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Mol Psychiatry. 2019 Apr;24(4):588-600. doi: 10.1038/s41380-018-0243-x. Epub 2018 Oct 3.

Adolescent exposure to Δ9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons.

Miller ML1,2,3,4,5, Chadwick B1,2,3,4, Dickstein DL1,4, Purushothaman I1,4, Egervari G1,2,3,4, Rahman T1,2,3,4, Tessereau C1,2,4, Hof PR1,4, Roussos P2,4,6, Shen L1,4, Baxter MG1,4, Hurd YL7,8,9.

Author information

1
Fishberg Department of Neuroscience, New York, NY, USA.
2
Department of Psychiatry, New York, NY, USA.
3
Graduate School of Biological Sciences, New York, NY, USA.
4
Addiction Institute of Mount Sinai, Friedman Brain Institute, New York, NY, USA.
5
Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
6
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, - all at the Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Fishberg Department of Neuroscience, New York, NY, USA. yasmin.hurd@mssm.edu.
8
Department of Psychiatry, New York, NY, USA. yasmin.hurd@mssm.edu.
9
Addiction Institute of Mount Sinai, Friedman Brain Institute, New York, NY, USA. yasmin.hurd@mssm.edu.

Abstract

Neuronal circuits within the prefrontal cortex (PFC) mediate higher cognitive functions and emotional regulation that are disrupted in psychiatric disorders. The PFC undergoes significant maturation during adolescence, a period when cannabis use in humans has been linked to subsequent vulnerability to psychiatric disorders such as addiction and schizophrenia. Here, we investigated in a rat model the effects of adolescent exposure to Δ9-tetrahydrocannabinol (THC), a psychoactive component of cannabis, on the morphological architecture and transcriptional profile of layer III pyramidal neurons-using cell type- and layer-specific high-resolution microscopy, laser capture microdissection and next-generation RNA-sequencing. The results confirmed known normal expansions in basal dendritic arborization and dendritic spine pruning during the transition from late adolescence to early adulthood that were accompanied by differential expression of gene networks associated with neurodevelopment in control animals. In contrast, THC exposure disrupted the normal developmental process by inducing premature pruning of dendritic spines and allostatic atrophy of dendritic arborization in early adulthood. Surprisingly, there was minimal overlap of the developmental transcriptomes between THC- and vehicle-exposed rats. THC altered functional gene networks related to cell morphogenesis, dendritic development, and cytoskeleton organization. Marked developmental network disturbances were evident for epigenetic regulators with enhanced co-expression of chromatin- and dendrite-related genes in THC-treated animals. Dysregulated PFC co-expression networks common to both the THC-treated animals and patients with schizophrenia were enriched for cytoskeletal and neurite development. Overall, adolescent THC exposure altered the morphological and transcriptional trajectory of PFC pyramidal neurons, which could enhance vulnerability to psychiatric disorders.

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