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.

  • Article
  • Published:

Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network

Molecular Psychiatry volume 28, pages 4234–4250 (2023)Cite this article

Subjects

Abstract

With increasing maternal cannabis use, there is a need to investigate the lasting impact of prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis, on cognitive/memory function. The endocannabinoid system (ECS), which relies on polyunsaturated fatty acids (PUFAs) to function, plays a crucial role in regulating prefrontal cortical (PFC) and hippocampal network-dependent behaviors essential for cognition and memory. Using a rodent model of prenatal cannabis exposure (PCE), we report that male and female offspring display long-term deficits in various cognitive domains. However, these phenotypes were associated with highly divergent, sex-dependent mechanisms. Electrophysiological recordings revealed hyperactive PFC pyramidal neuron activity in both males and females, but hypoactivity in the ventral hippocampus (vHIPP) in males, and hyperactivity in females. Further, cortical oscillatory activity states of theta, alpha, delta, beta, and gamma bandwidths were strongly sex divergent. Moreover, protein expression analyses at postnatal day (PD)21 and PD120 revealed primarily PD120 disturbances in dopamine D1R/D2 receptors, NMDA receptor 2B, synaptophysin, gephyrin, GAD67, and PPARα selectively in the PFC and vHIPP, in both regions in males, but only the vHIPP in females. Lastly, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we identified region-, age-, and sex-specific deficiencies in specific neural PUFAs, namely docosahexaenoic acid (DHA) and arachidonic acid (ARA), and related metabolites, in the PFC and hippocampus (ventral/dorsal subiculum, and CA1 regions). This study highlights several novel, long-term and sex-specific consequences of PCE on PFC-hippocampal circuit dysfunction and the potential role of specific PUFA signaling abnormalities underlying these pathological outcomes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Prenatal THC induces aberrations to cognition and memory, and male-only sensory processing disturbances.
Fig. 2: Prenatal THC induces sex-specific alterations to the PFC and vHIPP.
Fig. 3: Prenatal THC induces alterations to spontaneous mPFC and vHIPP oscillations.
Fig. 4: Prenatal THC induces significant alterations to the fatty acid phenotype of the PFC and Hippocampus.
Fig. 5: Prenatal THC induces significant pathological alterations to various molecular biomarkers.

References

  1. Zamberletti E, Rubino T. Impact of endocannabinoid system manipulation on neurodevelopmental processes relevant to Schizophrenia. Biol Psychiatry: Cogn Neurosci Neuroimaging. 2021;6:616–26.

    PubMed  Google Scholar 

  2. Arturo IF, Fabiana P. Endocannabinoidome. eLS. 2018:1–10.

  3. Solowij N, Monterrubio S. Cognitive and neuropsychiatric consequences of endocannabinoid signaling dysfunction. Neuropsychopharmacology. 2006;31:471–2.

    Article  CAS  PubMed  Google Scholar 

  4. Agrawal A, Rogers CE, Lessov-Schlaggar CN, Carter EB, Lenze SN, Grucza RA. Alcohol, cigarette, and cannabis use between 2002 and 2016 in pregnant women from a nationally representative sample. JAMA Pediatr. 2019;173:95–96.

    Article  PubMed  Google Scholar 

  5. Sarikahya MH, Cousineau S, De Felice M, Lee K, Wong KK, DeVuono MV. et al. Prenatal THC exposure induces sex-dependent neuropsychiatric endophenotypes in offspring and long-term disruptions in fatty-acid signaling pathways directly in the mesolimbic circuitry. ENeuro. 2022;9:ENEURO.0253-22.2022

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rava A, Trezza V. Emerging roles of endocannabinoids as key lipid mediators for a successful pregnancy. Int J Mol Sci. 2023;24:5220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Frau R, Miczán V, Traccis F, Aroni S, Pongor CI, Saba P, et al. Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone. Nat Neurosci. 2019;22:1975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Castelli V, Lavanco G, Feo S, D’Amico C, Micale V, Kuchar M, et al. Prenatal exposure to Δ9-Tetrahydrocannabinol affects hippocampus-related cognitive functions in the adolescent rat offspring: focus on specific markers of neuroplasticity. Pharmaceutics. 2023;15:692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Beggiato S, Borelli AC, Tomasini MC, Morgano L, Antonelli T, Tanganelli S, et al. Long-lasting alterations of hippocampal GABAergic neurotransmission in adult rats following perinatal Δ9-THC exposure. Neurobiol Learn Mem. 2017;139:135–43.

    Article  CAS  PubMed  Google Scholar 

  10. Bruijnzeel AW, Knight P, Panunzio S, Xue S, Bruner MM, Wall SC, et al. Effects in rats of adolescent exposure to cannabis smoke or THC on emotional behavior and cognitive function in adulthood. Psychopharmacology. 2019;236:2773–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Campolongo P, Trezza V, Ratano P, Palmery M, Cuomo V. Developmental consequences of perinatal cannabis exposure: behavioral and neuroendocrine effects in adult rodents. Psychopharmacology. 2011;214:5–15.

    Article  CAS  PubMed  Google Scholar 

  12. de Salas-Quiroga A, García-Rincón D, Gómez-Domínguez D, Valero M, Simón-Sánchez S, Paraíso-Luna J, et al. Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure. Neuropsychopharmacology. 2020;45:877–86

    Article  PubMed  PubMed Central  Google Scholar 

  13. Renard J, Szkudlarek HJ, Kramar CP, Jobson CEL, Moura K, Rushlow WJ, et al. Adolescent THC exposure causes enduring prefrontal cortical disruption of GABAergic inhibition and dysregulation of sub-cortical dopamine function. Sci Rep. 2017;7:1–14

    Article  CAS  Google Scholar 

  14. Szkudlarek HJ, Desai SJ, Renard J, Pereira B, Norris C, Jobson CEL, et al. Δ-9-Tetrahydrocannabinol and cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors. Neuropsychopharmacology. 2019;44:817–25.

    Article  CAS  PubMed  Google Scholar 

  15. Colgin LL. Oscillations and hippocampal–prefrontal synchrony. Curr Opin Neurobiol. 2011;21:467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tamura M, Spellman TJ, Rosen AM, Gogos JA, Gordon JA. Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task. Nat Commun. 2017;8:2182.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Phillips ML, Robinson HA, Pozzo-Miller L Ventral hippocampal projections to the medial prefrontal cortex regulate social memory. eLife. 2019;8:e44182.

  18. Barker GRI, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Howland JG, Harrison RA, Hannesson DK, Phillips AG. Ventral hippocampal involvement in temporal order, but not recognition, memory for spatial information. Hippocampus. 2008;18:251–7.

    Article  PubMed  Google Scholar 

  20. Shoemaker JM, Saint Marie RL, Bongiovanni MJ, Neary AC, Tochen LS, Swerdlow NR. Prefrontal D1 and ventral hippocampal N-methyl-d-aspartate regulation of startle gating in rats. Neuroscience. 2005;135:385–94.

    Article  CAS  PubMed  Google Scholar 

  21. Swerdlow NR, Shoemaker JM, Noh HR, Ma L, Gaudet I, Munson M, et al. The ventral hippocampal regulation of prepulse inhibition and its disruption by apomorphine in rats are not mediated via the fornix. Neuroscience. 2004;123:675–85.

    Article  CAS  PubMed  Google Scholar 

  22. Dana K, Finik J, Koenig S, Motter J, Zhang W, Linaris M, et al. Prenatal exposure to famine and risk for development of psychopathology in adulthood: a meta-analysis. J Psychiatry Psychiatr Disord. 2019;3:227–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Heath RJ, Klevebro S, Wood TR. Maternal and neonatal polyunsaturated fatty acid intake and risk of neurodevelopmental impairment in premature infants. Int J Mol Sci. 2022;23:700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Basak S, Mallick R, Banerjee A, Pathak S, Duttaroy AK. Maternal supply of both arachidonic and docosahexaenoic acids is required for optimal neurodevelopment. Nutrients. 2021;13:2061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Watson JE, Kim JS, Das. A Emerging class of omega-3 fatty acid endocannabinoids & their derivatives. Prostaglandins Other Lipid Mediat. 2019;143:106337.

  26. Ciappolino V, Mazzocchi A, Botturi A, Turolo S, Delvecchio G, Agostoni C, et al. The role of Docosahexaenoic Acid (DHA) on cognitive functions in psychiatric disorders. Nutrients. 2019;11:769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Maekawa M, Watanabe A, Iwayama Y, Kimura T, Hamazaki K, Balan S. et al. Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes. Transl Psychiatry. 2017;7:e1229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Carrié I, Clément M, De Javel D, Francès H, Bourre J-M. Specific phospholipid fatty acid composition of brain regions in mice: effects of n-3 polyunsaturated fatty acid deficiency and phospholipid supplementation. J Lipid Res. 2000;41:465–72.

  29. Gonzalez HF, Visentin S. Nutrients and neurodevelopment: lipids. Archivos Argentinos de Pediatr. 2016;114:472–6.

    Google Scholar 

  30. McNamara RK. Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation: mechanisms and implications for psychopathology. World J Psychiatry. 2015;5:15.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Davis-Bruno K, Tassinari MS. Essential fatty acid supplementation of DHA and ARA and effects on neurodevelopment across animal species: a review of the literature. Birth Defects Res Part B - Dev Reprod Toxicol. 2011;92:240–50.

    Article  CAS  Google Scholar 

  32. Maekawa M, Takashima N, Matsumata M, Ikegami S, Kontani M, Hara Y, et al. Arachidonic acid drives postnatal neurogenesis and elicits a beneficial effect on prepulse inhibition, a biological trait of psychiatric illnesses. PLoS one. 2009;4:e5085.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Westra M, Gutierrez Y, MacGillavry HD. Contribution of membrane lipids to postsynaptic protein organization. Front Synaptic Neurosci. 2021;13:790773.

  34. Aryal S, Hussain S, Drevon CA, Nagelhus E, Hvalby Ø, Jensen V, et al. Omega-3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses. Eur J Neurosci. 2019;49:40–50.

    Article  PubMed  Google Scholar 

  35. Devarshi PP, Grant RW, Ikonte CJ, Mitmesser SH. Maternal omega-3 nutrition, placental transfer and fetal brain development in gestational diabetes and preeclampsia. Nutrients. 2019;11:1107.

  36. Davis PF, Ozias MK, Carlson SE, Reed GA, Winter MK, McCarson KE, et al. Dopamine receptor alterations in female rats with diet-induced decreased brain docosahexaenoic acid (DHA): interactions with reproductive status. 2013;13:161-9. https://doi.org/10.1179/147683010x12611460764282.

  37. Tang M, Zhang M, Cai H, Li H, Jiang P, Dang R, et al. Maternal diet of polyunsaturated fatty acid altered the cell proliferation in the dentate gyrus of hippocampus and influenced glutamatergic and serotoninergic systems of neonatal female rats. Lipids Health Dis. 2016;15:1–10.

    Article  Google Scholar 

  38. Levant B, Radel JD, Carlson SE. Decreased brain docosahexaenoic acid during development alters dopamine-related behaviors in adult rats that are differentially affected by dietary remediation. Behav Brain Res. 2004;152:49–57.

    CAS  PubMed  Google Scholar 

  39. Natale BV, Gustin KN, Lee K, Holloway AC, Laviolette SR, Natale DRC, et al. Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta. Sci Rep. 2020;10:544.

  40. Oke SL, Lee K, Papp R, Laviolette SR, Hardy DB .In utero exposure to ∆9-Tetrahydrocannabinol leads to postnatal catch-up growth and dysmetabolism in the adult rat liver. 2021. https://doi.org/10.3390/ijms22147502.

  41. Lee K, Hardy DB. Metabolic consequences of gestational cannabinoid exposure. 2021. https://doi.org/10.3390/ijms22179528.

  42. Chen W, Liu N, Shen S, Zhu W, Qiao J, Chang S, et al. Fetal growth restriction impairs hippocampal neurogenesis and cognition via Tet1 in offspring. Cell Rep. 2021;37:109912.

    Article  CAS  PubMed  Google Scholar 

  43. Cetin I, Giovannini N, Alvino G, Agostoni C, Riva E, Giovannini M, et al. Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships. Pediatr Res. 2002;52:750–5

    Article  CAS  PubMed  Google Scholar 

  44. Baysal B, Miçili S, Engür D, Akokay P, Karabulut A, Keskinoğlu P, et al. Impact of postnatal nutrition on neurodevelopmental outcome in rat model of intrauterine growth restriction. Eur Rev Med Pharm Sci. 2022;26:7498–505.

    CAS  Google Scholar 

  45. Yan Z, Rein B. Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications. Mol Psychiatry. 2022;27:445–65.

    Article  PubMed  Google Scholar 

  46. Yuan N, Tang K, Da X, Gan H, He L, Li X, et al. Integrating clinical and genomic analyses of hippocampal-prefrontal circuit disorder in depression. Front Genet. 2021;11:565749.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zhang Y-X, Xing B, Li Y-C, Yan C-X, Gao W-J. NMDA receptor-mediated synaptic transmission in prefrontal neurons underlies social memory retrieval in female mice. Neuropharmacology. 2022;204:108895.

    Article  CAS  PubMed  Google Scholar 

  48. Burstein S. PPAR-γ: a nuclear receptor with affinity for cannabinoids. Life Sci. 2005;77:1674–84.

    Article  CAS  PubMed  Google Scholar 

  49. Iannotti FA, Vitale RM. The endocannabinoid system and PPARs: focus on their signalling crosstalk, action and transcriptional regulation. Cells. 2021;10:586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. O’Sullivan SE. An update on PPAR activation by cannabinoids. Br J Pharmacol. 2016;173:1899–910.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Gillies R, Lee K, Vanin S, Laviolette SR, Holloway AC, Arany E, et al. Maternal exposure to Δ9-tetrahydrocannabinol impairs female offspring glucose homeostasis and endocrine pancreatic development in the rat. Reprod Toxicol. 2020;94:84–91.

    Article  CAS  PubMed  Google Scholar 

  52. Vargish GA, Pelkey KA, Yuan X, Chittajallu R, Collins D, Fang C, et al. Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. Mol Psychiatry. 2017;22:56–67.

    Article  CAS  PubMed  Google Scholar 

  53. Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI. Prenatal stress generates deficits in rat social behavior: reversal by oxytocin. Brain Res. 2007;1156:152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sun Q, Li X, Li A, Zhang J, Ding Z, Gong H, et al. Ventral Hippocampal-prefrontal Interaction Affects Social Behavior Via Parvalbumin Positive Neurons In the Medial Prefrontal Cortex. iScience. 2020;3:100894.

  55. De Felice M, Renard J, Hudson R, Szkudlarek HJ, Pereira BJ, Schmid S, et al. L -Theanine prevents long-term affective and cognitive side effects of adolescent D -9-Tetrahydrocannabinol exposure and blocks associated molecular and neuronal abnormalities in the mesocorticolimbic circuitry.J Neurosci. 2021;41:739–50.

  56. Renard J, Rushlow WJ, Laviolette SR. Effects of adolescent THC exposure on the prefrontal GABAergic system: implications for schizophrenia-related psychopathology. Front Psychiatry. 2018;9:281.

  57. Paxinos G, Watson C .The rat brain in stereotaxic coordinates: hard cover edition. Elsevier; 2006.

  58. Lehmann J, Pryce CR, Feldon J. Sex differences in the acoustic startle response and prepulse inhibition in Wistar rats. Behav Brain Res. 1999;1-2:113–7.

    Article  Google Scholar 

  59. Neto J, Jantsch J, De Oliveira S, Braga MF, De Castro LFDS, Diniz BF, et al. DHA/EPA supplementation decreases anxiety-like behaviour, but it does not ameliorate metabolic profile in obese male rats. Br J Nutr. 2021:1–11.

  60. Jašarević E, Hecht PM, Fritsche KL, Beversdorf DQ, Geary DC. Dissociable effects of dorsal and ventral hippocampal DHA content on spatial learning and anxiety-like behavior. Neurobiol Learn Mem. 2014;116:59–68.

    Article  PubMed  Google Scholar 

  61. Dai B, Sun F, Tong X, Ding Y, Kuang A, Osakada T, et al. Responses and functions of dopamine in nucleus accumbens core during social behaviors. Cell Rep. 2022;40:111246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Scheggi S, Guzzi F, Braccagni G, De Montis MG, Parenti M, Gambarana C. Targeting PPARα in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences. Mol Autism. 2020;11:62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gunaydin LA, Deisseroth K. Dopaminergic dynamics contributing to social behavior. Cold Spring Harb Symp Quant Biol. 2014;79:221–7.

    Article  PubMed  Google Scholar 

  64. Inta D, Vogt MA, Perreau-Lenz S, Schneider M, Pfeiffer N, Wojcik SM, et al. Sensorimotor gating, working and social memory deficits in mice with reduced expression of the vesicular glutamate transporter VGLUT1. Behavioural Brain Res. 2012;228:328–32.

    Article  CAS  Google Scholar 

  65. Okuyama T, Kitamura T, Roy DS, Itohara S, Tonegawa S. Ventral CA1 neurons store social memory. Science 2016;353:1536–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Xing B, Mack NR, Guo K-M, Zhang Y-X, Ramirez B, Yang S-S, et al. A Subpopulation of Prefrontal Cortical Neurons Is Required for Social Memory. Biol Psychiatry. 2021;89:521–31.

    Article  CAS  PubMed  Google Scholar 

  67. Bicks LK, Koike H, Akbarian S, Morishita H Prefrontal cortex and social cognition in mouse and man. Front Psychol. 2015;6:1805.

  68. Kuga N, Abe R, Takano K, Ikegaya Y, Sasaki T. Prefrontal-amygdalar oscillations related to social behavior in mice. eLife. 2022;11:e78428.

  69. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636–45.

    Article  PubMed  Google Scholar 

  70. El Marroun H, Hudziak JJ, Tiemeier H, Creemers H, Steegers EAP, Jaddoe VWV, et al. Intrauterine cannabis exposure leads to more aggressive behavior and attention problems in 18-month-old girls. Drug Alcohol Depend. 2011;118:470–4.

    Article  PubMed  Google Scholar 

  71. Chen J, Chen P, Bo T, Luo K. Cognitive and behavioral outcomes of intrauterine growth restriction school-age children. Pediatrics. 2016;137:e20153868.

    Article  PubMed  Google Scholar 

  72. Løhaugen GCC, Østgård HF, Andreassen S, Jacobsen GW, Vik T, Brubakk A-M. et al.Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults.J Pediatr. 2013;163:447–453.e1.

    Article  PubMed  Google Scholar 

  73. Gilchrist C, Cumberland A, Walker D, Tolcos M. Intrauterine growth restriction and development of the hippocampus: implications for learning and memory in children and adolescents. Lancet Child Adolesc Health. 2018;2:755–64.

    Article  PubMed  Google Scholar 

  74. Rehn A, Van Den Buuse M, Copolov D, Briscoe T, Lambert G, Rees S. An animal model of chronic placental insufficiency: relevance to neurodevelopmental disorders including schizophrenia. Neuroscience. 2004;129:381–91.

    Article  CAS  PubMed  Google Scholar 

  75. Delcour M, Olivier P, Chambon C, Pansiot J, Russier M, Liberge M, et al. Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia. Brain Pathol. 2011;22:1–16.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Dell’Anna ME, Calzolari S, Molinari M, Iuvone L, Calimici R. Neonatal anoxia induces transitory hyperactivity, permanent spatial memory deficits and CA1 cell density reduction in developing rats. Behav Brain Res. 1991;45:125–34.

    Article  PubMed  Google Scholar 

  77. Basilious A, Yager J, Fehlings MG. Neurological outcomes of animal models of uterine artery ligation and relevance to human intrauterine growth restriction: a systematic review. Dev Med Child Neurol. 2015;57:420–30.

    Article  PubMed  Google Scholar 

  78. Hurd YL, Manzoni OJ, Pletnikov MV, Lee FS, Bhattacharyya S, Melis M. Cannabis and the developing brain: insights into its long-lasting effects. J Neurosci: Off J Soc Neurosci. 2019;39:8250–8.

    Article  Google Scholar 

  79. Hishikawa D, Valentine WJ, Iizuka-Hishikawa Y, Shindou H, Shimizu T. Metabolism and functions of docosahexaenoic acid-containing membrane glycerophospholipids. FEBS Lett. 2017;591:2730–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Farooqui AA, Horrocks LA, Farooqui T. Glycerophospholipids in brain: their metabolism, incorporation into membranes, functions, and involvement in neurological disorders. Chem Phys Lipids. 2000;106:1–29.

    Article  CAS  PubMed  Google Scholar 

  81. Mozzi R, Buratta S. Goracci G. metabolism and functions of phosphatidylserine in mammalian brain. Neurochem Res. 2003;28:195–214

    Article  CAS  PubMed  Google Scholar 

  82. Messamore E, Yao JK. Phospholipid, arachidonate and eicosanoid signaling in schizophrenia. OCL 2016;23:D112.

    Article  Google Scholar 

  83. Zhuo C, Hou W, Tian H, Wang L, Li R. Lipidomics of the brain, retina, and biofluids: from the biological landscape to potential clinical application in schizophrenia. Transl Psychiatry. 2020;10:1–9

    Article  Google Scholar 

  84. Brose SA, Marquardt AL, Golovko MY. Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia. J Neurochem. 2014;129:400–12.

    Article  CAS  PubMed  Google Scholar 

  85. Chen W, Wang M, Zhu M, Xiong W, Qin X, Zhu X. 14,15-Epoxyeicosatrienoic acid alleviates pathology in a mouse model of Alzheimer’s disease. J Neurosci. 2020;40:8188–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cao D, Kevala K, Kim J, Moon HS, Jun SB, Lovinger D, et al. Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J Neurochem. 2009;111:510–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Liu JJ, Green P, John Mann J, Rapoport SI, Sublette ME. Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease. Brain Res. 2015;1597:220–46.

    Article  CAS  PubMed  Google Scholar 

  88. Almeida DM, Jandacek RJ, Weber WA, McNamara RK. Docosahexaenoic acid biostatus is associated with event-related functional connectivity in cortical attention networks of typically developing children. Nutr Neurosci. 2017;20:246–54.

    Article  CAS  PubMed  Google Scholar 

  89. McNamara RK. Deciphering the role of docosahexaenoic acid in brain maturation and pathology with magnetic resonance imaging. Prostaglandins Leukot Essent Fat Acids. 2013;88:33–42.

    Article  CAS  Google Scholar 

  90. Grayson DS, Kroenke CD, Neuringer M, Fair DA. Dietary omega-3 fatty acids modulate large-scale systems organization in the rhesus macaque brain. J Neurosci. 2014;34:2065–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pongrac JL, Slack PJ, Innis SM. Dietary Polyunsaturated Fat that Is Low in (n-3) and High in (n-6) Fatty Acids Alters the SNARE Protein Complex and Nitrosylation in Rat Hippocampus 1,2. J Nutr. 2007;8:1852–56.

  92. Sidhu VK, Huang BX, Kim H-Y. Effects of docosahexaenoic acid on mouse brain synaptic plasma membrane proteome analyzed by mass spectrometry and 16O/18O labeling. J Proteome Res. 2011;10:5472–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sidhu VK, Huang BX, Desai A, Kevala K, Kim HY. Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome. Neurobiol Aging. 2016;41:73–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hajjar T, Goh YM, Rajion MA, Vidyadaran S, Li TA, Ebrahimi M. Alterations in neuronal morphology and synaptophysin expression in the rat brain as a result of changes in dietary n-6: N-3 fatty acid ratios. Lipids Health Dis. 2013;12:1–9.

    Article  Google Scholar 

  95. Choii G, Ko J .Gephyrin: a central GABAergic synapse organizer. Experimental & molecular medicine. Exp Mol Med. 2015:4:e158-e158.

  96. Sariñana J, Kitamura T, Künzler P, Sultzman L, Tonegawa S. Differential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory. Proc Natl Acad Sci USA. 2014;111:8245–50.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Titulaer J, Björkholm C, Feltmann K, Malmlöf T, Mishra D, Bengtsson Gonzales C, et al. The importance of ventral hippocampal dopamine and norepinephrine in recognition memory. Front Behav Neurosci. 2021;15:667244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Farquhar CE, Breivogel CS, Gamage TF, Gay EA, Thomas BF, Craft RM, et al. Sex, THC, and hormones: effects on density and sensitivity of CB1 cannabinoid receptors in rats. Drug Alcohol Depend. 2019;194:20–27.

    Article  CAS  PubMed  Google Scholar 

  99. Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry. 2015;77:1031–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Dickerson DD, Overeem KA, Wolff AR, Williams JM, Abraham WC, Bilkey DK. Association of aberrant neural synchrony and altered GAD67 expression following exposure to maternal immune activation, a risk factor for schizophrenia. Transl Psychiatry. 2014;4:e418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. McNamara RK, Able J, Jandacek R, Rider T, Tso P, Eliassen JC, et al. Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study. Am J Clin Nutr. 2010;91:1060–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. da Costa AEM, Gomes NS, Gadelha Filho CVJ, e Silva Linhares MGO, da Costa RO, Chaves Filho AJM, et al. Sex influences in the preventive effects of peripubertal supplementation with N-3 polyunsaturated fatty acids in mice exposed to the two-hit model of schizophrenia. Eur J Pharmacol. 2021;897:173949.

    Article  PubMed  Google Scholar 

  103. Roncero C, Valriberas-Herrero I, Mezzatesta-Gava M, Villegas JL, Aguilar L, Grau-López L. Cannabis use during pregnancy and its relationship with fetal developmental outcomes and psychiatric disorders. A systematic review. Reprod Health. 2020;17:25.

  104. Darcey VL, McQuaid GA, Fishbein DH, VanMeter JW. Dietary long-chain omega-3 fatty acids are related to impulse control and anterior cingulate function in adolescents. Front Neurosci. 2019;12:1012.

  105. Burdge GC. Polyunsaturated fatty acid biosynthesis and metabolism in adult mammals. Polyunsaturated fatty acid metab. 2018:15–30.

  106. Morselli E, de Souza Santos R, Gao S, Ávalos Y, Criollo A, Palmer BF, et al. Impact of estrogens and estrogen receptor-α in brain lipid metabolism. Am J Physiol - Endocrinol Metab. 2018;315:E7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Burdge GC, Jones AE, Wootton SA. Eicosapentaenoic and docosapentaenoic acids are the principal products of α-linolenic acid metabolism in young men. Br J Nutr. 2002;88:355–63.

    Article  CAS  PubMed  Google Scholar 

  108. Majou D. Synthesis of DHA (omega-3 fatty acid): FADS2 gene polymorphisms and regulation by PPARα. OCL. 2021;28:43.

    Article  CAS  Google Scholar 

  109. Decsi T, Kennedy K. Sex-specific differences in essential fatty acid metabolism. Am J Clin Nutr. 2011;94:1914S–1919S.

    Article  CAS  PubMed  Google Scholar 

  110. Kitson AP, Stroud CK, Stark KD, Kitson AP, Stroud ÁCK, Stark ÁKD. Elevated production of docosahexaenoic acid in females: potential molecular mechanisms. Lipids. 2010;45:209–24. 2010 45:3

    Article  CAS  PubMed  Google Scholar 

  111. Walczak R, Tontonoz P. PPARadigms and PPARadoxes: expanding roles for PPARγ in the control of lipid metabolism. J Lipid Res. 2002;43:177–86.

    Article  CAS  PubMed  Google Scholar 

  112. Cheng Y, Wei Z, Xie S, Peng Y, Yan Y, Qin D, et al. Alleviation of toxicity caused by overactivation of Pparα through Pparα-Inducible miR-181a2. Mol Ther - Nucleic Acids. 2017;9:195–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Warden A, Truitt J, Merriman M, Ponomareva O, Jameson K, Ferguson LB, et al. Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep. 2016;6:27618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Canadian Institutes of Health Research (CIHR) with grant #MOP-123378 to SRL, Canadian Institutes of Health Research Catalyst Grant #CRU1126 to D.B.H, as well as the Natural Sciences and Engineering Research Council of Canada (NSERC). The authors also greatly acknowledge the assistance of Ms. Kristina Jurcic (University of Western Ontario, UWO, MALDI-MS Facility) for assistance in the acquisition of MS and MS/MS spectra. Operational funding of this facility was provided by the Schulich School of Medicine and Dentistry and the Departments of Chemistry and Biochemistry, UWO.

Author information

Authors and Affiliations

  1. Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada

    Mohammed H. Sarikahya, Marta De Felice, Hanna J. Szkudlarek, Karen K. W. Wong, Marieka V. DeVuono, Mar Rodríguez-Ruiz, Dana Gummerson, Emma Proud, Tsun Hay Jason Ng, Roger Hudson, Tony Jung, Walter Rushlow & Steven R. Laviolette

  2. Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada

    Mohammed H. Sarikahya, Marta De Felice, Hanna J. Szkudlarek, Karen K. W. Wong, Marieka V. DeVuono, Mar Rodríguez-Ruiz, Dana Gummerson, Emma Proud, Tsun Hay Jason Ng, Roger Hudson, Tony Jung, Daniel B. Hardy, Susanne Schmid, Walter Rushlow & Steven R. Laviolette

  3. Departments of Chemistry and Biochemistry, Western University, London, Ontario, N6A 3K7, Canada

    Samantha L. Cousineau & Ken K.-C. Yeung

  4. Departments of Physiology and Pharmacology and Obstetrics and Gynaecology, Western University, London, Ontario, N6A 5C1, Canada

    Kendrick Lee & Daniel B. Hardy

  5. Children’s Health Research Institute, St. Josephs Health Care,, London, Ontario, N6C 2R5, Canada

    Kendrick Lee & Daniel B. Hardy

  6. Department of Psychology, Western University, London, Ontario, N6A 3K7, Canada

    Susanne Schmid

  7. Lawson Health Research Institute, St. Josephs Health Care, London, Ontario, N6C 2R5, Canada

    Walter Rushlow & Steven R. Laviolette

  8. Department of Psychiatry, Western University, London, Ontario, N6A 3K7, Canada

    Walter Rushlow & Steven R. Laviolette

Authors
  1. Mohammed H. Sarikahya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samantha L. Cousineau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marta De Felice
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanna J. Szkudlarek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karen K. W. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marieka V. DeVuono
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kendrick Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mar Rodríguez-Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dana Gummerson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Emma Proud
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tsun Hay Jason Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Roger Hudson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tony Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Daniel B. Hardy
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ken K.-C. Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Susanne Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Walter Rushlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Steven R. Laviolette
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MHS and SRL designed research; MHS, SC, MDF, HJS, KKWW, MR-R, MVD, DG, EP, and THJN, RH, TJ performed research; KL, DH, KK-CY, SS and WJR contributed unpublished reagents/analytic tools and advised on experimental designs; MHS, SC, MDF and KKWW analyzed data; MHS and SRL wrote the paper with contributions from other authors.

Corresponding author

Correspondence to Steven R. Laviolette.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sarikahya, M.H., Cousineau, S.L., De Felice, M. et al. Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network. Mol Psychiatry 28, 4234–4250 (2023). https://doi.org/10.1038/s41380-023-02190-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-023-02190-0

This article is cited by

Search

Advanced search

Quick links