GABAergic Abnormalities Associated with Sensorimotor Cortico-striatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naïve Patients with Schizophrenia

Zhang, Chengcheng; Ni, Peiyan; Liu, Yikang; Tian, Yang; Wei, Junnian; Xiang, Bo; Zhao, Liansheng; Li, Xiaojing; Ma, Xiaoyan; Deng, Wei; Guo, Wanjun; Ni, Rong-Jun; Zhang, Yamin; Wang, Qiang; Huang, Hailiang; Zhang, Nanyin; Li, Tao

doi:10.1007/s12264-019-00416-2

Cited by 8 publications

(6 citation statements)

References 58 publications

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“…Schizophrenia has been recognized as an abnormal development of brain networks. Involvement of neurodevelopmental mechanisms in the etiology of schizophrenia has been supported by various magnetic resonance imaging (MRI) and electrophysiological studies ( Lavoie, Maziade & Hébert, 2014 ; Di et al, 2019 ; Zhang et al, 2019 ). The apoptosis or blocked development of neurons can be manifested as thinning of gray matter, enlargement of ventricles and the deepening of sulci in childhood-to-adolescence-onset schizophrenia ( Gao et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Association of retinal nerve fiber abnormalities with serum CNTF and cognitive functions in schizophrenia patients

Liu

Huang

Tong

et al. 2020

PeerJ

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Background Recent studies have reported reductions in retinal nerve fiber layers (RNFL) in schizophrenia. Ciliary neurotrophic factor (CNTF) has shown protective effects on both the neurogenesis and retina. This study aimed at investigating retinal abnormalities and establishing their correlation with serum CNTF and cognitive impairments in schizophrenic Chinese patients. Methods In total, 221 patients diagnosed with schizophrenia and 149 healthy controls were enrolled. Serum CNTF and clinical features of patients were investigated. Cognitive functions were evaluated with Repeatable Battery for the Assessment of Neuropsychology Status (RBANS). RNFL thickness and macular thickness (MT) of both eyes were measured with optical coherence tomography (OCT). T-tests and analysis of covariance were used to compare the variables between the patient and control groups, while multiple linear regression analysis was performed to determine the associations of RNFL thickness, CNTF and cognitive impairments. Results RNFL was found thinner in patients than in healthy controls (right: 88.18 ± 25.84 µm vs.102.13 ± 14.32 µm, p = 0.001; left: 92.84 ± 13.54 µm vs.103.71 ± 11.94 µm, p < 0.001). CNTF was lower in the schizophrenia group (1755.45 ± 375.73 pg/ml vs. 1909.99 ± 368.08 pg/ml, p = 0.001). Decline in RNFL thickness was found correlated with course of illness and serum CNTF in patients (all p < 0.05). Similarly, cognitive functions such as immediate memory and visuospatial functions were also found correlated with decline in RNFL thickness. Conclusion Decline in RNFL thickness was associated with cognitive impairments of schizophrenia and CNFT serum concentration. The possibility of reduction in RNFL thickness as a biomarker for schizophrenia needs to be further examined.

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Section: Introductionmentioning

confidence: 99%

Association of retinal nerve fiber abnormalities with serum CNTF and cognitive functions in schizophrenia patients

Liu

Huang

Tong

et al. 2020

PeerJ

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“…Behavioral testing was not performed in our animals, which may have enabled investigating associations with the imaging data. However, the behavior of Erbb4 mutant mice has already been well characterized [55][56][57]100 and the scope of our study was limited to the neuroimaging phenotypes arising from PV+ interneuron dysfunction. Future studies may expand on these results and link neuroimaging with behavioral readouts to better understand their relationships in the context of this model system.…”

Section: Discussionmentioning

confidence: 99%

“…In another mouse model, deletion of the tyrosine kinase receptor Erbb4 (a susceptibility gene linked to psychosis 51,52 ) from PV+ interneurons 53,54 in the cortex and hippocampus leads to several psychosisrelevant phenotypes [55][56][57][58] . These include synaptic deficits (e.g., decreased interneuron signaling in the hippocampus, dysregulated glutamatergic activity of hippocampal pyramidal cells) 55 , elevated striatal dopamine 58 and psychosis-relevant behaviors (e.g., hyperlocomotion, impaired prepulse inhibition, impaired cognitive and social behavior) 55 .…”

Section: Introductionmentioning

confidence: 99%

Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes

Kiemes

Navacerrada

Kim

et al. 2022

Preprint

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Converging lines of evidence suggest that dysfunction of cortical parvalbumin-expressing (PV+) GABAergic interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and levels of glutamatergic metabolites, and decreases in binding of GABAA α5 receptors and the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between PV+ interneuron dysfunction and these neuroimaging readouts have yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal PV+ interneurons leads to several synaptic, behavioral and cognitive phenotypes relevant to psychosis in mice. Here, we investigated how this PV+ interneuron disruption affects the hippocampal in vivo neuroimaging readouts in the Erbb4 model. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n=12) and their wild-type littermates (Erbb4F/F, n=12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Erbb4 mutant mice showed significantly elevated CBF and glutamine levels, as well as decreased SV2A density compared to wild-type littermates. No significant GABAA receptor density differences were identified. These findings demonstrate that specific disruption of cortical PV+ interneurons in mice recapitulate some of the key neuroimaging findings in psychosis patients, and link PV+ interneuron deficits to non-invasive, translational measures of brain function and neurochemistry that can be used across species.

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“…After addition of 1NMPP1 to T796G-ErbB4 murine cortical neurons to specifically inhibit ErbB4 kinase activity, we found that PSD95 protein levels decreased while the amount of Gephyrin protein did not change significantly (Figure 4(C)), further demonstrating that ErbB4 kinase activity only regulated excitatory synapses in interneurons and did not affect the development of inhibitory synapses between neurons. Neuronal cells rely on excitatory synapses and inhibitory synapses to contact and transmit signals and ultimately form the brain's neural loop [14]. This study explored the effect of ErbB4, a susceptible gene of schizophrenia, on the excitability and inhibitory synaptogenesis and development of neurons in the cerebral cortex.…”

Section: Synaptic Psd and Gephyrin Protein Level In Cultured Pyramidamentioning

confidence: 99%

Association between ErbB4 gene function in synaptogenesis and schizophrenia pathogenesis

Chen

Tian

et al. 2020

Biotechnology & Biotechnological Equipment

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This study investigated the role of ErbB4, the schizophrenia susceptibility gene, in synaptogenesis and synaptic transmission and its association with the pathogenesis of schizophrenia. We found that there was no significant difference in the size of inhibitory synapsin Gephyrin clusters in the dendrites of gamma-aminobutyric acid (GABA) neurons in the cultured cortex of ErbB4 knockout (ErbB4À/À) mice and ErbB4þ/þ mice. The density and area of PSD-95 clusters in GABA-labelled neurons were not significantly different from those in the control group (p > 0.05). Specific pIkBa labelling of the pyramidal neurons and the axon initiation segments showed that the number of neuronal dendrites and the inhibitory postsynaptic proteins Gephyrin in the ErbB4 knockout group were significantly lower than those in the control group, whereas the size of the Gephyrin cluster remained unchanged. The number and area of the VGAT clusters on the somaclonal and axonal surfaces of the pyramidal neurons were also similar. ErbB4 knockout influenced excitatory synapses in intermediate neuronal cells and inhibitory synapses in pyramidal neurons, however, did not affect the inhibitory synapses in intermediate neuronal cells and excitatory synapses in pyramidal neurons. The number and area of PSD-95 clusters on the neuronal surface were significantly lower than those of the 1NMPP1 group, but the number and area of Gephyrin clusters on the neuronal surface were not changed (p > 0.05). These findings demonstrated that ErbB4 gene had no effect on the inhibitory synapses in interneurons and the excitatory synapses in pyramidal neurons.

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GABAergic Abnormalities Associated with Sensorimotor Cortico-striatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naïve Patients with Schizophrenia

Cited by 8 publications

References 58 publications

Association of retinal nerve fiber abnormalities with serum CNTF and cognitive functions in schizophrenia patients

Association of retinal nerve fiber abnormalities with serum CNTF and cognitive functions in schizophrenia patients

Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes

Association between ErbB4 gene function in synaptogenesis and schizophrenia pathogenesis

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