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Neuregulin 1 expression and electrophysiological abnormalities in the Neuregulin 1 transmembrane domain heterozygous mutant mouse.
PLoS One. 2015; 10(5):e0124114.Plos

Abstract

BACKGROUND

The Neuregulin 1 transmembrane domain heterozygous mutant (Nrg1 TM HET) mouse is used to investigate the role of Nrg1 in brain function and schizophrenia-like behavioural phenotypes. However, the molecular alterations in brain Nrg1 expression that underpin the behavioural observations have been assumed, but not directly determined. Here we comprehensively characterise mRNA Nrg1 transcripts throughout development of the Nrg1 TM HET mouse. In addition, we investigate the regulation of high-frequency (gamma) electrophysiological oscillations in this mutant mouse to associate molecular changes in Nrg1 with a schizophrenia-relevant neurophysiological profile.

METHODS

Using exonic probes spanning the cysteine-rich, epidermal growth factor (EGF)-like, transmembrane and intracellular domain encoding regions of Nrg1, mRNA levels were measured using qPCR in hippocampus and frontal cortex from male and female Nrg1 TM HET and wild type-like (WT) mice throughout development. We also performed electrophysiological recordings in adult mice and analysed gamma oscillatory at baseline, in responses to auditory stimuli and to ketamine.

RESULTS

In both hippocampus and cortex, Nrg1 TM HET mice show significantly reduced expression of the exon encoding the transmembrane domain of Nrg1 compared with WT, but unaltered mRNA expression encoding the extracellular bioactive EGF-like and the cysteine-rich (type III) domains, and development-specific and region-specific reductions in the mRNA encoding the intracellular domain. Hippocampal Nrg1 protein expression was not altered, but NMDA receptor NR2B subunit phosphorylation was lower in Nrg1 TM HET mice. We identified elevated ongoing and reduced sensory-evoked gamma power in Nrg1 TM HET mice.

INTERPRETATION

We found no evidence to support the claim that the Nrg1 TM HET mouse represents a simple haploinsufficient model. Further research is required to explore the possibility that mutation results in a gain of Nrg1 function.

Links

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Authors+Show Affiliations

Long LE
Schizophrenia Research Institute, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Anderson P
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
Frank E
Schizophrenia Research Institute, Sydney, New South Wales, Australia; University of Wollongong, Wollongong, New South Wales, Australia.
Shaw A
Schizophrenia Research Institute, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia.
Liu S
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
Huang XF
Schizophrenia Research Institute, Sydney, New South Wales, Australia; University of Wollongong, Wollongong, New South Wales, Australia.
Pinault D
INSERM U1114, psychopathologie cognitive et physiopathologie de la schizophrénie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Karl T
Schizophrenia Research Institute, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
O'Brien TJ
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
Shannon Weickert C
Schizophrenia Research Institute, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia; School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
Jones NC
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.

MeSH

AnimalsBrainElectroencephalographyFemaleHeterozygoteLocomotionMaleMiceMice, Mutant StrainsNeuregulin-1PhosphorylationRNA, MessengerReceptors, N-Methyl-D-Aspartate

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25992564

Citation

Long, Leonora E., et al. "Neuregulin 1 Expression and Electrophysiological Abnormalities in the Neuregulin 1 Transmembrane Domain Heterozygous Mutant Mouse." PloS One, vol. 10, no. 5, 2015, pp. e0124114.
Long LE, Anderson P, Frank E, et al. Neuregulin 1 expression and electrophysiological abnormalities in the Neuregulin 1 transmembrane domain heterozygous mutant mouse. PLoS One. 2015;10(5):e0124114.
Long, L. E., Anderson, P., Frank, E., Shaw, A., Liu, S., Huang, X. F., Pinault, D., Karl, T., O'Brien, T. J., Shannon Weickert, C., & Jones, N. C. (2015). Neuregulin 1 expression and electrophysiological abnormalities in the Neuregulin 1 transmembrane domain heterozygous mutant mouse. PloS One, 10(5), e0124114. https://doi.org/10.1371/journal.pone.0124114
Long LE, et al. Neuregulin 1 Expression and Electrophysiological Abnormalities in the Neuregulin 1 Transmembrane Domain Heterozygous Mutant Mouse. PLoS One. 2015;10(5):e0124114. PubMed PMID: 25992564.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuregulin 1 expression and electrophysiological abnormalities in the Neuregulin 1 transmembrane domain heterozygous mutant mouse. AU - Long,Leonora E, AU - Anderson,Paul, AU - Frank,Elisabeth, AU - Shaw,Alex, AU - Liu,Shijie, AU - Huang,Xu-Feng, AU - Pinault,Didier, AU - Karl,Tim, AU - O'Brien,Terence J, AU - Shannon Weickert,Cynthia, AU - Jones,Nigel C, Y1 - 2015/05/19/ PY - 2014/02/16/received PY - 2015/03/10/accepted PY - 2015/5/21/entrez PY - 2015/5/21/pubmed PY - 2016/4/12/medline SP - e0124114 EP - e0124114 JF - PloS one JO - PLoS One VL - 10 IS - 5 N2 - BACKGROUND: The Neuregulin 1 transmembrane domain heterozygous mutant (Nrg1 TM HET) mouse is used to investigate the role of Nrg1 in brain function and schizophrenia-like behavioural phenotypes. However, the molecular alterations in brain Nrg1 expression that underpin the behavioural observations have been assumed, but not directly determined. Here we comprehensively characterise mRNA Nrg1 transcripts throughout development of the Nrg1 TM HET mouse. In addition, we investigate the regulation of high-frequency (gamma) electrophysiological oscillations in this mutant mouse to associate molecular changes in Nrg1 with a schizophrenia-relevant neurophysiological profile. METHODS: Using exonic probes spanning the cysteine-rich, epidermal growth factor (EGF)-like, transmembrane and intracellular domain encoding regions of Nrg1, mRNA levels were measured using qPCR in hippocampus and frontal cortex from male and female Nrg1 TM HET and wild type-like (WT) mice throughout development. We also performed electrophysiological recordings in adult mice and analysed gamma oscillatory at baseline, in responses to auditory stimuli and to ketamine. RESULTS: In both hippocampus and cortex, Nrg1 TM HET mice show significantly reduced expression of the exon encoding the transmembrane domain of Nrg1 compared with WT, but unaltered mRNA expression encoding the extracellular bioactive EGF-like and the cysteine-rich (type III) domains, and development-specific and region-specific reductions in the mRNA encoding the intracellular domain. Hippocampal Nrg1 protein expression was not altered, but NMDA receptor NR2B subunit phosphorylation was lower in Nrg1 TM HET mice. We identified elevated ongoing and reduced sensory-evoked gamma power in Nrg1 TM HET mice. INTERPRETATION: We found no evidence to support the claim that the Nrg1 TM HET mouse represents a simple haploinsufficient model. Further research is required to explore the possibility that mutation results in a gain of Nrg1 function. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/25992564/Neuregulin_1_expression_and_electrophysiological_abnormalities_in_the_Neuregulin_1_transmembrane_domain_heterozygous_mutant_mouse_ DB - PRIME DP - Unbound Medicine ER -