Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression-1 and nuclear-deformed epidermal autoregulatory factor by chronic stress

Abstract

Chronic stress is known to affect brain areas involved in learning and emotional responses. These changes, thought to be related to the development of cognitive deficits are evident in major depressive disorder (MDD) and other stress related pathophysiologies. The serotoninrelated transcription factors ((Freud-1/CC2D1A; five prime repressor element under dual repression/coiled-coil C2 domain-1A and NUDR/Deaf-1; nuclear deformed epidermal autoregulatory factor) are two important regulators of the 5HT1A receptor. Using Western blotting and quantitative real-time polymerase chain reaction (qPCR) we examined the expression of mRNA and proteins for Freud-1, NUDR, and the 5-HT1A receptor in the prefrontal cortex (PFC) of male rats exposed to chronic restraint stress (CRS; 6h/day for 21 days). After 21 days of CRS, significant reductions in both Freud-1 mRNA and protein were observed in the prefrontal cortex (PFC) (36.8% and 32% respectively; p<0.001) while the levels of both NUDR protein and mRNA did not change significantly. Consistent with reduced Freud-1 protein, 5-HT1A receptor mRNA levels were equally upregulated in the PFC, while protein levels actually declined, suggesting post-transcriptional receptor downregulation. The data suggest that CRS produces distinct alterations in the serotonin system specifically altering Freud-1 and the 5-HT1A receptor in the PFC of the male rat while having no effect on NUDR. These results point to the importance of understanding the mechanism for the differential regulation of Freud-1 and NUDR in the PFC as a basis for understanding the related effects of chronic stress on the serotonin system (serotonin-related transcription factors) and stress-related disorders like depression.

Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior

“…This suggests that post-synaptic Freud-1 is also important for normal behavioral development. Consistent with this, Freud-1 levels are reduced in PFC following chronic stress in rats (Iyo et al, 2009), while both Freud-1 and 5-HT1A protein levels were reduced in PFC of young depressed subjects (Szewczyk et al, 2010), suggesting that early impairments in cortical Freud-1 levels may predispose to depression. The importance of presynaptic Freud-1 in 5-HT1A autoreceptor regulation and anxiety/depression behavior reported here, and its complementary role in the forebrain in anxiety and cognitive function suggest that enhancing Freud-1 expression or function may provide a useful target, particularly in treatment-resistant forms of these diseases.…”

Differential distribution of serotonin receptor subtypes in BNSTALG neurons: Modulation by unpredictable shock stress

“…These data were consistent with the significant reduction in 5-HT 1A receptor expression following USS, and suggest that Deaf-1 may be the principal regulator of 5-HT 1A receptor expression in BNST ALG neurons. Differential regulation of 5-HT 1A gene repressor expression has also been observed in the PFC (Iyo et al, 2009). Here chronic restraint stress caused a significant reduction in Freud-1 mRNA and protein expression but had no effect on Deaf-1 expression.…”

The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys

“…Moreover, regulation of 5-HT 1A receptor gene expression is complex (Raymond et al, 1999), and under the control of numerous transcription factors (Albert et al, 2011). The effect of chronic ethanol on these transcription factors remains unknown, although stress and depression have both been associated with differential control of regulators of 5-HT 1A receptor transcription (Iyo et al, 2009; Szewczyk et al, 2009, 2010), suggesting that similar alterations are plausible following chronic ethanol.…”