Adolescent exposure to \u03949-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons

Michael L Miller,Tanni Rahman,Dara L Dickstein,Gabor Egervari,Chloe Tessereau,Panos Roussos,Mark G Baxter,Li Shen,Patrick R Hof,Immanuel Purushothaman,Benjamin Chadwick,Yasmin L Hurd

doi:10.1038/s41380-018-0243-x

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.

Highlights

Adolescent THC exposure altered the developmental trajectory of dendritic arbors To investigate the morphological consequences of adolescent THC exposure, we reconstructed the apical and basal dendritic trees of layer III PrL pyramidal neurons (Fig. 1d)
We investigated the consequences of adolescent THC exposure on dendritic spines by reconstructing branches of dendritic arbors and quantifying the type—mushroom, stubby, or thin—and density of dendritic spines (Fig. 1e)
Prefrontal pyramidal neurons comprise circuits that modulate mesolimbic function dysregulated in psychiatric disorders

Summary

Introduction

Adolescent exposure to Δ9-tetrahydrocannabinol alters the transcriptional. Mediated predominately by Δ9-tetrahydrocannabinol (THC) binding to the cannabinoid 1 receptor (CB1R), a central component of the endocannabinoid (eCB) system [4]. Disturbances of CB1R signaling in the prefrontal cortex (PFC) are implicated in schizophrenia and THC administration acutely worsens core symptoms in patients with stable disease [5, 6]. Adolescent cannabis exposure likely induces longterm consequences by interfering with the architecture of PFC neurocircuitry. Human neuroimaging studies demonstrate that individuals with a history of adolescent cannabis use exhibit altered PFC volume [14,15,16] and function [17, 18], but the cellular and molecular phenotype of such disturbances remains unknown

Methods

Results

Conclusion