Neonatal exposure to an inflammatory cytokine, epidermal growth factor, results in the deficits of mismatch negativity in rats

Jodo, Eiichi; Inaba, Hiroyoshi; Narihara, Itaru; Sotoyama, Hidekazu; Kitayama, Eiko; Yabe, Hirooki; Namba, Hisaaki; Eifuku, Satoshi; Nawa, Hiroyuki

doi:10.1038/s41598-019-43923-y

Cited by 22 publications

(30 citation statements)

References 70 publications

(64 reference statements)

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“…Several postmortem studies have suggested that the hyper-signaling of ErbBs is associated with the neuropathology of schizophrenia 30,51–53 although the etiological contributions of the up- or downregulation of ErbB signaling to schizophrenia remain to be controversial 30,31,54 . The expression of EGF, neuregulins, or ErbB receptors is reported to increase in the brain of patients with schizophrenia as well as in the blood of the patients 52,53,55–57 . Conversely, EGF concentrations in blood are decreased in patients with schizophrenia 52 .…”

Section: Discussionmentioning

confidence: 99%

Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases

et al. 2019

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Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 μM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 μM clozapine and 30 μM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3–30 μM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.

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Section: Discussionmentioning

confidence: 99%

Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases

et al. 2019

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“…Three miniature stainless‐steel bolts were used as electrodes for recording electrocorticography (ECoG). The bolts were screwed to the skull to contact the dura mater at the following points: the right primary auditory cortex (4.5 mm posterior to bregma; 8.0 mm lateral to the midline; and 4.2 mm below the top plane of the skull), the frontal sinus (as a reference), and the cerebellum (as a ground) . All lead wires from the electrodes were soldered onto a miniature connector.…”

Section: Methodsmentioning

confidence: 99%

“…Recording occurred during the dark cycle, which is the active phase in rats . Each awake rat was placed in a transparent electrically shielded plastic box (dimensions 18 × 36 × 30 cm) during acclimation and recording sessions.…”

Section: Methodsmentioning

confidence: 99%

“…Surgery and electrode placement were performed as described previously. 20 Rats (9-10 weeks old) were anesthetized with pentobarbital (i.p., 65 mg/kg) or a combination anesthetic (i.p., 0.375 mg/kg medetomidine, 2 mg/kg midazolam, and 2.5 mg/kg butorphanol). Three miniature stainless-steel bolts were used as electrodes for recording electrocorticography (ECoG).…”

Section: Surgery and Electrode Placementmentioning

confidence: 99%

“…Recording occurred during the dark cycle, which is the active phase in rats. 19,20 Each awake rat was placed in a transparent electrically shielded plastic box (dimensions 18 × 36 × 30 cm) during acclimation and recording sessions. ECoG signals from the electrodes were fed by wire into an amplifier (DAM-80) and band-pass filtered at 0.1-1000 Hz.…”

Section: Recordingmentioning

confidence: 99%

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Sound frequency dependence of duration mismatch negativity recorded from awake rats

Inaba

Namba

Sotoyama

et al. 2019

Neuropsychopharm Rep

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Aims The brain function that detects deviations in the acoustic environment can be evaluated with mismatch negativity (MMN). MMN to sound duration deviance has recently drawn attention as a biomarker for schizophrenia. Nonhuman animals, including rats, also exhibit MMN‐like potentials. Therefore, MMN research in nonhuman animals can help to clarify the neural mechanisms underlying MMN production. However, results from preclinical MMN studies on duration deviance have been conflicting. We investigated the effect of sound frequency on MMN‐like potentials to duration deviance in rats. Methods Event‐related potentials were recorded from an electrode placed on the primary auditory cortex of free‐moving rats using an oddball paradigm consisting of 50‐ms duration tones (standards) and 150‐ms duration tones (deviants) at a 500‐ms stimulus onset asynchrony. The sound frequency was set to three conditions: 3, 12, and 50 kHz. Results MMN‐like potentials that depended on the short‐term stimulus history of background regularity were only observed in the 12‐kHz tone frequency condition. Conclusions MMN‐like potentials to duration deviance are subject to tone frequency of the oddball paradigm in rats, suggesting that rats have distinct sound duration recognition ability.

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The dopamine D2 agonist quinpirole impairs frontal mismatch responses to sound frequency deviations in freely moving rats

Inaba

Namba

Kida

et al. 2021

Neuropsychopharm Rep

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Aim A reduced mismatch negativity (MMN) response is a promising electrophysiological endophenotype of schizophrenia that reflects neurocognitive impairment. Dopamine dysfunction is associated with symptoms of schizophrenia. However, whether the dopamine system is involved in MMN impairment remains controversial. In this study, we investigated the effects of the dopamine D2‐like receptor agonist quinpirole on mismatch responses to sound frequency changes in an animal model. Methods Event‐related potentials were recorded from electrocorticogram electrodes placed on the auditory and frontal cortices of freely moving rats using a frequency oddball paradigm consisting of ascending and equiprobable (ie, many standards) control sequences before and after the subcutaneous administration of quinpirole. To detect mismatch responses, difference waveforms were obtained by subtracting nondeviant control waveforms from deviant waveforms. Results Here, we show the significant effects of quinpirole on frontal mismatch responses to sound frequency deviations in rats. Quinpirole delayed the frontal N18 and P30 mismatch responses and reduced the frontal N55 MMN‐like response, which resulted from the reduction in the N55 amplitude to deviant stimuli. Importantly, the magnitude of the N55 amplitude was negatively correlated with the time of the P30 latency in the difference waveforms. In contrast, quinpirole administration did not clearly affect the temporal mismatch responses recorded from the auditory cortex. Conclusion These results suggest that the disruption of dopamine D2‐like receptor signaling by quinpirole reduces frontal MMN to sound frequency deviations and that delays in early mismatch responses are involved in this MMN impairment.

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Neonatal exposure to an inflammatory cytokine, epidermal growth factor, results in the deficits of mismatch negativity in rats

Cited by 22 publications

References 70 publications

Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases

Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases

Sound frequency dependence of duration mismatch negativity recorded from awake rats

The dopamine D2 agonist quinpirole impairs frontal mismatch responses to sound frequency deviations in freely moving rats

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