GPR39 (Zinc Receptor) Knockout Mice Exhibit Depression-Like Behavior and CREB/BDNF Down-Regulation in the Hippocampus

Abstract

Background:Zinc may act as a neurotransmitter in the central nervous system by activation of the GPR39 metabotropic receptors.Methods:In the present study, we investigated whether GPR39 knockout would cause depressive-like and/or anxiety-like behavior, as measured by the forced swim test, tail suspension test, and light/dark test. We also investigated whether lack of GPR39 would change levels of cAMP response element-binding protein (CREB),brain-derived neurotrophic factor (BDNF) and tropomyosin related kinase B (TrkB) protein in the hippocampus and frontal cortex of GPR39 knockout mice subjected to the forced swim test, as measured by Western-blot analysis.Results:In this study, GPR39 knockout mice showed an increased immobility time in both the forced swim test and tail suspension test, indicating depressive-like behavior and displayed anxiety-like phenotype. GPR39 knockout mice had lower CREB and BDNF levels in the hippocampus, but not in the frontal cortex, which indicates region specificity for the impaired CREB/BDNF pathway (which is important in antidepressant response) in the absence of GPR39. There were no changes in TrkB protein in either structure. In the present study, we also investigated activity in the hypothalamus-pituitary-adrenal axis under both zinc- and GPR39-deficient conditions. Zinc-deficient mice had higher serum corticosterone levels and lower glucocorticoid receptor levels in the hippocampus and frontal cortex.Conclusions:There were no changes in the GPR39 knockout mice in comparison with the wild-type control mice, which does not support a role of GPR39 in hypothalamus-pituitary-adrenal axis regulation. The results of this study indicate the involvement of the GPR39 Zn2+-sensing receptor in the pathophysiology of depression with component of anxiety.

Investigation of the GPR39 zinc receptor following inhibition of monoaminergic neurotransmission and potentialization of glutamatergic neurotransmission

“…6). Moreover, we found that mice lacking the GPR39 gene, which show 'depressive-like' behavior (Młyniec et al, 2015a), have decreased tryptophan and tyrosine concentrations in the hippocampus, but not in the frontal cortex. We did not observe any changes in glutamate levels between the GPR39 KO and WT groups, neither in the hippocampus nor in the frontal cortex.…”

“…This could be a potential mechanism linking GPR39 with physiological disturbances observed in depression. In our previous study we showed a decreased CREB and BDNF levels in the hippocampus of GPR39 knockout mice, indicating a possible role of GPR39 receptor in regulation of hippocampal CREB/BDNF pathway that is also important in antidepressant response and synaptic plasticity (Młyniec et al, 2015a). A study by Besser et al (2009) provided evidence that synaptically released zinc ions activate the postsynaptic zinc receptor in the CA3 region of the hippocampus, which plays a pivotal role in mood disorders.…”

“…Activation of GPR39 by zinc ions in the brain triggers three diverse neuronal pathways, resulting in activation of the serum response element (SRE) and in cAMP response element (CRE) transcriptional activity (Holst et al, 2004). It was hypothesized that GPR39 may be involved in the pathophysiology of depression and in the antidepressant response (Młyniec et al, 2015a(Młyniec et al, , 2015b, since zinc was observed to be decreased under stress conditions. Indeed, in our previous studies we observed GPR39 down-regulation under zinc deficiency in rodents as well as in http://dx.doi.org/10.1016/j.brainresbull.2015.04.005 0361-9230/© 2015 Elsevier Inc. All rights reserved.…”

Beclin-1- mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice

“…Western Blot was performed as described previously [29]. The hippocampus tissues from mice were homogenized using RIPA (20mgorganizationwith 200 μl RIPA).…”

Bidirectional Control of Coronary Vascular Resistance by Eicosanoids via a Novel GPCR

“…Multiple studies have linked GPR39 with metabolism including two studies of GPR39 knockout mice, one where body weight and food intake were reported to be normal (25), while the other noted higher body weight and fat composition with no change in food intake (26). A report has also linked GPR39 loss with impaired insulin secretion (27), yet synthetic agonists of GPR39 fail to drive insulin secretion (28), and still others associate GPR39 loss with nervous system symptoms such as seizures (29) and depressionlike behavior (30). GPR39 has also been proposed to function as a Zn 2+ receptor (14).…”