Neuregulin 3 Knockout Mice Exhibit Behaviors Consistent with Psychotic Disorders

Hayes, Lindsay N.; Shevëlkin, A. V.; Zeledon, Mariela; Steel, Gary; Chen, Pei‐Lung; Obie, Cassandra; Pulver, Ann E.; Avramopoulos, Dimitrios; Valle, David; Sawa, Akira; Pletnikov, Mikhail V.

doi:10.1159/000445836

Cited by 25 publications

(24 citation statements)

References 56 publications

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“…Examples of known human genes associated with memory also identified in our study include: NTM and KLHl20 that are associated with Alzheimer's disease and DOCK8 and KANK1 that are associated with neurodevelopmental disorders including memory potential [29][30][31]. Examples of known mouse genes associated with memory include Specc1 that was identified in a mouse genetic screen for avoidance learning [32], Prdx6 that was associated with neurogenesis and Alzheimer's disease in mice [33,34] and knock-out mice for Abl2, Nrg3, Shank2, Gria1, and Fgf14 that caused neurodevelopmental defects [35][36][37][38][39]. The other set contains 135 genes not previously associated with memory of which 65 have brain expression [40] (http:// connectivity.brain-map.org/).…”

Section: Discussionmentioning

confidence: 96%

Genetic and metabolic links between the murine microbiome and memory

et al. 2020

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Background: Recent evidence has linked the gut microbiome to host behavior via the gut-brain axis [1-3]; however, the underlying mechanisms remain unexplored. Here, we determined the links between host genetics, the gut microbiome and memory using the genetically defined Collaborative Cross (CC) mouse cohort, complemented with microbiome and metabolomic analyses in conventional and germ-free (GF) mice. Results: A genome-wide association analysis (GWAS) identified 715 of 76,080 single-nucleotide polymorphisms (SNPs) that were significantly associated with short-term memory using the passive avoidance model. The identified SNPs were enriched in genes known to be involved in learning and memory functions. By 16S rRNA gene sequencing of the gut microbial community in the same CC cohort, we identified specific microorganisms that were significantly correlated with longer latencies in our retention test, including a positive correlation with Lactobacillus. Inoculation of GF mice with individual species of Lactobacillus (L. reuteri F275, L. plantarum BDGP2 or L. brevis BDGP6) resulted in significantly improved memory compared to uninoculated or E. coli DH10B inoculated controls. Untargeted metabolomics analysis revealed significantly higher levels of several metabolites, including lactate, in the stools of Lactobacillus-colonized mice, when compared to GF control mice. Moreover, we demonstrate that dietary lactate treatment alone boosted memory in conventional mice. Mechanistically, we show that both inoculation with Lactobacillus or lactate treatment significantly increased the levels of the neurotransmitter, gamma-aminobutyric acid (GABA), in the hippocampus of the mice. Conclusion: Together, this study provides new evidence for a link between Lactobacillus and memory and our results open possible new avenues for treating memory impairment disorders using specific gut microbial inoculants and/or metabolites.

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Section: Discussionmentioning

confidence: 96%

Genetic and metabolic links between the murine microbiome and memory

et al. 2020

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“…Genetic studies have reported a consistent relationship between single nucleotide polymorphisms (SNPs) located within the first intron of Nrg3 and the SZ endophenotype of delusional behavior (Morar et al, 2011). The characterization of Nrg3 −/− mice further revealed behaviors that are consistent with animal models of SZ, showing increased levels of novelty-induced hyperactivity, impaired prepulse inhibition and a reduction in fear conditioning (Hayes et al, 2016). Increased levels of Nrg3 expression in mice correlate with impulsivity, with the opposite effect seen in Nrg3-deficient mice (Loos et al, 2014).…”

Section: Introductionmentioning

confidence: 97%

“…Neuregulin-3 (Nrg3) is a member of the neuregulin (Nrg1-4) family of growth factors, which play important roles in the developing and mature nervous system (Birchmeier & Bennett, 2016;Grieco, Holmes, & Xu, 2018;Mei & Nave, 2014;Mei & Xiong, 2008). Nrg3 is of particular interest as it has emerged as a candidate risk gene for several neuropsychiatric disorders including bipolar disorder and schizophrenia (SZ) (Avramopoulos, 2018; P. L. Chen et al, 2009;Hayes et al, 2016;Loos et al, 2014;Paterson et al, 2017). Recent studies have also indicated that Nrg3 plays important roles in cortical development (Bartolini et al, 2017) and glutamatergic neurotransmission (Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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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“…NRG1 is essential for the development of the nervous system and heart. Thus, global deletion of NRG1 results in embryonic lethality, while knockouts of NRG2-4 develop normally (Meyer and Birchmeier, 1995;Britto et al, 2004;Hayes et al, 2016). More recently, several lines of evidence point to a role of NRGs in the control of metabolism via actions on muscle, liver, adipose tissue and the hypothalamus Zhang et al, 2018).…”

Section: The Neuregulinsmentioning

confidence: 99%

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

et al. 2020

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Integrative Physiology, a section of the journal Frontiers in PhysiologyMetabolic diseases, such as diabetes, obesity, and fatty liver disease, have now reached epidemic proportions. Receptor tyrosine kinases (RTKs) are a family of cell surface receptors responding to growth factors, hormones, and cytokines to mediate a diverse set of fundamental cellular and metabolic signaling pathways. These ligands signal by endocrine, paracrine, or autocrine means in peripheral organs and in the central nervous system to control cellular and tissue-specific metabolic processes. Interestingly, the expression of many RTKs and their ligands are controlled by changes in metabolic demand, for example, during starvation, feeding, or obesity. In addition, studies of RTKs and their ligands in regulating energy homeostasis have revealed unexpected diversity in the mechanisms of action and their specific metabolic functions. Our current understanding of the molecular, biochemical and genetic control of energy homeostasis by the endocrine RTK ligands insulin, FGF21 and FGF19 are now relatively well understood. In addition to these classical endocrine signals, non-endocrine ligands can govern local energy regulation, and the intriguing crosstalk between the RTK family and the TGFβ receptor family demonstrates a signaling network that diversifies metabolic process between tissues. Thus, there is a need to increase our molecular and mechanistic understanding of signal diversification of RTK actions in metabolic disease. Here we review the known and emerging molecular mechanisms of RTK signaling that regulate systemic glucose and lipid metabolism, as well as highlighting unexpected roles of non-classical RTK ligands that crosstalk with other receptor pathways.

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Neuregulin 3 Knockout Mice Exhibit Behaviors Consistent with Psychotic Disorders

Cited by 25 publications

References 56 publications

Genetic and metabolic links between the murine microbiome and memory

Genetic and metabolic links between the murine microbiome and memory

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

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

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