Journal
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
Volume 13, Issue 8, Pages 1089-1101Publisher
OXFORD UNIV PRESS
DOI: 10.1017/S1461145710000301
Keywords
Major depression; prefrontal cortex; 5-HT1A receptors; serotonin; transcription factor
Funding
- National Institute of Mental Health [MH63187, MH67996, MH61578, MH60451]
- National Center for Research Resources [RR17701]
- Canadian Institutes of Health Research [FRN36437]
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Serotonin1A (5-HT1A) receptors are reported altered in the brain of subjects with major depressive disorder (MDD). Recent studies have identified transcriptional regulators of the 5-HT1A receptor and have documented gender-specific alterations in 5-HT1A transcription factor and 5-HT1A receptors in female MDD subjects. The 5' repressor element under dual repression binding protein-1 (Freud-1) is a calcium-regulated repressor that negatively regulates the 5-HT1A receptor gene. This study documented the cellular expression of Freud-1 in the human prefrontal cortex (PFC) and quantified Freud-1 protein in the PFC of MDD and control subjects as well as in the PFC of rhesus monkeys chronically treated with fluoxetine. Freud-1 immunoreactivity was present in neurons and glia and was co-localized with 5-HT1A receptors. Freud-1 protein level was significantly decreased in the PFC of male MDD subjects (37%, p = 0.02) relative to gender-matched control subjects. Freud-1 protein was also reduced in the PFC of female MDD subjects (36%, p = 0.18) but was not statistically significant. When the data was combined across genders and analysed by age, the decrease in Freud-1 protein level was greater in the younger MDD subjects (48%, p = 0.01) relative to age-matched controls as opposed to older depressed subjects. Similarly, 5-HT1A receptor protein was significantly reduced in the PFC of the younger MDD subjects (48%, p = 0.01) relative to age-matched controls. Adult male rhesus monkeys administered fluoxetine daily for 39 wk revealed no significant change in cortical Freud-1 or 5-HT1A receptor proteins compared to vehicle-treated control monkeys. Reduced protein expression of Freud-1 in MDD subjects may reflect dysregulation of this transcription factor, which may contribute to the altered regulation of 5-HT1A receptors observed in subjects with MDD. These data may also suggest that reductions in Freud-1 protein expression in the PFC may be associated with early onset of MDD.
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