Low nNOS protein in the locus coeruleus in major depression

Karolewicz, Beata; Szebeni, Katalin; Stockmeier, Craig A.; Konick, Lisa C.; Overholser, James C.; Jurjus, George J.; Roth, Bryan L.; Ordway, Gregory A.

doi:10.1111/j.1471-4159.2004.02792.x

Cited by 78 publications

(44 citation statements)

References 62 publications

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“…Several other studies which observed reductions in CB-IR or PV-IR neurons in manicdepressive illness or schizophrenia did not include pH as a covariate in their analyses (Beasley and Reynolds, 1997;Benes et al, 2000;Daviss and Lewis, 1995;Iritani et al, 1999;Kalus et al, 1997;Pierri et al, 1999;Reynolds and Beasley, 2001;Woo et al, 1997Woo et al, , 1998. The intriguing correlation between pH and cell density observed in the present study was also noted in three other analyses on our post-mortem brain samples (Karolewicz et al, 2004;Rajkowska et al, 2005;Van Otterloo et al, 2005). The exact mechanisms by which tissue pH and neuronal density may influence each other are not known yet.…”

Section: Discussionsupporting

confidence: 70%

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

Rajkowska

O'Dwyer

Teleki

et al. 2006

Neuropsychopharmacol

366

234

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Post-mortem morphometric studies report reductions in the average density and size of cortical neurons in the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (ORB) in major depressive disorder (MDD). The contribution of specific neuronal phenotypes to this general pathology in depression is still unclear. Post-mortem sections from the dlPFC and ORB regions of 14 subjects with MDD and 11 controls were immunostained to visualize calbindin-immunoreactive (CB-IR) and parvalbumin-immunoreactive (PV-IR) presumptive GABAergic neurons. A three-dimensional cell counting probe was used to assess the cell packing density and size of CB-IR neurons in layers II + IIIa and PV-IR neurons in layers III-VI. The density of CB-IR neurons was significantly reduced by 50% in depression in the dlPFC and there was a trend toward reduction in the ORB. The size of CB-IR somata was significantly decreased (18%) in depression in the dlPFC with a trend toward reduction in the ORB. In contrast, there was no difference in the density of PV-IR neurons between the depressed and control groups in the dlPFC. The size of PV-IR neuronal soma was unchanged in depressed compared to control subjects in either dlPFC or ORB. In depression, subpopulations of GABAergic neurons may be affected differently in dlPFC and ORB. A significant reduction in the density and size of GABAergic interneurons immunoreactive for calcium binding proteins was found predominantly in the dlPFC region. These cellular changes are consistent with recent neuroimaging studies revealing a reduction in the cortical levels of GABA in depression.

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Section: Discussionsupporting

confidence: 70%

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

Rajkowska

O'Dwyer

Teleki

et al. 2006

Neuropsychopharmacol

366

234

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“…In fact, previous post-mortem studies provide evidence that radioligand binding to NMDAR regulatory sites are altered in suicide victims and depressive disorders (Nowak et al, 1995;Nudmamud-Thanoi and Reynolds, 2004). Moreover, low levels of nNOS in the LC have been observed (Karolewicz et al, 2004) in the majority of same depressed subjects as were investigated in the present study. The activation of NMDAR leads to the activation of nNOS and stimulation of soluble guanylyl cyclase.…”

Section: Role Of Glutamatergic Signaling In Depressionsupporting

confidence: 60%

“…Recently, a low amount of nNOS was reported in subjects diagnosed with major depression (Karolewicz et al, 2004). The aim of the present study was to (1) examine the composition of the NMDAR in the human LC, and (2) investigate potential abnormalities in the concentrations of NMDAR subunits in the LC that might occur in depressed subjects.…”

Section: Introductionmentioning

confidence: 96%

“…The exact cellular localization of these glutamate/nitrergic signaling proteins within the human LC is still unknown. However, immunohistochemical labeling of nNOS, an intracellular mediator of glutamate-NMDAR signaling, revealed localization of nNOS in neurons and glial cells in the region of the LC of a psychiatrically normal subject (Karolewicz et al, 2004).…”

Section: Introductionmentioning

confidence: 97%

“…Stimulation of NMDARs results in, at least in part, the activation of nNOS. The LC region contains NMDAR (Allgaier et al, 2001;Shaw et al, 1992;Van Bockstaele and Colago, 1996), neuronal nitric oxide synthase (nNOS)-positive neurons (Cuellar et al, 2000;Karolewicz et al, 2004;Xu et al, 1994), and guanosine 3 0 ,5 0 cyclic monophosphate (cGMP) (Vulliemoz et al, 1999;Xu et al, 1998), suggesting the existence of a glutamate/nitrergic transduction pathway. The exact cellular localization of these glutamate/nitrergic signaling proteins within the human LC is still unknown.…”

Section: Introductionmentioning

confidence: 99%

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Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz

Stockmeier

Ordway

2005

Neuropsychopharmacol

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Low levels of the intracellular mediator of glutamate receptor activation, neuronal nitric oxide synthase (nNOS) were previously observed in locus coeruleus (LC) from subjects diagnosed with major depression. This finding implicates abnormalities in glutamate signaling in depression. Receptors responding to glutamate in the LC include ionotropic N-methyl-D-aspartate receptors (NMDARs). The functional NMDAR is a hetero-oligomeric structure composed of NR1 and NR2 (A-D) subunits. Tissue containing the LC and a nonlimbic LC projection area (cerebellum) was obtained from 13 and 9 matched pairs, respectively, of depressed subjects and control subjects lacking major psychiatric diagnoses. NMDAR subunit composition in the LC was evaluated in a psychiatrically normal subject. NR1 and NR2C subunit immunoreactivities in LC homogenates showed prominent bands at 120 and 135 kDa, respectively. In contrast to NR1 and NR2C, very weak immunoreactivity of NR2A and NR2B subunits was observed in the LC. Possible changes in concentrations of NR1 and NR2C that might occur in depression were assessed in the LC and cerebellum. The overall amount of NR1 immunoreactivity was normal in the LC and cerebellum in depressed subjects. Amounts of NR2C protein were significantly higher ( þ 61%, p ¼ 0.003) in the LC and modestly, but not significantly, elevated in the cerebellum ( þ 35%) of depressives as compared to matched controls. Higher levels of NR2C subunit implicate altered glutamatergic input to the LC in depressive disorders.

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γ‐Oryzanol Ameliorates Depressive Behavior in Ovariectomized Mice by Regulating Hippocampal Nitric Oxide Synthase: A Potential Therapy for Menopausal Depression

Kim,

Yoon,

Cho

et al. 2023

Molecular Nutrition Food Res

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ScopeDepression is a severe mental condition, common among menopausal women. γ‐Oryzanol (ORY) has various biological properties; however, the effect of ORY on menopausal depression and its underlying mechanisms have not been investigated.Methods and resultsORY is orally administered to ovariectomized (OVX) mice for 20 weeks. ORY administration results in lower immobility time in the tail suspension and forced swim test and increases locomotor activity in the open field test. In the primary hippocampal neurons and hippocampi of OVX mice, ORY treatment increases nitric oxide (NO) production and neuronal NO synthase (nNOS) expression. Further, the phosphorylation of extracellular signal‐regulated kinase (ERK), cAMP response element‐binding protein (CREB), and tropomyosin receptor kinase B, along with the expression of brain‐derived neurotrophic factior (BDNF), is upregulated. These stimulatory effects of ORY are diminished by treatment with estrogen receptor β (ERβ) antagonist. ORY similarly interacts with ERβ in the molecular docking analysis. Moreover, intracerebroventricular injection of 7‐nitroindazole, a nNOS inhibitor, abolishes the antidepressant effects of ORY.ConclusionsThe results indicate that ORY attenuates depressive behavior in OVX mice by upregulating ERβ‐mediated hippocampal nNOS expression and activating the ERK‐CREB‐BDNF signaling networks. The findings suggest that ORY is a potential therapeutic agent for attenuating menopausal depression.

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Low nNOS protein in the locus coeruleus in major depression

Cited by 78 publications

References 62 publications

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

γ‐Oryzanol Ameliorates Depressive Behavior in Ovariectomized Mice by Regulating Hippocampal Nitric Oxide Synthase: A Potential Therapy for Menopausal Depression

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