Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances.
Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-beta and tumor necrosis factor-alpha, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. We hypothesized that, in depression, the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis are upregulated, whereas the transcript levels of the genes involved in the inhibition of the HPA axis are downregulated. We performed laser microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-alpha, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF neurons was decreased significantly. These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA axis in depression.
Wang
S-S
SS
Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
Kamphuis
W
W
Huitinga
I
I
Zhou
J-N
JN
Swaab
D F
DF
D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000235:genetics*; D003863:Depression / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007031:Hypothalamus / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011180:Postmortem Changes; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
D018160:Receptors, Cytoplasmic and Nuclear