The International Journal of Neuropsychopharmacology

Research Article

Decreased expression of Freud-1/CC2D1A, a transcriptional repressor of the 5-HT1A receptor, in the prefrontal cortex of subjects with major depression

Bernadeta Szewczyka1a6, Paul R. Alberta2, Anastasia Rogaevaa2, Heidi Fitzgibbona1, Warren L. Maya3, Grazyna Rajkowskaa1, Jose J. Miguel-Hidalgoa1, Craig A. Stockmeiera1a5, William L. Woolvertona1, Patrick B. Kylea4, Zhixia Wanga1 and Mark C. Austina1 c1

a1 Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

a2 Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, Ontario, Canada

a3 Department of Preventive Medicine, University of Mississippi Medical Center, Jackson, MS, USA

a4 Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA

a5 Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA

a6 Department of Neurobiology, Institute of Pharmacology, Polish Academy of Science, Krakow, Poland


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.

(Received October 28 2009)

(Reviewed December 15 2009)

(Revised January 27 2010)

(Accepted February 27 2010)

(Online publication April 15 2010)