Low gene expression of bone morphogenetic protein 7 in brainstem astrocytes in major depression

Abstract

The noradrenergic locus coeruleus (LC) is the principal source of brain norepinephrine, a neurotransmitter thought to play a major role in the pathology of major depressive disorder (MDD) and in the therapeutic action of many antidepressant drugs. The goal of this study was to identify potential mediators of brain noradrenergic dysfunction in MDD. Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β superfamily, is a critical mediator of noradrenergic neuron differentiation during development and has neurotrophic and neuroprotective effects on mature catecholaminergic neurons. Real-time PCR of reversed transcribed RNA isolated from homogenates of LC tissue from 12 matched pairs of MDD subjects and psychiatrically normal control subjects revealed low levels of BMP7 gene expression in MDD. No differences in gene expression levels of other members of the BMP family were observed in the LC, and BMP7 gene expression was normal in the prefrontal cortex and amygdala in MDD subjects. Laser capture microdissection of noradrenergic neurons, astrocytes, and oligodendrocytes from the LC revealed that BMP7 gene expression was highest in LC astrocytes relative to the other cell types, and that the MDD-associated reduction in BMP7 gene expression was limited to astrocytes. Rats exposed to chronic social defeat exhibited a similar reduction in BMP7 gene expression in the LC. BMP7 has unique developmental and trophic actions on catecholamine neurons and these findings suggest that reduced astrocyte support for pontine LC neurons may contribute to pathology of brain noradrenergic neurons in MDD.

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder

“…Since inflammation increases GFAP expression, and since MDD has been associated with elevated indices of inflammation, 47 a possible interpretation of the present findings is that brainstem astrocytes are generally deficient in their inflammatory response. In fact, the multiple deficiencies in gene expression in these cells in MDD (reduced BMP7, 26 SLC1A2, SLC1A3, GFAP) are consistent with the postulate that LC astrocytes are unhealthy in individuals with MDD. A possible cause of these gene expression changes in astrocytes in individuals with depression is that they occur after prolonged changes in noradrenergic transmission.…”

“…26 The present study provides further evidence of astrocyte dysfunction in the noradrenergic LC region. Reduced SLC1A3 and SLC1A2 expression on astrocytes would be expected to elevate synaptic glutamate and increase excitatory glutamatergic input to LC neurons found in human MDD.…”

“…15 Tissue sections for laser capture microdissection (LCM) were prepared as described previously. 26 For Western blotting, frozen sections (50 µm) were cut, and tissue containing the LC was punch-dissected (10 punches isolated per tissue donor).…”

“…26 We used quantitative rtPCR to assess transcript levels in tissue homogenates, as described previously; briefly, target genes were normalized to the geometric mean of GAPDH, ACTB and UBC. 28 All qPCR products were single, individual peaks identical to a synthesized oligonucleotide standard incorporating the complementary sequences to each primer set.…”

Further evidence of an association between a genetic variant in BMP7 and treatment response to SSRIs in major depressive disorder

“…This post-mortem finding suggests that BMP7 has a possible role on brain noradrenergic systems in MDD, thus supporting the association between BMP7 and MDD (or antidepressant action). 7 A recent mega-analysis of three pharmacogenomic studies, including STAR*D, did not detect this BMP7 SNP in the top findings. 5 Several reasons can be proposed for the discrepancy between the results of our study, the STAR*D study and the mega-analysis.…”