5α-reductase type I expression is downregulated in the prefrontal cortex/Brodmann's area 9 (BA9) of depressed patients

被引:72
作者
Agis-Balboa, Roberto Carlos [1 ]
Guidotti, Alessandro [1 ]
Pinna, Graziano [1 ]
机构
[1] Univ Illinois, Inst Psychiat, Coll Med, Chicago, IL 60607 USA
关键词
Allopregnanolone; Selective brain steroidogenic stimulants (SBSSs); 5 alpha-reductase type I; Major unipolar depression; GABA(A) receptor; POSTTRAUMATIC-STRESS-DISORDER; ADULT HIPPOCAMPAL NEUROGENESIS; SEROTONIN REUPTAKE INHIBITORS; OLFACTORY-BULBECTOMIZED RAT; PROTRACTED SOCIAL-ISOLATION; GABA(A) RECEPTOR FUNCTION; NEUROACTIVE STEROIDS; NEUROSTEROID BIOSYNTHESIS; MAJOR DEPRESSION; A RECEPTOR;
D O I
10.1007/s00213-014-3567-5
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The implications of the neurosteroid 3 alpha-hydroxy-5 alpha-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 GABA(A) receptors. It is synthesized in both the human and rodent brain cortices by principal glutamatergic pyramidal neurons from progesterone by the sequential action of 5 alpha-reductase type I (5 alpha-RI), which is the rate-limiting step enzyme in Allo biosynthesis, and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), which converts 5 alpha-dehydroprogesterone into Allo. We thus hypothesized that decreased CSF levels of Allo in depressed patients could reflect a brain dysfunction of 5 alpha-RI. In a pilot study of samples from six patients per group [six depressed patients and six nonpsychiatric subjects (NPS)], we studied the expression of 5 alpha-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. The levels of 5 alpha-RI mRNA were decreased from 25 +/- 5.8 in NPS to 9.1 +/- 3.1 fmol/pmol neuronal specific enolase (NSE) (t(1,10) = 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, t(1,9) = 2.4, P = 0.047) when compared with nontreated depressed patients. 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.
引用
收藏
页码:3569 / 3580
页数:12
相关论文
共 100 条
[1]   Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice [J].
Agis-Balboa, Roberto C. ;
Pinna, Graziano ;
Pibiri, Fabio ;
Kadriu, Bashkim ;
Costa, Erminio ;
Guidotti, Alessandro .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (47) :18736-18741
[2]   Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis [J].
Agis-Balboa, Roberto C. ;
Pinna, Graziano ;
Zhubi, Adrian ;
Maloku, Ekrem ;
Veldic, Marin ;
Costa, Erminio ;
Guidotti, Alessandro .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (39) :14602-14607
[3]   Neurosteroid access to the GABAA receptor [J].
Akk, G ;
Shu, HJ ;
Wang, C ;
Steinbach, JH ;
Zorumski, CF ;
Covey, DF ;
Mennerick, S .
JOURNAL OF NEUROSCIENCE, 2005, 25 (50) :11605-11613
[4]   DELETION OF STEROID 5-ALPHA-REDUCTASE 2-GENE IN MALE PSEUDOHERMAPHRODITISM [J].
ANDERSSON, S ;
BERMAN, DM ;
JENKINS, EP ;
RUSSELL, DW .
NATURE, 1991, 354 (6349) :159-161
[5]  
[Anonymous], CURR TOP BEHAV NEURO
[6]   Pathogenesis in menstrual cycle-linked CNS disorders [J].
Bäckström, T ;
Andersson, A ;
Andreé, L ;
Birzniece, V ;
Bixo, M ;
Björn, I ;
Haage, D ;
Isaksson, M ;
Johansson, IM ;
Lindblad, C ;
Lundgren, P ;
Nyberg, S ;
Ödmark, IS ;
Strömberg, J ;
Sundström-Poromaa, I ;
Turkmen, S ;
Wahlström, G ;
Wang, MD ;
Wohlbäck, AC ;
Zhu, D ;
Zingmark, E .
STEROIDS AND THE NERVOUS SYSTEM, 2003, 1007 :42-53
[7]   Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression [J].
Baghai, TC ;
di Michele, F ;
Schüle, C ;
Eser, D ;
Zwanzger, P ;
Pasini, A ;
Romeo, E ;
Rupprecht, R .
NEUROPSYCHOPHARMACOLOGY, 2005, 30 (06) :1181-1186
[8]   Multifunctional aspects of allopregnanolone in stress and related disorders [J].
Bali, Anjana ;
Jaggi, Amteshwar Singh .
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 2014, 48 :64-78
[9]   Time-dependent changes in rat brain neuroactive steroid concentrations and GABA(A) receptor function after acute stress [J].
Barbaccia, ML ;
Roscetti, G ;
Trabucchi, M ;
Mostallino, MC ;
Concas, A ;
Purdy, RH ;
Biggio, G .
NEUROENDOCRINOLOGY, 1996, 63 (02) :166-172
[10]   Neurosteroids:: Endogenous regulators of the GABAA receptor [J].
Belelli, D ;
Lambert, JJ .
NATURE REVIEWS NEUROSCIENCE, 2005, 6 (07) :565-575