Adolescent cannabis exposure interacts with mutant DISC1 to produce impaired adult emotional memory

作者：Ballinger Michael D; Saito Atsushi; Abazyan Bagrat; Taniguchi Yu; Huang Ching Hsun; Ito Koki; Zhu Xiaolei; Segal Hadar; Jaaro Peled Hanna; Sawa Akira; Mackie Ken; Pletnikov Mikhail V; Kamiya Atsushi^*

来源：Neurobiology of Disease, 2015, 82: 176-184.

DOI：10.1016/j.nbd.2015.06.006

• Chronic cannabis use
• Gene-environment interaction
• Adolescent development
• DISC1
• Fear memory

Cannabis is an increasingly popular and controversial drug used worldwide. Cannabis use often begins during adolescence, a highly susceptible period for environmental stimuli to alter functional and structural organization of the developing brain. Given that adolescence is a critical time for the emergence of mental illnesses before full-onset in early adulthood, it is particularly important to investigate how genetic insults and adolescent cannabis exposure interact to affect brain development and function. Here we show for the first time that a perturbation in disrupted in schizophrenia 1 (DISC1) exacerbates the response to adolescent exposure to delta-9-tetrahydrocannabinol (Delta(9)-THC), a major psychoactive ingredient of cannabis, consistent with the concept that gene-environment interaction may contribute to the pathophysiology of psychiatric conditions. We found that chronic adolescent treatment with Delta(9)-THC exacerbates deficits in fear-associated memory in adult mice that express a putative dominant-negative mutant of DISC1 (DN-DISC1). Synaptic expression of cannabinoid receptor 1 (CB1R) is down-regulated in the prefrontal cortex, hippocampus, and amygdala, critical brain regions for fear-associated memory, by either expression of DN-DISC1 or adolescent Delta(9)-THC treatment Notably, elevation of c-Fos expression evoked by context-dependent fear memory retrieval is impaired in these brain regions in DN-DISC1 mice. We also found a synergistic reduction of c-Fos expression induced by cue-dependent fear memory retrieval in DN-DISC1 with adolescent Delta(9)-THC exposure. These results suggest that alteration of CB1R-mediated signaling in DN-DISC1 mice may underlie susceptibility to detrimental effects of adolescent cannabis exposure on adult behaviors.

• 出版日期2015-10