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Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.

Bhardwaj SK, Ryan RT, Wong TP, Srivastava LK - Front Behav Neurosci (2015)

Bottom Line: This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5) or in another mGluRI signaling pathway, i.e., protein kinase C (PKC).Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD) at CA1 excitatory synapses was significantly reduced.Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Integrated Programme in Neuroscience, Douglas Mental Health University Institute, McGill University Montreal, QC, Canada.

ABSTRACT
The expression of dysbindin-1, a protein coded by the risk gene dtnbp1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR) family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI) function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy) mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S)-3, 5-dihydroxyphenylglycine] (DHPG)-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2). This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5) or in another mGluRI signaling pathway, i.e., protein kinase C (PKC). Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD) at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1, 3-diphenyl-1H-pyrazol-5-yl benzamide), a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis of hippocampal mGluR1 and mGluR5 protein levels show no significant differences between wildtype (WT) and dysbindin deficient (sdy) animals. Top panel show representative immunoblots of mGluR1 (A), mGluR5 (B) and respective β-actin expression. Lower panel shows relative optical density (ROD) ± SEM (n = 5–6 per genotype) of mGluR1 (C) and mGluR5 (D) normalized to β-actin levels.
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Figure 1: Western blot analysis of hippocampal mGluR1 and mGluR5 protein levels show no significant differences between wildtype (WT) and dysbindin deficient (sdy) animals. Top panel show representative immunoblots of mGluR1 (A), mGluR5 (B) and respective β-actin expression. Lower panel shows relative optical density (ROD) ± SEM (n = 5–6 per genotype) of mGluR1 (C) and mGluR5 (D) normalized to β-actin levels.

Mentions: Figure 1 shows representative Western blots and analyses of protein levels of mGluR1 and mGluR5. ROD data (normalized to β-actin) revealed no significant differences in either mGluR1 or mGluR5 levels between WT and sdy mice (Student’s two-tailed t-test t(9) = 1.471, p = 0.175 and t(9) = 0.192, p = 0.852 respectively for mGluR1 and mGluR5).


Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.

Bhardwaj SK, Ryan RT, Wong TP, Srivastava LK - Front Behav Neurosci (2015)

Western blot analysis of hippocampal mGluR1 and mGluR5 protein levels show no significant differences between wildtype (WT) and dysbindin deficient (sdy) animals. Top panel show representative immunoblots of mGluR1 (A), mGluR5 (B) and respective β-actin expression. Lower panel shows relative optical density (ROD) ± SEM (n = 5–6 per genotype) of mGluR1 (C) and mGluR5 (D) normalized to β-actin levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374471&req=5

Figure 1: Western blot analysis of hippocampal mGluR1 and mGluR5 protein levels show no significant differences between wildtype (WT) and dysbindin deficient (sdy) animals. Top panel show representative immunoblots of mGluR1 (A), mGluR5 (B) and respective β-actin expression. Lower panel shows relative optical density (ROD) ± SEM (n = 5–6 per genotype) of mGluR1 (C) and mGluR5 (D) normalized to β-actin levels.
Mentions: Figure 1 shows representative Western blots and analyses of protein levels of mGluR1 and mGluR5. ROD data (normalized to β-actin) revealed no significant differences in either mGluR1 or mGluR5 levels between WT and sdy mice (Student’s two-tailed t-test t(9) = 1.471, p = 0.175 and t(9) = 0.192, p = 0.852 respectively for mGluR1 and mGluR5).

Bottom Line: This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5) or in another mGluRI signaling pathway, i.e., protein kinase C (PKC).Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD) at CA1 excitatory synapses was significantly reduced.Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Integrated Programme in Neuroscience, Douglas Mental Health University Institute, McGill University Montreal, QC, Canada.

ABSTRACT
The expression of dysbindin-1, a protein coded by the risk gene dtnbp1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR) family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI) function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy) mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S)-3, 5-dihydroxyphenylglycine] (DHPG)-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2). This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5) or in another mGluRI signaling pathway, i.e., protein kinase C (PKC). Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD) at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1, 3-diphenyl-1H-pyrazol-5-yl benzamide), a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

No MeSH data available.


Related in: MedlinePlus