The Absence of Serotonin in the Brain Alters Acute Stress Responsiveness by Interfering With the Genomic Function of the Glucocorticoid Receptors

Abstract

Alterations in serotonergic transmission have been related to a major predisposition to develop psychiatric pathologies, such as depression. We took advantage of tryptophan hydroxylase (TPH) 2 deficient rats, characterized by a complete absence of serotonin in the brain, to evaluate whether a vulnerable genotype may influence the reaction to an acute stressor. In this context, we investigated if the glucocorticoid receptor (GR) genomic pathway activation was altered by the lack of serotonin in the central nervous system. Moreover, we analyzed the transcription pattern of the clock genes that can be affected by acute stressors. Adult wild type (TPH2 +/+) and TPH2-deficient (TPH2 −/−) male rats were sacrificed after exposure to one single session of acute restraint stress. Protein and gene expression analyses were conducted in the prefrontal cortex (PFC). The acute stress enhanced the translocation of GRs in the nucleus of TPH2 +/+ animals. This effect was blunted in TPH2 −/− rats, suggesting an impairment of the GR genomic mechanism. This alteration was mirrored in the expression of GR-responsive genes: acute stress led to the up-regulation of GR-target gene expression in TPH2 +/+ , but not in TPH2 −/− animals. Finally, clock genes were differently modulated in the two genotypes after the acute restraint stress. Overall our findings suggest that the absence of serotonin within the brain interferes with the ability of the HPA axis to correctly modulate the response to acute stress, by altering the nuclear mechanisms of the GR and modulation of clock genes expression.

A molecular framework for autistic experiences: Mitochondrial allostatic load as a mediator between autism and psychopathology

“…Glutamate is involved in both driving HPA responses and limiting HPA overactivation (355)(356)(357), and conversely, GC signaling is known to modulate glutamatergic synapse plasticity and excitability (358). Serotonergic neurotransmission excites CRH-producing neurons in the amygdala (209) and acts as an important regulator of GR signaling in the pre-frontal cortex after exposure to acute stress (359). On the other hand, animal models show that corticosteroids decrease serotonin receptor binding densities (360,361) and this relationship is implicated as a mediator of suicidality following ELS (317).…”

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