title: Dietary magnesium restriction reduces amygdala-hypothalamic GluN1 receptor complex levels in mice.
abstract: Reduced daily intake of magnesium (Mg(2+)) is suggested to contribute to depression. Indeed, preclinical studies show dietary magnesium restriction (MgR) elicits enhanced depression-like behaviour establishing a causal relationship. Amongst other mechanisms, Mg(2+) gates the activity of N-methyl-D-asparte (NMDA) receptors; however, it is not known whether reduced dietary Mg(2+) intake can indeed affect brain NMDA receptor complexes. Thus, the aim of the current study was to reveal whether MgR induces changes in brain NMDA receptor subunit composition that would indicate altered NMDA receptor regulation. The results revealed that enhanced depression-like behaviour elicited by MgR was associated with reduced amygdala-hypothalamic protein levels of GluN1-containing NMDA complexes. No change in GluN1 mRNA levels was observed indicating posttranslational changes were induced by dietary Mg(2+) restriction. To reveal possible protein interaction partners, GluN1 immunoprecipitation and proximity ligation assays were carried out revealing the expected GluN1 subunit association with GluN2A, GluN2B, but also novel interactions with GluA1, GluA2 in addition to known downstream signalling proteins. Chronic paroxetine treatment in MgR mice normalized enhanced depression-like behaviour, but did not alter protein levels of GluN1-containing NMDA receptors, indicating targets downstream of the NMDA receptor. Collectively, present data demonstrate that dietary MgR alters brain levels of GluN1-containing NMDA receptor complexes, containing GluN2A, GluN2B, AMPA receptors GluA1, GluA2 and several protein kinases. These data indicate that the modulation of dietary Mg(2+) intake may alter the function and signalling of this receptor complex indicating its involvement in the enhanced depression-like behaviour elicited by MgR.
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18, 1090, Vienna, Austria.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ghafari
authors.forename: Nigel
authors.initials: N
authors.lastname: Whittle
authors.forename: András G
authors.initials: AG
authors.lastname: Miklósi
authors.forename: Caroline
authors.initials: C
authors.lastname: Kotlowski
authors.forename: Caroline
authors.initials: C
authors.lastname: Kotlowsky
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmuckermair
authors.forename: Johannes
authors.initials: J
authors.lastname: Berger
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D003863:Depression / Q000150:complications* / Q000188:drug therapy; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D008274:Magnesium / Q000009:adverse effects* / Q000378:metabolism; D008275:Magnesium Deficiency / Q000150:complications / Q000209:etiology / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017374:Paroxetine / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
chemical_list: D008274:Magnesium; D009419:Nerve Tissue Proteins; D017374:Paroxetine; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; C121673:Gprin1 protein, mouse