Chronic exposure to Δ-9-tetrahydrocannabinol (THC) during adolescence is associated with long-lasting cognitive impairments and enhanced susceptibility to anxiety and mood disorders. Previous evidence has revealed functional and anatomical dissociations between the posterior vs. anterior portions of the hippocampal formation, which are classified as the dorsal and ventral regions in rodents, respectively. Notably, the dorsal hippocampus is critical for cognitive and contextual processing, whereas the ventral region is critical for affective and emotional processing. While adolescent THC exposure can induce significant morphological disturbances and glutamatergic signaling abnormalities in the hippocampus, it is not currently understood how the dorsal vs. ventral hippocampal regions are affected by THC during neurodevelopment. In the present study, we used an integrative combination of behavioral, molecular, and neural assays in a neurodevelopmental rodent model of adolescent THC exposure. We report that adolescent THC exposure induces long-lasting memory deficits and anxiety like-behaviors concomitant with a wide range of differential molecular and neuronal abnormalities in dorsal vs. ventral hippocampal regions. In addition, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), we show for the first time that adolescent THC exposure induces significant and enduring dysregulation of GABA and glutamate levels in dorsal vs. ventral hippocampus. Finally, adolescent THC exposure induced dissociable dysregulations of hippocampal glutamatergic signaling, characterized by differential glutamatergic receptor expression markers, profound alterations in pyramidal neuronal activity and associated oscillatory patterns in dorsal vs. ventral hippocampal subregions.
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Andréasson S, Allebeck P, Engström A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet. 1987;2:1483–6.
Krebs MO, Kebir O, Jay TM. Exposure to cannabinoids can lead to persistent cognitive and psychiatric disorders. Eur J Pain. 2019;23:1225–33.
Murray RM, Englund A, Abi-Dargham A, Lewis DA, Di Forti M, Davies C, et al. Cannabis-associated psychosis: Neural substrate and clinical impact. Neuropharmacology 2017;124:89–104.
Gobbi G, Atkin T, Zytynski T, Wang S, Askari S, Boruff J, et al. Association of cannabis use in adolescence and risk of depression, anxiety, and suicidality in young adulthood: a systematic review and meta-analysis. JAMA Psychiatry 2019;76:426–34.
Mato S, Del Olmo E, Pazos A. Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain. Eur J Neurosci. 2003;17:1747–54.
Yücel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis C, et al. Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry. 2008;65:694–701.
Cousijn J, Wiers RW, Ridderinkhof KR, Van den Brink W, Veltman DJ, Goudriaan AE. Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls. Neuroimage. 2012;59:3845–51.
Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, et al. Effect of long-term cannabis use on axonal fibre connectivity. Brain. 2012;135:2245–55.
Poulia N, Delis F, Brakatselos C, Polissidis A, Koutmani Y, Kokras N, et al. Detrimental effects of adolescent escalating low-dose Δ9-tetrahydrocannabinol leads to a specific bio-behavioural profile in adult male rats. Br J Pharm. 2021;178:1722–36.
Poulia N, Delis F, Brakatselos C, Lekkas P, Kokras N, Dalla C, et al. Escalating low-dose Δ9-tetrahydrocannabinol exposure during adolescence induces differential behavioral and neurochemical effects in male and female adult rats. Eur J Neurosci. 2020;52:2681–93.
Zamberletti E, Gabaglio M, Grilli M, Prini P, Catanese A, Pittaluga A, et al. Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats. Pharm Res. 2016;111:459–70.
Stringfield SJ, Torregrossa MM. Intravenous self-administration of delta-9-THC in adolescent rats produces long-lasting alterations in behavior and receptor protein expression. Psychopharmacology. 2021;238:305–19.
Avery SN, Rogers BP, Heckers S. Hippocampal network modularity is associated with relational memory dysfunction in schizophrenia. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3:423–32.
Ragland JD, Layher E, Hannula DE, Niendam TA, Lesh TA, Solomon M, et al. Impact of schizophrenia on anterior and posterior hippocampus during memory for complex scenes. NeuroImage Clin. 2017;13:82–88.
Bannerman DM, Rawlins JNP, McHugh SB, Deacon RMJ, Yee BK, Bast T, et al. Regional dissociations within the hippocampus-Memory and anxiety. Neurosci Biobehav Rev. 2004;28:273–83.
Fanselow MS, Dong H-W. Are The Dorsal and Ventral Hippocampus functionally distinct structures? Neuron. 2010;14:7–19.
Moser MB, Moser EI, Forrest E, Andersen P, Morris RGM. Spatial learning with a minislab in the dorsal hippocampus. Proc Natl Acad Sci USA. 1995;92:9697–701.
Moser E, Moser MB, Andersen P. Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions. J Neurosci. 1993;13:3916–25.
Pothuizen HHJ, Zhang WN, Jongen-Rêlo AL, Feldon J, Yee BK. Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: A within-subject, within-task comparison of reference and working spatial memory. Eur J Neurosci. 2004;19:705–12.
Hock BJ, Bunsey MD. Differential effects of dorsal and ventral hippocampal lesions. J Neurosci. 1998;18:7027–32.
Bannerman DM, Good MA, Yee BK, Heupel MJ, Iversen SD, Rawlins JNP. Double dissociation of function within the hippocampus: A comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions. Behav Neurosci. 1999;113:1170–88.
Bannerman DM, Grubb M, Deacon RMJ, Yee BK, Feldon J, Rawlins JNP. Ventral hippocampal lesions affect anxiety but not spatial learning. Behav Brain Res. 2003;139:197–213.
Maren S. Neurotoxic or electrolytic lesions of the ventral subiculum produce deficits in the acquisition and expression of Pavlovian fear conditioning in rats. Behav Neurosci. 1999;113:283–90.
Maren S, Holt WG. Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus. Behav Neurosci. 2004;118:97–110.
Kjelstrup KG, Tuvnes FA, Steffenach HA, Murison R, Moser EI, Moser MB. Reduced fear expression after lesions of the ventral hippocampus. Proc Natl Acad Sci USA. 2002;99:10825–30.
Strange BA, Witter MP, Lein ES, Moser EI. Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci. 2014;15:655–69.
Jung MW, Wiener SI, McNaughton BL. Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat. J Neurosci. 1994;14:7347–56.
Howland JG, MacKenzie EM, Yim TT, Taepavarapruk P, Phillips AG. Electrical stimulation of the hippocampus disrupts prepulse inhibition in rats: Frequency- and site-dependent effects. Behav Brain Res. 2004;152:187–97.
Pouzet B, Zhang WN, Weiner I, Feldon J, Yee BK. Latent inhibition is spared by N-methyl-D-aspartate (NMDA)-induced ventral hippocampal lesions, but is attenuated following local activation of the ventral hippocampus by intracerebral NMDA infusion. Neuroscience. 2004;124:183–94.
Zhang WN, Bast T, Feldon J. Prepulse inhibition in rats with temporary inhibition/inactivation of ventral or dorsal hippocampus. Pharm Biochem Behav. 2002;73:929–40.
Peleg-Raibstein D, Feldon J. Effects of dorsal and ventral hippocampal NMDA stimulation on nucleus accumbens core and shell dopamine release. Neuropharmacology. 2006;51:947–57.
Hudson R, Renard J, Norris C, Rushlow WJ, Laviolette SR. Cannabidiol counteracts the psychotropic side-effects of Δ-9-tetrahydrocannabinol in the ventral hippocampus through bidirectional control of ERK1-2 phosphorylation. J Neurosci. 2019;39:8762–77.
Loureiro M, Renard J, Zunder J, Laviolette SR. Hippocampal cannabinoid transmission modulates dopamine neuron activity: impact on rewarding memory formation and social interaction. Neuropsychopharmacology. 2015;40:1436–47.
Renard J, Rosen LG, Loureiro M, De Oliveira C, Schmid S, Rushlow WJ, et al. Adolescent cannabinoid exposure induces a persistent sub-cortical hyper-dopaminergic state and associated molecular adaptations in the prefrontal cortex. Cereb Cortex. 2017;27:1297–310.
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.
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 Δ-9-tetrahydrocannabinol exposure and blocks associated molecular and neuronal abnormalities in the mesocorticolimbic circuitry. J Neurosci. 2021;41:739–50.
Chen C, Laviolette SR, Whitehead SN, Renaud JB, Yeung KKC. Imaging of neurotransmitters and small molecules in brain tissues using laser desorption/ionization mass spectrometry assisted with zinc oxide nanoparticles. J Am Soc Mass Spectrom. 2021;32:1065–79.
Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, et al. Adolescent rats find repeated Δ9-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology. 2008;33:1113–26.
Heckers S, Konradi C. Hippocampal neurons in schizophrenia. J Neural Transm. 2002;109:891–905.
Moghaddam B, Javitt D. From revolution to evolution: The glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012;37:4–15.
De Gregorio D, Dean Conway J, Canul M-L, Posa L, Bambico FR, Gobbi G. Effects of chronic exposure to low-dose delta-9-tetrahydrocannabinol in adolescence and adulthood on serotonin/norepinephrine neurotransmission and emotional behavior. Int J Neuropsychopharmacol. 2020;23:751–61.
Llorente-berzal A, Puighermanal E, Burokas A. Sex-dependent psychoneuroendocrine effects of THC and MDMA in an animal model of adolescent drug consumption. PLoS One. 2013;8:e78386.
Viravathana P, Marr DWM. Differential effects of Δ9-THC on spatial reference and working memory in mice. Psychopharmacology. 2001;157:142–50.
Bhattacharyya S, Schoeler T. The effect of cannabis use on memory function: an update. Subst Abuse Rehabil. 2013;4:11–27.
Noorbakhsh S, Afzali MH, Boers E, Conrod PJ. Cognitive function impairments linked to alcohol and cannabis use during adolescence: a study of gender differences. Front Hum Neurosci. 2020;14:1–11.
Barker GRI, Warburton EC. When is the hippocampus involved in recognition memory? J Neurosci. 2011;31:10721–31.
Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H. Hippocampal damage and exploratory preferences in rats: Memory for objects, places, and contexts. Learn Mem. 2002;9:49–57.
Lieberman JA, Girgis RR, Brucato G, Moore H, Provenzano F, Kegeles L, et al. Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention. Mol Psychiatry. 2018;23:1764–72.
Kalmady SV, Shivakumar V, Arasappa R, Subramaniam A, Gautham S, Venkatasubramanian G, et al. Clinical correlates of hippocampus volume and shape in antipsychotic-naïve schizophrenia. Psychiatry Res Neuroimaging. 2017;263:93–102.
Nesvadeni M, Matsumoto I, Sivagnanasundaram S. Anterior hippocampus in schizophrenia pathogenesis: molecular evidence from a proteome study. Aust N Z J Psychiatry. 2009;43:310–22.
Ma YN, Sun YX, Wang T, Wang H, Zhang Y, Su YA, et al. Subchronic MK-801 treatment during adolescence induces long-term, not permanent, excitatory-inhibitory imbalance in the rat hippocampus. Eur J Pharmacol. 2020;867:172807.
Gao R, Penzes P. Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med. 2015;15:146–67.
Liu Y, Ouyang P, Zheng Y, Mi L, Zhao J, Ning Y, et al. A selective review of the excitatory-inhibitory imbalance in schizophrenia: underlying biology, genetics, microcircuits, and symptoms. Front Cell Dev Biol. 2021;9:1–15.
Dogra S, Conn PJ. Metabotropic glutamate receptors as emerging targets for the treatment of schizophrenia. Mol Pharm. 2022;101:275–85.
Adell A. Brain NMDA receptors in schizophrenia and depression. Biomolecules. 2020;10:244.
Balu DT. The NMDA receptor and schizophrenia: from pathophysiology to treatment. Adv Pharm. 2016;76:351–82.
Hashimoto K, Malchow B, Falkai P, Schmitt A. Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci. 2013;263:367–77.
Hsia AY, Malenka RC, Nicoll RA. Development of excitatory circuitry in the hippocampus. J Neurophysiol. 1998;79:2013–24.
Bakshi VP, Geyer MA. Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci. 1998;18:8394–401.
Zhang W, Pouzet B, Jongen-Rêlo AL, Weiner I, Feldon J. Disruption of prepulse inhibition following N-methyl-D-aspartate infusion into the ventral hippocampus is antagonized by clozapine but not by haloperidol: A possible model for the screening of atypical antipsychotics. Neuroreport. 1999;10:2533–8.
Pacheco A, Aguayo FI, Aliaga E, Muñoz M, García-Rojo G, Olave FA, et al. Chronic stress triggers expression of immediate early genes and differentially affects the expression of AMPA and NMDA subunits in dorsal and ventral hippocampus of rats. Front Mol Neurosci. 2017;10:244.
Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, et al. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999;20:106–18.
Lorigooini Z, Nasiri boroujeni S, Balali-Dehkordi S, Ebrahimi L, Bijad E, Rahimi-Madiseh M, et al. Possible involvement of NMDA receptor in the anxiolytic-like effect of caffeic acid in mice model of maternal separation stress. Heliyon. 2020;6:e04833.
Jafari-Sabet M. NMDA receptor blockers prevents the facilitatory effects of post-training intra-dorsal hippocampal NMDA and physostigmine on memory retention of passive avoidance learning in rats. Behav Brain Res. 2006;169:120–7.
Nascimento Häckl LP, Carobrez AP. Distinct ventral and dorsal hippocampus AP5 anxiolytic effects revealed in the elevated plus-maze task in rats. Neurobiol Learn Mem. 2007;88:177–85.
Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry. 2002;59:521–9.
Laaris N, Good CH, Lupica CR. Δ9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology. 2010;59:121–7.
Suo L, Zhao L, Si J, Liu J, Zhu W, Chai B, et al. Predictable chronic mild stress in adolescence increases resilience in adulthood. Neuropsychopharmacology. 2013;38:1387–1400.
Xie R, Xie J, Ye Y, Wang X, Chen F, Yang L, et al. mTOR expression in hippocampus and prefrontal cortex is downregulated in a rat model of schizophrenia induced by chronic administration of ketamine. J Mol Neurosci. 2020;70:269–75.
Zhao T, Gao X, Huang G-B. Effects of chronic social defeat stress on behavior and dopamine receptors in adolescent mice with 6-hydroxydopamine lesions of the medial prefrontal cortex. Front Behav Neurosci. 2021;15:731373.
Angulo MC, Kozlov AS, Charpak S, Audinat E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci. 2004;24:6920–7.
Rubino T, Realini N, Braida D, Guidi S, Capurro V, Guidali C, et al. Changes in hippocampal morphology and neuroplasticity induced by adolescent thc treatment are associated with cognitive impairment in adulthood. Hippocampus. 2009;772:763–72.
Sampedro-Piquero P, De Bartolo P, Petrosini L, Zancada-Menendez C, Arias JL, Begega A. Astrocytic plasticity as a possible mediator of the cognitive improvements after environmental enrichment in aged rats. Neurobiol Learn Mem. 2014;114:16–25.
Goonawardena AV, Riedel G, Hampson RE. Cannabinoids alter spontaneous firing, bursting and cell synchrony of hippocampal principal cells. Hippocampus. 2011;5:520–31.
Robinson L, Goonawardena AV, Pertwee RG, Hampson RE, Riedel G. The synthetic cannabinoid HU210 induces spatial memory deficits and suppresses hippocampal firing rate in rats. Br J Pharm. 2007;151:688–700.
Lodge DJ, Grace AA. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci. 2007;27:11424–30.
Sonnenschein SF, Grace AA. Peripubertal mGluR2/3 agonist treatment prevents hippocampal dysfunction and dopamine system hyperactivity in adulthood in MAM model of schizophrenia. Schizophr Bull. 2021;47:1806–14.
Speers LJ, Bilkey DK. Disorganization of oscillatory activity in animal models of schizophrenia. Front Neural Circuits. 2021;15:1–25.
Skosnik PD, Cortes-Briones JA, Hajós M. It’s all in the rhythm: The role of cannabinoids in neural oscillations and psychosis. Biol Psychiatry. 2016;79:568–77.
Sargent K, Chavez-Baldini UY, Master SL, Verweij KJH, Lok A, Sutterland AL, et al. Resting-state brain oscillations predict cognitive function in psychiatric disorders: A transdiagnostic machine learning approach. NeuroImage Clin. 2021;30:102617.
Jeannin-Mayer S, André-Obadia N, Rosenberg S, Boutet C, Honnorat J, Antoine JC, et al. EEG analysis in anti-NMDA receptor encephalitis: Description of typical patterns. Clin Neurophysiol. 2019;130:289–96.
Hanson JE, Ma K, Elstrott J, Weber M, Saillet S, Khan AS, et al. GluN2A NMDA receptor enhancement improves brain oscillations, synchrony, and cognitive functions in dravet syndrome and Alzheimer’s disease models. Cell Rep. 2020;30:381–.e4.
Goyal A, Miller J, Qasim SE, Watrous AJ, Zhang H, Stein JM, et al. Functionally distinct high and low theta oscillations in the human hippocampus. Nat Commun. 2020;11:2469.
Jacinto LR, Reis JS, Dias NS, Cerqueira JJ, Correia JH, Sousa N. Stress affects theta activity in limbic networks and impairs novelty-induced exploration and familiarization. Front Behav Neurosci. 2013;7:1–11.
Sirota A, Montgomery S, Fujisawa S, Isomura Y, Zugaro M, Buzsáki G. Entrainment of neocortical neurons and gamma oscillations by the Hippocampal theta rhythm. Neuron. 2008;60:683–97.
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;19:536–43.
Katona I, Sperlágh B, Sík A, Käfalvi A, Vizi ES, Mackie K, et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci. 1999;19:4544–58.
Shen M, Piser TM, Seybold VS, Thayer SA. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci. 1996;16:4322–34.
Sullivan JM. Cellular and molecular mechanisms underlying learning and memory impairments produced by cannabinoids. Learn Mem. 2000;7:132–9.
Baglot SL, Hume C, Petrie GN, Aukema RJ, Lightfoot SHM, Grace LM, et al. Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats. Sci Rep. 2021;11:23990.
Oeltzschner G, Wijtenburg SA, Mikkelsen M, Edden RAE, Barker PB, Joo JH, et al. Neurometabolites and associations with cognitive deficits in mild cognitive impairment: a magnetic resonance spectroscopy study at 7 Tesla. Neurobiol Aging. 2019;73:211–8.
Spurny B, Seiger R, Moser P, Vanicek T, Reed MB, Heckova E, et al. Hippocampal GABA levels correlate with retrieval performance in an associative learning paradigm. Neuroimage. 2020;204:116244.
Malik R, Li Y, Schamiloglu S, Sohal VS. Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition. Cell. 2022;185:1602-1617.e17.
Renard J, Rushlow WJ, Laviolette SR. Effects of adolescent THC exposure on the prefrontal GABAergic system: Implications for schizophrenia-related psychopathology. Front Psychiatry. 2018;9:1–13.
Canadian Cannabis Survey 2021: Summary. Gov Canada. https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/research-data/canadian-cannabis-survey-2021-summary.html. Accessed 23 Dec 2021.
Shanahan L, Steinhoff A, Bechtiger L, Copeland WE, Ribeaud D, Eisner M, et al. Frequent teenage cannabis use: Prevalence across adolescence and associations with young adult psychopathology and functional well-being in an urban cohort. Drug Alcohol Depend. 2021;228:109063.
This work was supported by Canadian Institute of Health Research (CIHR; MOP-123378); Natural Sciences and Engineering Research Council (NSERC); MITACS Canada; Canada First Research Excellence Fund (CFREF) awarded to BrainsCAN at Western University.
The authors declare no competing interests.
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De Felice, M., Chen, C., Rodríguez-Ruiz, M. et al. Adolescent Δ-9-tetrahydrocannabinol exposure induces differential acute and long-term neuronal and molecular disturbances in dorsal vs. ventral hippocampal subregions. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01496-x