.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Rogers JT, Zhao L, Trotter JH, Rusiana I, Peters MM, Li Q et al. Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse. J Psychopharmacol 2013; 27: 386–395.

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Goldman-Rakic PS . Regional and cellular fractionation of working memory. Proc Natl Acad Sci U S A 1996; 93: 13473–13480.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Hamilton DA, Brigman JL . Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions. Genes Brain Behav 2015; 14: 4–21.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Alcantara S, Ruiz M, D’Arcangelo G, Ezan F, de Lecea L, Curran T et al. Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse. J Neurosci 1998; 18: 7779–7799.

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Krueger DD, Howell JL, Hebert BF, Olausson P, Taylor JR, Nairn AC . Assessment of cognitive function in the heterozygous reeler mouse. Psychopharmacology (Berl) 2006; 189: 95–104.

    CAS  Article  Google Scholar 

  51. 51

    Brigman JL, Padukiewicz KE, Sutherland ML, Rothblat LA . Executive functions in the heterozygous reeler mouse model of schizophrenia. Behav Neurosci 2006; 120: 984–988.

    Article  PubMed  Google Scholar 

  52. 52

    Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–324.

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Campo CG, Sinagra M, Verrier D, Manzoni OJ, Chavis P . Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis. PLoS One 2009; 4: e5505.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Herz J, Chen Y . Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci 2006; 7: 850–859.

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Collingridge GL, Peineau S, Howland JG, Wang YT . Long-term depression in the CNS. Nat Rev Neurosci 2010; 11: 459–473.

    CAS  Article  Google Scholar 

  56. 56

    Vazdarjanova A, Bunting K, Muthusamy N, Bergson C . Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood. Mol Psychiatry 2011; 16: 672–684.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Ma J, Duan Y, Qin Z, Wang J, Liu W, Xu M et al. Overexpression of αCaMKII impairs behavioral flexibility and NMDAR-dependent long-term depression in the medial prefrontal cortex. Neuroscience 2015; 310: 528–540.

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Labouesse MA, Stadlbauer U, Langhans W, Meyer U . Chronic high fat diet consumption impairs sensorimotor gating in mice. Psychoneuroendocrinology 2013; 38: 2562–2574.

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Maren S, Phan KL, Liberzon I . The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 2013; 14: 417–428.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Rogers JT, Rusiana I, Trotter J, Zhao L, Donaldson E, Pak DTS et al. Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density. Learn Mem 2011; 18: 558–564.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Kolb B, Mychasiuk R, Muhammad A, Li Y, Frost DO, Gibb R . Experience and the developing prefrontal cortex. Proc Natl Acad Sci USA 2012; 109 (Suppl): 17186–17193.

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Cass DK, Thomases DR, Caballero A, Tseng KY . Developmental disruption of gamma-aminobutyric acid function in the medial prefrontal cortex by noncontingent cocaine exposure during early adolescence. Biol Psychiatry 2013; 74: 490–501.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Reichelt AC, Killcross S, Hambly LD, Morris MJ, Westbrook RF . Impact of adolescent sucrose access on cognitive control, recognition memory, and parvalbumin immunoreactivity. Learn Mem 2015; 22: 215–224.

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Cabungcal J-H, Steullet P, Kraftsik R, Cuenod M, Do KQ . Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. Biol Psychiatry 2013; 73: 574–582.

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Macdiarmid JI, Vail A, Cade JE, Blundell JE . The sugar-fat relationship revisited: differences in consumption between men and women of varying BMI. Int J Obes Relat Metab Disord 1998; 22: 1053–1061.

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Castanon N, Lasselin J, Capuron L . Neuropsychiatric comorbidity in obesity: role of inflammatory processes. Front Endocrinol (Lausanne) 2014; 5: 74.

    Article  Google Scholar 

  67. 67

    Stranahan AM . Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience 2015; 309: 125–139.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Jais A, Solas M, Backes H, Chaurasia B, Kleinridders A, Theurich S et al. Myeloid-cell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. Cell 2016; 165: 882–895.

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766–781.

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Mendez MA, Sotres-Alvarez D, Miles DR, Slining MM, Popkin BM . Shifts in the recent distribution of energy intake among U.S. children aged 2–18 years reflect potential abatement of earlier declining trends. J Nutr 2014; 144: 1291–1297.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Elman I, Borsook D, Lukas SE . Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology 2006; 31: 2091–2120.

    CAS  Article  PubMed  Google Scholar 

  72. 72

    Grayson DR, Guidotti A . The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology 2012; 38: 138–166.

    Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Glantz LA, Lewis DA . Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Boyer L, Richieri R, Dassa D, Boucekine M, Fernandez J, Vaillant F et al. Association of metabolic syndrome and inflammation with neurocognition in patients with schizophrenia. Psychiatry Res 2013; 210: 381–386.

    Article  PubMed  Google Scholar 

  75. 75

    Krstic D, Pfister S, Notter T, Knuesel I . Decisive role of reelin signaling during early stages of Alzheimer’s disease. Neuroscience 2013; 246: 108–116.

    CAS  Article  PubMed  Google Scholar 

Download references


This work was supported by the Swiss National Science Foundation (Grant No. 310030_146217) and the European Union Seventh Framework Program (FP7/2007–2011) (Grant No. 259679) (to UM), by INSERM (to PC), by ETH Zurich (to WL) and by MINECO (Spain, SAF2013-42445R) (to ES). ACR is the recipient of an Australian Research Council Discovery Early Career Research Award (DE140101071). We are grateful to F Mouttet, E Weber, F Müller, S Giovanoli and S Kaufman for assistance in experimentation or genotyping; M Riva and D Ramachandran for helpful discussions; N Jejelava and M Arnold for advice on surgery; and the animal technician team for contribution to animal husbandry. We thank the National Institute of Mental Health's Chemical Synthesis and Drug Supply Program for providing CNQX, NBQX and D-APV.

Author contributions

MAL designed the study, analyzed data, wrote the original manuscript and performed the behavioral, surgical, metabolic and imaging experiments. OL performed and analyzed the electrophysiology experiments. JR and MAL did the western blots. UW contributed to behavior and surgeries. JI developed the LTD protocol. TN, TG and MAL did the immunostainings. LP and ES generated the transgenic mice and contributed to writing. AR, CL and WL contributed to data interpretation and writing. PC and UM designed and supervised the entire study, analyzed data and wrote the manuscript.

Author information



Corresponding authors

Correspondence to M A Labouesse or P Chavis or U Meyer.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Labouesse, M., Lassalle, O., Richetto, J. et al. Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency. Mol Psychiatry 22, 961–971 (2017). https://doi.org/10.1038/mp.2016.193

Download citation

Further reading