Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex

Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex

PDF

J Psychiatry Neurosci 2018;43(2):87-101

Pamela Prini, PhD; Franceso Rusconi, PhD; Erica Zamberletti, PhD; Marina Gabaglio, MSc; Federica Penna, MSc; Mauro Fasano, PhD; Elena Battaglioli, PhD; Daniela Parolaro, PhD; Tiziana Rubino, PhD

Abstract

Background: Increasing cannabis consumption among adolescents, studies that link its early use with mental illnesses, and the political debate on cannabis legalization together call for an urgent need to study molecular underpinnings of adolescent brain vulnerability. The emerging role of epigenetic mechanisms in psychiatric diseases led us to hypothesize that epigenetic alterations could play a role in causes and subsequent development of the depressive/psychotic-like phenotype induced by adolescent, but not adult, Δ9-tetrahydrocannabinol (THC) exposure in female rats.

Methods: We performed a time-course analysis of histone modifications, chromatin remodelling enzymes and gene expression in the prefrontal cortex of female rats after adolescent and adult THC exposure. We also administered a specific epigenetic drug (chaetocin) with THC to investigate its impact on THC-induced behavioural alterations.

Results: Adolescent THC exposure induced alterations of selective histone modifications (mainly H3K9me3), impacting the expression of genes closely associated with synaptic plasticity. Changes in both histone modifications and gene expression were more widespread and intense after adolescent treatment, suggesting specific adolescent susceptibility. Adolescent THC exposure significantly increased Suv39H1 levels, which could account for the enhanced H3K9me3. Pharmacological blockade of H3K9me3 during adolescent THC treatment prevented THC-induced cognitive deficits, suggesting the relevant role played by H3K9me3 in THC-induced effects.

Limitations: Only female rats were investigated, and the expression studies were limited to a specific subset of genes.

Conclusion: Through a mechanism involving SUV39H1, THC modifies histone modifications and, thereby, expression of plasticity genes. This pathway appears to be relevant for the development of cognitive deficits.


Submitted Apr. 20, 2017; Revised June 22, 2017; Accepted July 13, 2017; Online first Oct. 10, 2017

Acknowledgements: This work was supported by Fondazione Zardi Gori (bando 2014) and Dipartimento delle Politiche Antidroga (EpiCa) to T. Rubino, F. Rusconi (Cariplo 2014-0972) and E. Battaglioli (Telethon GGP14074). The authors thank Giorgio Binelli for his help with statistical analysis.

Affiliations: From the Department of Biotechnology and Life Sciences, University of Insubria, Busto Arsizio VA, Italy (Prini, Zamberletti, Gabaglio, Penna, Parolaro, Rubino); the Neuroscience Center, University of Insubria, Busto Arsizio VA, Italy (Prini, Zamberletti, Gabaglio, Fasano, Parolaro, Rubino); the Department of Medical Biotecnology and Translational Medicine, University of Milan, Milano, Segrate MI, Italy (Rusconi, Battaglioli); and the Department of Science and High Technology, University of Insubria, Busto Arsizio VA, Italy (Fasano).

Competing interests: None declared.

Contributors: P. Prini and T. Rubino designed the study. P. Prini, F. Rusconi, E. Zamberletti, M. Gabaglio, F. Penna, M. Fasano and E. Battaglioli acquired the data, which P. Prini, F. Rusconi, M. Fasano, E. Battaglioli, D. Parolaro and T. Rubino analyzed. P. Prini, F. Rusconi, E. Battaglioli and T. Rubino wrote the article, which all authors critically reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.170082

Correspondence to: T. Rubino, Department of Biotechnology and Life Sciences and Neuroscience Center, University of Insubria, Via Manara 7, 21052 Busto Arsizio VA, Italy; tiziana.rubino@uninsubria.it