Cannabis modulation of social interaction in psychosis : neurobiological correlates in humans and mouse models
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Document Type
Document Version
Author
Director
Robledo, Patricia
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Publication Date
Pages
230 p.
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Citation
Barrera Conde, M. Cannabis modulation of social interaction in psychosis : neurobiological correlates in humans and mouse models. Universitat Pompeu Fabra; 2023. handle: http://hdl.handle.net/10803/688970
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Doctoral program
Programa de Doctorat en Biomedicina
Abstract
Els pacients diagnosticats amb esquizofrènia o un primer episodi psicòtic (PEP) que consumeixen cànnabis presenten alteracions clíniques diferencials comparats amb els no consumidors. En aquesta tesi doctoral, hem emprat un enfocament translacional per investigar els mecanismes subjacents als efectes moduladors del cànnabis en la conducta social en la psicosi. En primer lloc, vam trobar que l'expressió de la proteïna quinasa depenent de ciclina 5 (CDK5 per les seves sigles en anglès) era diferent en el neuroepiteli olfactiu (NO) dels pacients amb esquizofrènia en funció del consum de cànnabis. Aleshores, vam observar que els pacients amb PEP sense consum previ de cànnabis presentaven nivells més alts de CDK5 al NO i que aquests nivells es correlacionaven amb més dèficits de sociabilitat, mentre que els pacients que consumien cànnabis mostraven nivells de CDK5 més baixos i menys alteracions socials. En un model de psicosi de ratolí, consistent en l'exposició a la fenciclidina (PCP pel seu nom en anglès) i el cannabinoide sintètic WIN 55, 212-2 (WIN) durant l'adolescència, es van obtenir resultats de comportament similars als dels humans. De fet, el tractament amb WIN va reduir els dèficits de sociabilitat i va normalitzar els canvis cerebrals en l'expressió de CDK5. A més a més, vam revelar que l'exposició dels ratolins adolescents a WIN millorava les alteracions persistents de sociabilitat induïdes per PCP i normalitzava el senyal GABAèrgic en la via de l'escorça entorrinal (EC) a la CA2. Finalment, vam utilitzar la quimiogenètica per augmentar o disminuir la transmissió en aquest circuit i vam demostrar que WIN rescata la transmissió a la via de l'EC-CA2 per millorar els dèficits de sociabilitat induïts per PCP.
Schizophrenia and first-episode psychosis (FEP) patients who use cannabis exhibit differential clinical alterations as compared to non-users. In this thesis, we used a translational approach to investigate the mechanisms underlying the modulatory effects of cannabis on social deficits in psychosis. First, we found that cyclin-dependent kinase 5 (CDK5) was differently expressed in the olfactory neuroepithelium (ON) of schizophrenia patients depending on cannabis use. Then, we found that FEP patients without prior use of cannabis exhibited higher ON levels of CDK5 which correlated with more sociability deficits, while patients who used cannabis showed lower CDK5 levels and less social alterations. In a dual-hit mouse model of psychosis, consisting of a concomitant exposure to phencyclidine (PCP) and the synthetic cannabinoid WIN 55, 212-2 (WIN) during adolescence, we obtained similar behavioral results as FEP. Indeed, WIN treatment reduced sociability deficits and normalized brain changes in CDK5 expression. We then revealed that adolescent exposure to WIN in mice improved persistent sociability alterations induced by PCP and normalized the GABAergic control of distal excitatory inputs from the entorhinal cortex (EC) to CA2. Finally, we used chemogenetics to enhance or inhibit transmission in this circuit and demonstrated that WIN rescues transmission in the EC-CA2 to ameliorate sociability deficits induced by PCP.
Schizophrenia and first-episode psychosis (FEP) patients who use cannabis exhibit differential clinical alterations as compared to non-users. In this thesis, we used a translational approach to investigate the mechanisms underlying the modulatory effects of cannabis on social deficits in psychosis. First, we found that cyclin-dependent kinase 5 (CDK5) was differently expressed in the olfactory neuroepithelium (ON) of schizophrenia patients depending on cannabis use. Then, we found that FEP patients without prior use of cannabis exhibited higher ON levels of CDK5 which correlated with more sociability deficits, while patients who used cannabis showed lower CDK5 levels and less social alterations. In a dual-hit mouse model of psychosis, consisting of a concomitant exposure to phencyclidine (PCP) and the synthetic cannabinoid WIN 55, 212-2 (WIN) during adolescence, we obtained similar behavioral results as FEP. Indeed, WIN treatment reduced sociability deficits and normalized brain changes in CDK5 expression. We then revealed that adolescent exposure to WIN in mice improved persistent sociability alterations induced by PCP and normalized the GABAergic control of distal excitatory inputs from the entorhinal cortex (EC) to CA2. Finally, we used chemogenetics to enhance or inhibit transmission in this circuit and demonstrated that WIN rescues transmission in the EC-CA2 to ameliorate sociability deficits induced by PCP.
Keywords
Esquizofrènia, Biomarcadors, CDK5, Receptor cannabinoide tipus 1, CA2, Schizophrenia, Biomarkers, CDK5, Cannabinoid receptor type 1, CA2
Subjects
616.8 - Neurology. Neuropathology. Nervous system
Publisher
Universitat Pompeu Fabra
