Neurosteroids and Neurotrophic Factors: What Is Their Promise as Biomarkers for Major Depression and PTSD?

Abstract

Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world, their diagnosis still relies solely on the characterization of subjective symptoms (many of which are shared by multiple disorders) self-reported by patients. Thus, the need for objective measures that aid in the detection of and differentiation between psychiatric disorders becomes urgent. In this paper, we explore the potential of neurosteroids and neurotrophic proteins as biomarkers for MDD and PTSD. Circulating levels of the GABAergic neuroactive steroid, allopregnanolone, are diminished in MDD and PTSD patients, which corroborates the finding of depleted neurosteroid levels observed in animal models of these disorders. The neurotrophic protein, brain-derived neurotropic factor (BDNF), is also reduced in the periphery and in the brain of MDD patients and depressed-like animals that express lower neurosteroid levels. Although the role of BDNF in PTSD psychopathology seems less clear and merits more research, we propose a causal link between allopregnanolone levels and BDNF expression that could function as a biomarker axis for the diagnosis of both MDD and PTSD.

Keywords: BDNF; MDD; PTSD; allopregnanolone; biomarkers; rodent models.

Figure 1

Allopregnanolone biosynthetic pathway starting from cholesterol metabolism. Abbreviations: StAR: steroidogenic acute regulatory protein; TSPO: 18 kDa translocator protein; scc: side-chain cleavage.

Figure 2

Diagram of the functional role of BDNF isoforms. Conversion of the precursor proBDNF to the mature form mBDNF occurs mainly intracellularly. Both isoforms are secreted and exert their actions on neurotrophin receptor p75 (p75^NTR) or the tropomyosin receptor kinase B (TrkB). Downstream effects of proBDNF and mBDNF are functionally opposite.

Figure 3

Schematic representation of a putative functional link between allopregnanolone and BDNF. Allopregnanolone (ALLO) potentiation of GABAergic neurotransmission is thought to be involved in BDNF mRNA expression upregulation, though the precise mechanism still needs to be elucidated. One proposed pathway, in immature neurons, is the phosphorylation of the calcium/calmodulin-dependent protein kinase II δ3 subunit (CaMKIIδ3) as a response to allopregnanolone-induced voltage-gated L-type Ca²⁺ channel (VGLCC), which upregulates BDNF gene expression [68].