Bidirectional Signaling of Neuregulin-2 Mediates Formation of GABAergic Synapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells of Postnatal Hippocampus

Lee, Kyu-Hee; Lee, Hyunsu; Yang, Che Ho; Ko, Jeong Soon; Park, Chang Hwan; Woo, Ran-Sook; Kim, Joo Yeon; Sun, Woong; Kim, Joung Hun; Ho, Won Kyung; Lee, Suk Ho

doi:10.1523/jneurosci.1585-15.2015

Cited by 25 publications

(19 citation statements)

References 63 publications

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“…Recent studies have also indicated that Nrg3 plays important roles in cortical development (Bartolini et al, ) and glutamatergic neurotransmission (Wang et al, ). Along with studies on Nrg2 as a regulator of dopaminergic and glutamatergic function (Lee et al, ; Vullhorst et al, ; Yan et al, ), the current evidence supports the concept that Nrgs 1, 2, and 3 perform distinct functions in the central nervous system (CNS). In order to gain an improved understanding of the roles played by these factors in the nervous system, it is essential to characterize their developmental expression patterns.…”

Section: Introductionsupporting

confidence: 84%

Developmental expression of Neuregulin‐3 in the rat central nervous system

Rahman

Weber

Labin

et al. 2018

J of Comparative Neurology

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Neuregulin‐3 (Nrg3) is a member of the Nrg family of growth factors identified as risk factors for schizophrenia. There are three Nrgs expressed in the nervous system (Nrg1‐3) and of these Nrg1 has been the best characterized. To set the groundwork for elucidating neural roles for Nrg3, we studied its expression in the rat brain at both the RNA and protein levels. Using an antibody developed against Nrg3, we observed a developmental increase of Nrg3 protein expression from embryonic stages to adulthood and determined that it carries O‐linked carbohydrates. In cortical neuronal cultures, transfected Neuro2a cells, and brain tissue sections Nrg3 protein was localized to the soma, neurites, and to the Golgi apparatus, where it is prominently expressed. Nrg3 was detected in excitatory, GABAergic and parvalbumin‐expressing inhibitory neurons while expression in glia was limited. Nrg3 mRNA and protein were widely expressed during both embryonic and postnatal ages. At E17, Nrg3 was detected within the cortical plate and ventricular zone suggesting possible roles in cell proliferation or migration. At postnatal ages, Nrg3 was abundantly expressed throughout the cerebral cortex and hippocampus. Multiple thalamic nuclei expressed Nrg3, while detection in the striatum was limited. In the cerebellum, Nrg3 was found in both Purkinje cells and granule neurons. In the rodent brain, Nrg3 is the most abundantly expressed of the Nrgs and its patterns of expression differ both temporally and spatially from that of Nrg1 and Nrg2. These findings suggest that Nrg3 plays roles that are distinct from the other Nrg family members.

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Section: Introductionsupporting

confidence: 84%

Developmental expression of Neuregulin‐3 in the rat central nervous system

Rahman

Weber

Labin

et al. 2018

J of Comparative Neurology

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“…The NSD-S and disruptive sets of variants (Table 1, Ten other genes that harboured prioritized variants, have been implicated in neuropsychiatric syndromes. We identified a variant (rs148371256) in NRG2 gene (Neuregulin 2) which was earlier reported to be associated with gamma band oscillations in schizophrenia with suggestive genome wide significance ( Konte et al, 2017 ) and the encoded protein neuregulin-2 has been shown to be critical for the formation and maturation of GABAergic synapses ( Lee et al, 2015 ) and its ablation results in dopamine dysregulation ( Yan et al, 2017 ). Another novel variant We also noted a variant (rs534059912) in GOLM1 gene (Golgi membrane protein 1), which was earlier reported in sporadic Alzheimer's dementia (AD) to influence the pre-frontal cortical volume ( Inkster et al, 2012 ).…”

Section: Rare Deleterious Variants In Mendelian Genes Segregate Withimentioning

confidence: 99%

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

Ganesh

Pallikonda

Nadella

et al. 2018

Preprint

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Introduction: Severe Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation.Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs. Methods:We analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n=26; schizophrenia, n=4; schizoaffective disorder, n=1 schizophrenia like psychosis, n=1) from 8 multiplex families; and 33 healthy individuals by whole exome sequencing. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the controls and rarity in South Asian sample of Exome Aggregation Consortium. Results:We identified a total of 42 unique rare, non-synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a 'private' mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype.Conclusion: NGS approaches in family based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.Not a peer reviewed or publication accepted version 5

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“…Supporting this interaction are the findings that both NRG3 and ErbB4 mutant mice have increased gamma oscillations (Del Pino et al, ; Muller et al, ). NRG2 is thought to accumulate postsynaptically on the proximal dendrites of ErbB4 expressing dendrites of PV interneurons to act in an autocrine manner (Lee et al, ; Vullhorst et al, , ). As NRGs have multiple sources and express as membrane‐bound versus cleaved extracellular pools, it is of interest to determine how these different sources regulate visual plasticity.…”

Section: Introductionmentioning

confidence: 99%

Neuregulin and ErbB expression is regulated by development and sensory experience in mouse visual cortex

Grieco

Wang

Mahapatra

et al. 2019

J of Comparative Neurology

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Neuregulins (NRGs) are protein ligands that impact neural development and circuit function. NRGs signal through the ErbB receptor tyrosine kinase family. NRG1/ErbB4 signaling in parvalbumin-expressing (PV) inhibitory interneurons is critical for visual cortical plasticity. There are multiple types of NRGs and ErbBs that can potentially contribute to visual cortical plasticity at different developmental stages. Thus, it is important to understand the normal developmental expression profiles of NRGs and ErbBs in specific neuron types in the visual cortex, and to study whether and how their expression changes in PV inhibitory neurons and excitatory neurons track with sensory perturbation. Cell type-specific translating ribosome affinity purification and qPCR was used to compare mRNA expression of nrg1,2,3,4 and erbB1,2,3,4 in PV and excitatory neurons in mouse visual cortex. We show that the expression of nrg1 and nrg3 decreases in PV neurons at the critical period peak, postnatal day 28 (P28) after monocular deprivation and dark rearing, and in the adult cortex (at P104) after 2-week long dark exposure. In contrast, nrg1 expression by excitatory neurons is unchanged at P28 and P104 following sensory deprivation, whereas nrg3 expression by excitatory neurons shows changes depending on the age and the mode of sensory deprivation. ErbB4 expression in PV neurons remains consistently high and does not appear to change in response to sensory deprivation. These data provide new important details of cell type-specific NRG/ErbB expression in the visual cortex and support that NRG1/ErbB4 signaling is implicated in both critical period and adult visual cortical plasticity.

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Bidirectional Signaling of Neuregulin-2 Mediates Formation of GABAergic Synapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells of Postnatal Hippocampus

Cited by 25 publications

References 63 publications

Developmental expression of Neuregulin‐3 in the rat central nervous system

Developmental expression of Neuregulin‐3 in the rat central nervous system

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

Neuregulin and ErbB expression is regulated by development and sensory experience in mouse visual cortex

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