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A negative regulator of MAP kinase causes depressive behavior.

Duric V, Banasr M, Licznerski P, Schmidt HD, Stockmeier CA, Simen AA, Newton SS, Duman RS - Nat. Med. (2010)

Bottom Line: MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival.We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors.Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Yale University, New Haven, Connecticut, USA.

ABSTRACT
The lifetime prevalence (∼16%) and the economic burden ($100 billion annually) associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival. We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions.

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MKP-1 is dysregulated in major depressive disorder (MDD). a) Microarray analysis of MDD postmortem brain samples demonstrates significant alterations in the expression of DUSP genes in hippocampal subfields. b) Microarray findings for MKP-1 gene expression were validated by qRT-PCR of samples from the same cohort. Data are expressed as mean fold change ± S.E.M. (n = 6); *P ≤ 0.05 compared to the healthy controls (Student’s t-test). c) Representative autoradiographs and quantitative analysis of hippocampal MKP-1 mRNA levels by in situ hybridization in a separate cohort of MDD subjects and matched controls (scale bar = 5 mm). Results are shown as percent increase for each control and MDD subject. *P < 0.02 compared to the healthy controls (Student’s t-test). Microarray-based expression levels of (d) MAP kinases and (e) downstream transcription factors and target genes. (f) Model for neurotrophic/growth factor receptor activation of MAPK, down-stream transcription factors, and target genes that play a key role in neuronal proliferation, survival and plasticity. Microarray results (a, d, and e) are shown as an average fold change (dentate gyrus, n = 14; CA1, n = 15); *P < 0.05, †P < 0.06 compared to the healthy controls (permutation tests, p-value adjusted to FDR at 0.05). Fold change for specific splice variants is reported for DUSP19.2, DUSP24.2, RPS6KA5.2 (MSK1) and VEGFa.2. BDNF, brain-derived neurotrophic factor; CREB, cyclic-AMP response element binding protein; CBP, CREB binding protein; CREBL, CREB-like; ERK, extracellular signal-regulated kinase; MAPK, mitogen activated protein kinase; MEK, MAPK kinase; MSK, mitogen and stress-activated protein kinase; NPY, neuropeptide Y; RAF, v-raf-1 murine leukemia viral oncogene homolog 1; RSK, ribosomal S6 kinase; VEGF, vascular endothelial growth factor; VGF, VGF nerve growth factor inducible.
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Figure 1: MKP-1 is dysregulated in major depressive disorder (MDD). a) Microarray analysis of MDD postmortem brain samples demonstrates significant alterations in the expression of DUSP genes in hippocampal subfields. b) Microarray findings for MKP-1 gene expression were validated by qRT-PCR of samples from the same cohort. Data are expressed as mean fold change ± S.E.M. (n = 6); *P ≤ 0.05 compared to the healthy controls (Student’s t-test). c) Representative autoradiographs and quantitative analysis of hippocampal MKP-1 mRNA levels by in situ hybridization in a separate cohort of MDD subjects and matched controls (scale bar = 5 mm). Results are shown as percent increase for each control and MDD subject. *P < 0.02 compared to the healthy controls (Student’s t-test). Microarray-based expression levels of (d) MAP kinases and (e) downstream transcription factors and target genes. (f) Model for neurotrophic/growth factor receptor activation of MAPK, down-stream transcription factors, and target genes that play a key role in neuronal proliferation, survival and plasticity. Microarray results (a, d, and e) are shown as an average fold change (dentate gyrus, n = 14; CA1, n = 15); *P < 0.05, †P < 0.06 compared to the healthy controls (permutation tests, p-value adjusted to FDR at 0.05). Fold change for specific splice variants is reported for DUSP19.2, DUSP24.2, RPS6KA5.2 (MSK1) and VEGFa.2. BDNF, brain-derived neurotrophic factor; CREB, cyclic-AMP response element binding protein; CBP, CREB binding protein; CREBL, CREB-like; ERK, extracellular signal-regulated kinase; MAPK, mitogen activated protein kinase; MEK, MAPK kinase; MSK, mitogen and stress-activated protein kinase; NPY, neuropeptide Y; RAF, v-raf-1 murine leukemia viral oncogene homolog 1; RSK, ribosomal S6 kinase; VEGF, vascular endothelial growth factor; VGF, VGF nerve growth factor inducible.

Mentions: To characterize the molecular changes underlying the pathophysiology of MDD, we conducted whole genome expression analysis of postmortem hippocampal tissues from 21 depressed patients and 18 healthy controls that were matched for age, gender, tissue pH, and postmortem interval (Supplementary Tables 1 and 2). To decrease tissue heterogeneity, the analysis was conducted on two microdissected (micropunches) hippocampal subfields, the dentate gyrus (DG) granule cell layer and CA1 pyramidal cell layer. Rodent studies have demonstrated that stress causes atrophy of CA3 pyramidal cells, but this cell layer could not be reliably dissected from human sections and therefore was not analyzed. Total RNA was extracted and the resulting cDNA used for whole genome microarray analysis (48,958 probes). We identified MKP-1 (DUSP1) as significantly dysregulated in both the DG (2.3 fold, P = 0.038) and CA1 (2.4 fold, P = 0.004) of MDD subjects (Fig. 1a). Of the subjects with depression, 12 had a prescription for an antidepressant drug filled in the last month of life, but only one depressed subject had measurable levels of an antidepressant (Supplementary Table 2). Expression levels of other members of the DUSP family were also examined. Levels of DUSP2 and DUSP19 were increased in the DG, while DUSP9, DUSP12 and DUSP24 were significantly regulated in the CA1 (Fig. 1a) (see Supplementary Table 3 for complete list). MKP-1 was the only DUSP that was significantly increased in both hippocampal subregions. Secondary validation of the microarray results using qPCR confirmed that MKP-1 mRNA was increased by over two-fold in the DG and CA1 of MDD subjects (Fig. 1b). MKP-1 expression was also assessed by in situ hybridization (ISH) in a separate cohort of MDD subjects and matched healthy controls (Supplementary Table 4). The results showed that levels of MKP-1 mRNA in the DG and CA1 of MDD subjects are increased by 31% (P = 0.016) and 16% (P = 0.128), respectively (Fig. 1c).


A negative regulator of MAP kinase causes depressive behavior.

Duric V, Banasr M, Licznerski P, Schmidt HD, Stockmeier CA, Simen AA, Newton SS, Duman RS - Nat. Med. (2010)

MKP-1 is dysregulated in major depressive disorder (MDD). a) Microarray analysis of MDD postmortem brain samples demonstrates significant alterations in the expression of DUSP genes in hippocampal subfields. b) Microarray findings for MKP-1 gene expression were validated by qRT-PCR of samples from the same cohort. Data are expressed as mean fold change ± S.E.M. (n = 6); *P ≤ 0.05 compared to the healthy controls (Student’s t-test). c) Representative autoradiographs and quantitative analysis of hippocampal MKP-1 mRNA levels by in situ hybridization in a separate cohort of MDD subjects and matched controls (scale bar = 5 mm). Results are shown as percent increase for each control and MDD subject. *P < 0.02 compared to the healthy controls (Student’s t-test). Microarray-based expression levels of (d) MAP kinases and (e) downstream transcription factors and target genes. (f) Model for neurotrophic/growth factor receptor activation of MAPK, down-stream transcription factors, and target genes that play a key role in neuronal proliferation, survival and plasticity. Microarray results (a, d, and e) are shown as an average fold change (dentate gyrus, n = 14; CA1, n = 15); *P < 0.05, †P < 0.06 compared to the healthy controls (permutation tests, p-value adjusted to FDR at 0.05). Fold change for specific splice variants is reported for DUSP19.2, DUSP24.2, RPS6KA5.2 (MSK1) and VEGFa.2. BDNF, brain-derived neurotrophic factor; CREB, cyclic-AMP response element binding protein; CBP, CREB binding protein; CREBL, CREB-like; ERK, extracellular signal-regulated kinase; MAPK, mitogen activated protein kinase; MEK, MAPK kinase; MSK, mitogen and stress-activated protein kinase; NPY, neuropeptide Y; RAF, v-raf-1 murine leukemia viral oncogene homolog 1; RSK, ribosomal S6 kinase; VEGF, vascular endothelial growth factor; VGF, VGF nerve growth factor inducible.
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Figure 1: MKP-1 is dysregulated in major depressive disorder (MDD). a) Microarray analysis of MDD postmortem brain samples demonstrates significant alterations in the expression of DUSP genes in hippocampal subfields. b) Microarray findings for MKP-1 gene expression were validated by qRT-PCR of samples from the same cohort. Data are expressed as mean fold change ± S.E.M. (n = 6); *P ≤ 0.05 compared to the healthy controls (Student’s t-test). c) Representative autoradiographs and quantitative analysis of hippocampal MKP-1 mRNA levels by in situ hybridization in a separate cohort of MDD subjects and matched controls (scale bar = 5 mm). Results are shown as percent increase for each control and MDD subject. *P < 0.02 compared to the healthy controls (Student’s t-test). Microarray-based expression levels of (d) MAP kinases and (e) downstream transcription factors and target genes. (f) Model for neurotrophic/growth factor receptor activation of MAPK, down-stream transcription factors, and target genes that play a key role in neuronal proliferation, survival and plasticity. Microarray results (a, d, and e) are shown as an average fold change (dentate gyrus, n = 14; CA1, n = 15); *P < 0.05, †P < 0.06 compared to the healthy controls (permutation tests, p-value adjusted to FDR at 0.05). Fold change for specific splice variants is reported for DUSP19.2, DUSP24.2, RPS6KA5.2 (MSK1) and VEGFa.2. BDNF, brain-derived neurotrophic factor; CREB, cyclic-AMP response element binding protein; CBP, CREB binding protein; CREBL, CREB-like; ERK, extracellular signal-regulated kinase; MAPK, mitogen activated protein kinase; MEK, MAPK kinase; MSK, mitogen and stress-activated protein kinase; NPY, neuropeptide Y; RAF, v-raf-1 murine leukemia viral oncogene homolog 1; RSK, ribosomal S6 kinase; VEGF, vascular endothelial growth factor; VGF, VGF nerve growth factor inducible.
Mentions: To characterize the molecular changes underlying the pathophysiology of MDD, we conducted whole genome expression analysis of postmortem hippocampal tissues from 21 depressed patients and 18 healthy controls that were matched for age, gender, tissue pH, and postmortem interval (Supplementary Tables 1 and 2). To decrease tissue heterogeneity, the analysis was conducted on two microdissected (micropunches) hippocampal subfields, the dentate gyrus (DG) granule cell layer and CA1 pyramidal cell layer. Rodent studies have demonstrated that stress causes atrophy of CA3 pyramidal cells, but this cell layer could not be reliably dissected from human sections and therefore was not analyzed. Total RNA was extracted and the resulting cDNA used for whole genome microarray analysis (48,958 probes). We identified MKP-1 (DUSP1) as significantly dysregulated in both the DG (2.3 fold, P = 0.038) and CA1 (2.4 fold, P = 0.004) of MDD subjects (Fig. 1a). Of the subjects with depression, 12 had a prescription for an antidepressant drug filled in the last month of life, but only one depressed subject had measurable levels of an antidepressant (Supplementary Table 2). Expression levels of other members of the DUSP family were also examined. Levels of DUSP2 and DUSP19 were increased in the DG, while DUSP9, DUSP12 and DUSP24 were significantly regulated in the CA1 (Fig. 1a) (see Supplementary Table 3 for complete list). MKP-1 was the only DUSP that was significantly increased in both hippocampal subregions. Secondary validation of the microarray results using qPCR confirmed that MKP-1 mRNA was increased by over two-fold in the DG and CA1 of MDD subjects (Fig. 1b). MKP-1 expression was also assessed by in situ hybridization (ISH) in a separate cohort of MDD subjects and matched healthy controls (Supplementary Table 4). The results showed that levels of MKP-1 mRNA in the DG and CA1 of MDD subjects are increased by 31% (P = 0.016) and 16% (P = 0.128), respectively (Fig. 1c).

Bottom Line: MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival.We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors.Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Yale University, New Haven, Connecticut, USA.

ABSTRACT
The lifetime prevalence (∼16%) and the economic burden ($100 billion annually) associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival. We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions.

Show MeSH
Related in: MedlinePlus