Changes in brain protein expression are linked to magnesium restriction-induced depression-like behavior
- 573 Downloads
There is evidence to suggest that low levels of magnesium (Mg) are associated with affective disorders, however, causality and central neurobiological mechanisms of this link are largely unproven. We have recently shown that mice fed a low Mg-containing diet (10% of daily requirement) display enhanced depression-like behavior sensitive to chronic antidepressant treatment. The aim of the present study was to utilize this model to gain insight into underlying mechanisms by quantifying amygdala/hypothalamus protein expression using gel-based proteomics and correlating changes in protein expression with changes in depression-like behavior. Mice fed Mg-restricted diet displayed reduced brain Mg tissue levels and altered expression of four proteins, N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1), manganese-superoxide dismutase (MnSOD), glutamate dehydrogenase 1 (GDH1) and voltage-dependent anion channel 1. The observed alterations in protein expression may indicate increased nitric oxide production, increased anti-oxidant response to increased oxidative stress and potential alteration in energy metabolism. Aberrant expressions of DDAH1, MnSOD and GDH1 were normalized by chronic paroxetine treatment which also normalized the enhanced depression-like behavior, strengthening the link between the changes in these proteins and depression-like behavior. Collectively, these findings provide first evidence of low magnesium-induced alteration in brain protein levels and biochemical pathways, contributing to central dysregulation in affective disorders.
KeywordsMagnesium restricted diet Amygdala Hypothalamus Depression Gel-based proteomics
The authors thank Dr. Richard Tessadri for the determination of Mg levels. This work was funded by the FWF (P22931-B18).
Conflict of interest
The authors declare that they have no conflict of interest.
- Banki CM, Vojnik M, Papp Z et al (1985) Cerebrospinal fluid magnesium and calcium related to amine metabolites, diagnosis, and suicide attempts. Biol Psychiatry 20:163–171Google Scholar
- Burgos M, Fradejas N, Calvo S, Kang SU, Tranque P, Lubec G (2010) A proteomic analysis of PKCepsilon targets in astrocytes: implications for astrogliosis. Amino Acids (in press)Google Scholar
- Carboni L, Vighini M, Piubelli C, Castelletti L, Milli A, Domenici E (2006b) Proteomic analysis of rat hippocampus and frontal cortex after chronic treatment with fluoxetine or putative novel antidepressants: CRF1 and NK1 receptor antagonists. Eur Neuropsychopharmacol 16:521–537PubMedCrossRefGoogle Scholar
- German-Fattal M, Lecerf F, Sabbagh F, Maurois P, Durlach J, Bac P(2008) Neuroprotective gene profile in the brain of magnesium-deficient mice. Biomed Pharmacother 62:264–272Google Scholar
- Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH (2000) Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry 5:142–149PubMedCrossRefGoogle Scholar
- Keller JN, Kindy MS, Holtsberg FW, St Clair DK, Yen HC, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB, Mattson MP (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci 18:687–697PubMedGoogle Scholar
- Levine J, Stein D, Rapoport A, Kurtzman L (1999) High serum and cerebrospinal fluid Ca/Mg ratio in recently hospitalized acutely depressed patients. Neuropsychobiology 39:63–70Google Scholar
- Muroyama A, Inaka M, Matsushima H, Sugino H, Marunaka Y, Mitsumoto Y (2009) Enhanced susceptibility to MPTP neurotoxicity in magnesium-deficient C57BL/6N mice. Neurosci Res 63:72–75Google Scholar
- Rasmussen HH, Mortensen PB, Jensen IW (1989) Depression and magnesium deficiency. Int J Psychiatry Med 19:57–63Google Scholar
- Singewald N, Sartori SB, Shin JH, Lin L, Lubec G, Whittle N (2010) Magnesium- and zinc-deficiency models for depression: Involvement of NMDA/NO pathways. Biol Psychiatry 67:689Google Scholar
- Spasov AA, Iezhitsa IN, Kharitonova MV, Kravchenko MS (2008) Depression-like and anxiety-related behaviour of rats fed with magnesium-deficient diet. Zh Vyssh Nerv Deiat Im I P Pavlova 58:476–485Google Scholar
- Wegener G, Harvey BH, Bonefeld B, Müller HK, Volke V, Overstreet DH, Elfving B (2010) Increased stress-evoked nitric oxide signalling in the Flinders sensitive line (FSL) rat: a genetic animal model of depression. Int J Neuropsychopharmacol 13:461–473Google Scholar