5α-reductase type I expression is downregulated in the prefrontal cortex/Brodmann's area 9 (BA9) of depressed patients.
BACKGROUND
The implications of the neurosteroid 3α-hydroxy-5α-pregnan-20-one [allopregnanolone (Allo)] in neuropsychiatric disorders have been highlighted in several recent clinical investigations. For instance, Allo levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants [i.e., selective brain steroidogenic stimulants (SBSSs)], including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms. Allo positively and allosterically modulates GABA action at postsynaptic and extrasynaptic GABAA receptors. It is synthesized in both the human and rodent brain cortices by principal glutamatergic pyramidal neurons from progesterone by the sequential action of 5α-reductase type I (5α-RI), which is the rate-limiting step enzyme in Allo biosynthesis, and 3α-hydroxysteroid dehydrogenase (3α-HSD), which converts 5α-dehydroprogesterone into Allo.


OBJECTIVE
We thus hypothesized that decreased CSF levels of Allo in depressed patients could reflect a brain dysfunction of 5α-RI.


METHODS
In a pilot study of samples from six patients per group [six depressed patients and six nonpsychiatric subjects (NPS)], we studied the expression of 5α-RI messenger RNA (mRNA) in prefrontal cortex Brodmann's area 9 (BA9) and cerebellum from depressed patients obtained from the Maryland Brain Collection at the Maryland Psychiatric Research Center (Baltimore, MD) that were age-matched with NPS.


RESULTS
The levels of 5α-RI mRNA were decreased from 25 ± 5.8 in NPS to 9.1 ± 3.1 fmol/pmol neuronal specific enolase (NSE) (t1,10 = 2.7, P = 0.02) in depressed patients. These differences are absent in the cerebellum of the same patients. The levels of neurosteroids were determined in the prefrontal cortex BA9 of depressed patients obtained from the Stanley Foundation Brain Bank Neuropathology Consortium, Bethesda (MD). The BA9 levels of Allo in male depressed patients failed to reach statistical difference from the levels of NPS (1.63 ± 1.01 pg/mg, n = 8, in NPS and 0.82 ± 0.33 pg/mg, n = 5, in nontreated depressed patients). However, depressed patients who had received antidepressant treatment (three patients SSRI and one TCA) exhibited increased BA9 Allo levels (6.16 ± 2.5 pg/mg, n = 4, t1,9 = 2.4, P = 0.047) when compared with nontreated depressed patients.


CONCLUSIONS
Although in a small number of patients, this finding is in-line with previous reports in the field that have observed an increase of Allo levels in CSF and plasma of depressed patients following antidepressant treatment. Hence, the molecular mechanisms underlying major depression may include a GABAergic neurotransmission deficit caused by a brain Allo biosynthesis downregulation, which can be normalized by SBSSs.
The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Roberto Carlos
RC
Agis-Balboa
Alessandro
A
Guidotti
Graziano
G
Pinna
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics*; D000328:Adult; D003865:Major Depressive Disorder / Q000134:cerebrospinal fluid / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D017397:Prefrontal Cortex / Q000201:enzymology*; D011280:Pregnanolone / Q000134:cerebrospinal fluid; D017966:Pyramidal Cells / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013405:Suicide; D014015:Tissue Banks; D055815:Young Adult
D012333:RNA, Messenger; D011280:Pregnanolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C476566:steroid-5alpha-reductase type 1