MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients

Dwir, Daniella; Giangreco, Basilio; Xin, Lijing; Tenenbaum, Liliane; Cabungcal, Jan Harry; Steullet, Pascal; Goupil, Audrey; Cleusix, Martine; Jenni, Raoul; Chtarto, Abdelwahed; Baumann, Philipp S.; Klauser, Paul; Conus, Philippe; Tirouvanziam, Rabindra; Cuénod, Michel; Q., Kim

doi:10.1038/s41380-019-0393-5

Cited by 89 publications

(95 citation statements)

References 85 publications

(103 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dopaminergic hyperactivity in the striatum is thought to underlie the symptoms of schizophrenia, particularly psychosis [2][3][4][5]. Supporting this, 3,4-dihydroxy-6- 18 F-fluoro-l-phenylalanine ([ 18 F]-FDOPA) positron emission tomography (PET) imaging studies have revealed higher striatal dopamine synthesis capacity in patients with schizophrenia [6][7][8][9]. Furthermore, increased dopamine synthesis capacity is associated with both the development of psychosis [10] and the severity of symptoms [11].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to dopaminergic dysfunction, the glutamate hypothesis of schizophrenia has developed from the observations that N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine induce psychotic symptoms in healthy humans and exacerbate symptoms in patients [14,15]. Furthermore, schizophrenia is associated with a reduction in parvalbumin (PV)-expressing GABAergic interneurons, which are regulated by NMDARs in the cortex and hippocampus [16][17][18]. It has been suggested that impaired PV neuronal function in the cortex and hippocampus may lead to disinhibition of mesostriatal dopamine neuron activity via a polysynaptic pathway [19].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

et al. 2020

View full text Add to dashboard Cite

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen's d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in prelimbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT 1A receptors but no appreciable action at dopamine D 2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT 1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for treating major depression.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

et al. 2020

View full text Add to dashboard Cite

show abstract

“…(*P < 0.05) nervous system in a knockout mouse study [31]. In addition, MMP9 indirectly regulates PNNs via the activation of advanced glycation end-products and inflammatory cytokine cascades [32]. The increased expression level of MMP9 in the noise group might have decreased PNN and brevican expression, thereby influencing the neuroplastic changes associated with auditory sensory deficits after noise exposure in this study.…”

Section: Discussionmentioning

confidence: 66%

Noise exposure alters MMP9 and brevican expression in the rat primary auditory cortex

Park

Lee

et al. 2020

BMC Neurosci

View full text Add to dashboard Cite

Background: This study aimed to investigate the changes in molecules related to perineuronal nets (PNNs) and synaptic transporters in the primary auditory cortices of rats with noise-induced hearing loss. Female Sprague-Dawley rats at postnatal day 7 were divided into the noise and control groups. Four hours of 115 dB SPL white noise was delivered for 10 days to the noise group. Thirty days after noise exposure, the primary auditory cortex and the inferior colliculus were harvested. The expression levels of vesicular glutamatergic transporter (VGLUT)1, VGLUT2, vesicular GABA transporter (VGAT), glutamate decarboxylase (GAD)67, brevican, aggrecan, MMP9, and MMP14 were evaluated using real-time reverse transcription polymerase chain reaction or western blot. An immunofluorescence assay was conducted to assess parvalbumin (PV), Wisteria floribunda agglutinin (WFA), and brevican. The immune-positive cells were counted in the primary auditory cortex. Results: The expression level of VGLUT1 in the primary auditory cortex was decreased in the noise group. The expression level of VGLUT2 in the inferior colliculus was elevated in the noise group. The expression levels of brevican and PV + WFA in the primary auditory cortex were decreased in the noise group. The expression level of MMP9 in the primary auditory cortex was increased in the noise group. Conclusion: Noise-induced hearing loss during the precritical period impacted PNN expression in the primary auditory cortex. Increased MMP9 expression may have contributed to the decrease in brevican expression. These changes were accompanied by the attenuation of glutamatergic synaptic transporters.

show abstract

“…In addition to dopaminergic dysfunction, the glutamate hypothesis of schizophrenia has developed from the observations that N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine induce psychotic symptoms in healthy humans and exacerbate symptoms in patients (14, 15). Furthermore, schizophrenia is associated with a reduction in parvalbumin (PV)-expressing GABAergic interneurons, which are regulated by NMDAR in the cortex and hippocampus (16–18). It has been suggested that impaired PV neuronal function in the cortex and hippocampus may lead to disinhibition of mesostriatal dopamine neuron activity via a polysynaptic pathway (19).…”

Section: Introductionmentioning

confidence: 99%

Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

Kokkinou

Irvine

Bonsall

et al. 2019

Preprint

View full text Add to dashboard Cite

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d=2.5, P<0.001) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.

show abstract

MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients

Cited by 89 publications

References 85 publications

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

Noise exposure alters MMP9 and brevican expression in the rat primary auditory cortex

Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

Contact Info

Product

Resources

About