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.

  • Original Article
  • Published:

Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure

Abstract

Placental transfer of Δ9-tetrahydrocannabinol (THC) during pregnancy has the potential to interfere with endogenous cannabinoid (CB) regulation of fetal nervous system development in utero. Here we examined the effect of maternal CB intake on mouse hippocampal interneurons largely focusing on cholecystokinin-expressing interneurons (CCK-INTs), a prominent CB subtype-1 receptor (CB1R) expressing neuronal population throughout development. Maternal treatment with THC or the synthetic CB1R agonist WIN55,212-2 (WIN) produced a significant loss of CCK-INTs in the offspring. Further, residual CCK-INTs in animals prenatally treated with WIN displayed decreased dendritic complexity. Consistent with these anatomical deficits, pups born to CB-treated dams exhibited compromised CCK-INT-mediated feedforward and feedback inhibition. Moreover, pups exposed to WIN in utero lacked constitutive CB1R-mediated suppression of inhibition from residual CCK-INTs and displayed altered social behavior. Our findings add to a growing list of potential cell/circuit underpinnings that may underlie cognitive impairments in offspring of mothers that abuse marijuana during pregnancy.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. National Survey on Drug Use and Health (U.S.), United States. Results from the National Survey on Drug Use and Health: National Findings. National Survey on Drug Use and Health Series. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Office of Applied Studies: Rockville, MD, 2003.

  2. Grotenhermen F . Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 2003; 42: 327–360.

    Article  CAS  Google Scholar 

  3. Pijlman FT, Rigter SM, Hoek J, Goldschmidt HM, Niesink RJ . Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops. Addict Biol 2005; 10: 171–180.

    Article  CAS  Google Scholar 

  4. Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel AS et al. Potency trends of Delta9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci 2010; 55: 1209–1217.

    Article  CAS  Google Scholar 

  5. Hayatbakhsh MR, Flenady VJ, Gibbons KS, Kingsbury AM, Hurrion E, Mamun AA et al. Birth outcomes associated with cannabis use before and during pregnancy. Pediatr Res 2012; 71: 215–219.

    Article  Google Scholar 

  6. Goldschmidt L, Day NL, Richardson GA . Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol Teratol 2000; 22: 325–336.

    Article  CAS  Google Scholar 

  7. Goldschmidt L, Richardson GA, Willford JA, Severtson SG, Day NL . School achievement in 14-year-old youths prenatally exposed to marijuana. Neurotoxicol Teratol 2012; 34: 161–167.

    Article  CAS  Google Scholar 

  8. Leech SL, Larkby CA, Day R, Day NL . Predictors and correlates of high levels of depression and anxiety symptoms among children at age 10. J Am Acad Child Adolesc Psychiatry 2006; 45: 223–230.

    Article  Google Scholar 

  9. Noland JS, Singer LT, Short EJ, Minnes S, Arendt RE, Kirchner HL et al. Prenatal drug exposure and selective attention in preschoolers. Neurotoxicol Teratol 2005; 27: 429–438.

    Article  CAS  Google Scholar 

  10. Howlett AC . The cannabinoid receptors. Prostaglandins Other Lipid Mediat 2002; 68-69: 619–631.

    Article  CAS  Google Scholar 

  11. Berghuis P, Dobszay MB, Wang X, Spano S, Ledda F, Sousa KM et al. Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor. Proc Natl Acad Sci USA 2005; 102: 19115–19120.

    Article  CAS  Google Scholar 

  12. Berghuis P, Rajnicek AM, Morozov YM, Ross RA, Mulder J, Urban GM et al. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 2007; 316: 1212–1216.

    Article  CAS  Google Scholar 

  13. Mulder J, Aguado T, Keimpema E, Barabas K, Ballester Rosado CJ, Nguyen L et al. Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning. Proc Natl Acad Sci USA 2008; 105: 8760–8765.

    Article  CAS  Google Scholar 

  14. Diaz-Alonso J, Aguado T, Wu CS, Palazuelos J, Hofmann C, Garcez P et al. The CB(1) cannabinoid receptor drives corticospinal motor neuron differentiation through the Ctip2/Satb2 transcriptional regulation axis. J Neurosci 2012; 32: 16651–16665.

    Article  CAS  Google Scholar 

  15. Tortoriello G, Morris CV, Alpar A, Fuzik J, Shirran SL, Calvigioni D et al. Miswiring the brain: Delta9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J 2014; 33: 668–685.

    Article  CAS  Google Scholar 

  16. Alpar A, Tortoriello G, Calvigioni D, Niphakis MJ, Milenkovic I, Bakker J et al. Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nat Commun 2014; 5: 4421.

    Article  CAS  Google Scholar 

  17. Wu CS, Zhu J, Wager-Miller J, Wang S, O'Leary D, Monory K et al. Requirement of cannabinoid CB(1) receptors in cortical pyramidal neurons for appropriate development of corticothalamic and thalamocortical projections. Eur J Neurosci 2010; 32: 693–706.

    Article  Google Scholar 

  18. de Salas-Quiroga A, Diaz-Alonso J, Garcia-Rincon D, Remmers F, Vega D, Gomez-Canas M et al. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons. Proc Natl Acad Sci USA 2015; 112: 13693–13698.

    Article  CAS  Google Scholar 

  19. Morozov YM, Freund TF . Post-natal development of type 1 cannabinoid receptor immunoreactivity in the rat hippocampus. Eur J Neurosci 2003; 18: 1213–1222.

    Article  Google Scholar 

  20. Morozov YM, Torii M, Rakic P . Origin, early commitment, migratory routes, and destination of cannabinoid type 1 receptor-containing interneurons. Cereb Cortex 2009; 19 (Suppl 1): i78–i89.

    Article  Google Scholar 

  21. Antypa M, Faux C, Eichele G, Parnavelas JG, Andrews WD . Differential gene expression in migratory streams of cortical interneurons. Eur J Neurosci 2011; 34: 1584–1594.

    Article  Google Scholar 

  22. Saez TM, Aronne MP, Caltana L, Brusco AH . Prenatal exposure to the CB1 and CB2 cannabinoid receptor agonist WIN 55,212-2 alters migration of early-born glutamatergic neurons and GABAergic interneurons in the rat cerebral cortex. J Neurochem 2014; 129: 637–648.

    Article  CAS  Google Scholar 

  23. Morozov YM, Freund TF . Postnatal development and migration of cholecystokinin-immunoreactive interneurons in rat hippocampus. Neuroscience 2003; 120: 923–939.

    Article  CAS  Google Scholar 

  24. Nagode DA, Tang AH, Yang K, Alger BE . Optogenetic identification of an intrinsic cholinergically driven inhibitory oscillator sensitive to cannabinoids and opioids in hippocampal CA1. J Physiol 2014; 592 (Pt 1): 103–123.

    Article  CAS  Google Scholar 

  25. Sauer JF, Struber M, Bartos M . Impaired fast-spiking interneuron function in a genetic mouse model of depression. eLife 2015; 4: e04979.

    Article  Google Scholar 

  26. Yang M, Silverman JL, Crawley JN . Automated three-chambered social approach task for mice. Curr Protoc Neurosci 2011; Chapter 8: Unit 8.26.

  27. Mereu G, Fa M, Ferraro L, Cagiano R, Antonelli T, Tattoli M et al. Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release. Proc Natl Acad Sci USA 2003; 100: 4915–4920.

    Article  CAS  Google Scholar 

  28. Mato S, Chevaleyre V, Robbe D, Pazos A, Castillo PE, Manzoni OJ . A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity. Nat Neurosci 2004; 7: 585–586.

    Article  CAS  Google Scholar 

  29. Chittajallu R, Craig MT, McFarland A, Yuan X, Gerfen S, Tricoire L et al. Dual origins of functionally distinct O-LM interneurons revealed by differential 5-HT(3 A)R expression. Nat Neurosci 2013; 16: 1598–1607.

    Article  CAS  Google Scholar 

  30. Tricoire L, Pelkey KA, Erkkila BE, Jeffries BW, Yuan X, McBain CJ . A blueprint for the spatiotemporal origins of mouse hippocampal interneuron diversity. J Neurosci 2011; 31: 10948–10970.

    Article  CAS  Google Scholar 

  31. Xu Q, Tam M, Anderson SA . Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J Comp Neurol 2008; 506: 16–29.

    Article  CAS  Google Scholar 

  32. Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B . The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 2010; 30: 16796–16808.

    Article  CAS  Google Scholar 

  33. Somogyi J, Baude A, Omori Y, Shimizu H, El Mestikawy S, Fukaya M et al. GABAergic basket cells expressing cholecystokinin contain vesicular glutamate transporter type 3 (VGLUT3) in their synaptic terminals in hippocampus and isocortex of the rat. Eur J Neurosci 2004; 19: 552–569.

    Article  Google Scholar 

  34. Bezaire MJ, Soltesz I . Quantitative assessment of CA1 local circuits: knowledge base for interneuron-pyramidal cell connectivity. Hippocampus 2013; 23: 751–785.

    Article  Google Scholar 

  35. Hill EL, Gallopin T, Ferezou I, Cauli B, Rossier J, Schweitzer P et al. Functional CB1 receptors are broadly expressed in neocortical GABAergic and glutamatergic neurons. J Neurophysiol 2007; 97: 2580–2589.

    Article  CAS  Google Scholar 

  36. Donato F, Rompani SB, Caroni P . Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature 2013; 504: 272–276.

    Article  CAS  Google Scholar 

  37. Cope DW, Maccaferri G, Marton LF, Roberts JD, Cobden PM, Somogyi P . Cholecystokinin-immunopositive basket and Schaffer collateral-associated interneurones target different domains of pyramidal cells in the CA1 area of the rat hippocampus. Neuroscience 2002; 109: 63–80.

    Article  CAS  Google Scholar 

  38. Kawamura Y, Fukaya M, Maejima T, Yoshida T, Miura E, Watanabe M et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci 2006; 26: 2991–3001.

    Article  CAS  Google Scholar 

  39. Pitler TA, Alger BE . Depolarization-induced suppression of GABAergic inhibition in rat hippocampal pyramidal cells: G protein involvement in a presynaptic mechanism. Neuron 1994; 13: 1447–1455.

    Article  CAS  Google Scholar 

  40. Wilson RI, Nicoll RA . Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 2001; 410: 588–592.

    Article  CAS  Google Scholar 

  41. Glickfeld LL, Scanziani M . Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells. Nat Neurosci 2006; 9: 807–815.

    Article  CAS  Google Scholar 

  42. Basu J, Srinivas KV, Cheung SK, Taniguchi H, Huang ZJ, Siegelbaum SA . A cortico-hippocampal learning rule shapes inhibitory microcircuit activity to enhance hippocampal information flow. Neuron 2013; 79: 1208–1221.

    Article  CAS  Google Scholar 

  43. Neu A, Foldy C, Soltesz I . Postsynaptic origin of CB1-dependent tonic inhibition of GABA release at cholecystokinin-positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus. J Physiol 2007; 578 (Pt 1): 233–247.

    Article  CAS  Google Scholar 

  44. Kim J, Alger BE . Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses. Nat Neurosci 2010; 13: 592–600.

    Article  CAS  Google Scholar 

  45. Hefft S, Jonas P . Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron-principal neuron synapse. Nat Neurosci 2005; 8: 1319–1328.

    Article  CAS  Google Scholar 

  46. Foldy C, Malenka RC, Sudhof TC . Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron 2013; 78: 498–509.

    Article  CAS  Google Scholar 

  47. Trezza V, Campolongo P, Cassano T, Macheda T, Dipasquale P, Carratu MR et al. Effects of perinatal exposure to delta-9-tetrahydrocannabinol on the emotional reactivity of the offspring: a longitudinal behavioral study in Wistar rats. Psychopharmacology (Berl) 2008; 198: 529–537.

    Article  CAS  Google Scholar 

  48. Omiya Y, Uchigashima M, Konno K, Yamasaki M, Miyazaki T, Yoshida T et al. VGluT3-expressing CCK-positive basket cells construct invaginating synapses enriched with endocannabinoid signaling proteins in particular cortical and cortex-like amygdaloid regions of mouse brains. J Neurosci 2015; 35: 4215–4228.

    Article  CAS  Google Scholar 

  49. Aguado T, Palazuelos J, Monory K, Stella N, Cravatt B, Lutz B et al. The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. J Neurosci 2006; 26: 1551–1561.

    Article  CAS  Google Scholar 

  50. Keimpema E, Mackie K, Harkany T . Molecular model of cannabis sensitivity in developing neuronal circuits. Trends Pharmacol Sci 2011; 32: 551–561.

    Article  CAS  Google Scholar 

  51. Shabani M, Hosseinmardi N, Haghani M, Shaibani V, Janahmadi M . Maternal exposure to the CB1 cannabinoid agonist WIN 55212-2 produces robust changes in motor function and intrinsic electrophysiological properties of cerebellar Purkinje neurons in rat offspring. Neuroscience 2011; 172: 139–152.

    Article  CAS  Google Scholar 

  52. Campolongo P, Trezza V, Cassano T, Gaetani S, Morgese MG, Ubaldi M et al. Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict Biol 2007; 12: 485–495.

    Article  CAS  Google Scholar 

  53. Spano MS, Ellgren M, Wang X, Hurd YL . Prenatal cannabis exposure increases heroin seeking with allostatic changes in limbic enkephalin systems in adulthood. Biol Psychiatry 2007; 61: 554–563.

    Article  CAS  Google Scholar 

  54. Maccarrone M, Guzman M, Mackie K, Doherty P, Harkany T . Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 2014; 15: 786–801.

    Article  CAS  Google Scholar 

  55. Kehrer C, Maziashvili N, Dugladze T, Gloveli T . Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia. Front Mol Neurosci 2008; 1: 6.

    Article  Google Scholar 

  56. Calfa G, Li W, Rutherford JM, Pozzo-Miller L . Excitation/Inhibition imbalance and impaired synaptic inhibition in hippocampal area CA3 of Mecp2 knockout mice. Hippocampus 2014; 25: 159–168.

    Article  Google Scholar 

  57. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O'Shea DJ et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 2011; 477: 171–178.

    Article  CAS  Google Scholar 

  58. Ziburkus J, Cressman JR, Schiff SJ . Seizures as imbalanced up states: excitatory and inhibitory conductances during seizure-like events. J Neurophysiol 2013; 109: 1296–1306.

    Article  Google Scholar 

  59. Cass DK, Flores-Barrera E, Thomases DR, Vital WF, Caballero A, Tseng KY . CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex. Mol Psychiatry 2014; 19: 536–543.

    Article  CAS  Google Scholar 

  60. Lee SH, Soltesz I . Requirement for CB1 but not GABAB receptors in the cholecystokinin mediated inhibition of GABA release from cholecystokinin expressing basket cells. J Physiol 2011; 589 (Pt 4): 891–902.

    Article  CAS  Google Scholar 

  61. Etherton M, Foldy C, Sharma M, Tabuchi K, Liu X, Shamloo M et al. Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc Natl Acad Sci USA 2011; 108: 13764–13769.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr George Kunos of NIAAA, NIH, for generously providing THC. G.A.V. is in the Brown University-NIH Neuroscience Partnership Program. This work is supported by an NICHD intramural award to C.J.M.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C J McBain.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vargish, G., Pelkey, K., Yuan, X. et al. Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. Mol Psychiatry 22, 56–67 (2017). https://doi.org/10.1038/mp.2016.17

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2016.17

This article is cited by

Search

Quick links