Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone

Abstract

Major depressive disorder is often linked to stress. Whereas short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1h/day for 7days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-α1(NF-α1) (also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6h/day for 21days) CRS, mice show decreased hippocampal NF-α1 and FGF2 levels and depressive-like responses. In NF-α1-knock out mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior which is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reveal that NF-α1 treatment directly up-regulates FGF2 expression through ERK-Sp1 signaling. Thus, during short-term CRS, hippocampal NF-α1 expression is up-regulated and it plays a key role in preventing the onset of depressive-like behavior through enhanced FGF2-mediated neurogenesis. To evaluate the therapeutic potential of this pathway, we examined, rosiglitazone, a PPARγ agonist, which has been shown to have antidepressant activity in rodents and humans. Rosiglitazone up-regulates FGF2 expression in a NF-α1-dependent manner in hippocampal neurons. Mice fed rosiglitazone show increased hippocampal NF-α1 levels and neurogenesis compared to controls; thereby indicating the antidepressant action of this drug. Development of drugs that activate the NF-α1/FGF2/neurogenesis pathway can offer a new approach to depression therapy.

Pathogenesis of depression: Insights from human and rodent studies

“…Repeated restraint stress is an inescapable paradigm similar to LH where the animal is enclosed daily in a narrow tube (1–6h/day) for up to 21 consecutive days (Watanabe et al, 1992, Magarinos and McEwen, 1995, Kim and Han, 2006, Ulloa et al, 2010, Yu et al, 2012, Lee et al, 2013, Voorhees et al, 2013, Cheng et al, 2014). Adult rodents exposed to repeated restraint stress exhibit a depression-like phenotype marked by reduced sucrose preference, anxiety-like exploratory deficits and increased immobility in the forced swim test (Kim and Han, 2006, Ulloa et al, 2010, Lee et al, 2013, Voorhees et al, 2013), Some of these phenotypes can only be reversed by chronic treatments with antidepressants (Stone et al, 1984, Ulloa et al, 2010, Yu et al, 2012).…”

Dysregulated fibroblast growth factor (FGF) signaling in neurological and psychiatric disorders

“…Recently, chronic stress in mice sufficient to produce depression-like behavior was shown to decrease CPE along with decreased expression of FGF2 [19]. Furthermore, CPE knock-out mice exhibit depression-like behavior that was reversed by FGF2 administration.…”

Neuroprotective effects of LMW and HMW FGF2 against amyloid beta toxicity in primary cultured hippocampal neurons

“…FGF2 has been linked to major depression, since it is down-regulated in serum of patients with major depressive disorder compared to normal controls [11]. Recent studies have demonstrated exogenous FGF2 rescued depression-like behavior in mice [12] and anxiety-like behavior in rats [13] by promoting hippocampal neurogenesis. In AD, a study showed that delivery of FGF2 gene to hippocampus restored the hippocampal functions in mouse models of AD [14].…”