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Reduced exploratory behavior in neuronal nucleoredoxin knockout mice.

ABSTRACT: Nucleoredoxin is a thioredoxin-like redoxin that has been recognized as redox modulator of WNT signaling. Using a Yeast-2-Hybrid screen, we identified calcium calmodulin kinase 2a, Camk2a, as a prominent prey in a brain library. Camk2a is crucial for nitric oxide dependent processes of neuronal plasticity of learning and memory. Therefore, the present study assessed functions of NXN in neuronal Nestin-NXN^-/- deficient mice. The NXN-Camk2a interaction was confirmed by coimmunoprecipitation, and by colocalization in neuropil and dendritic spines. Functionally, Camk2a activity was reduced in NXN deficient neurons and restored with recombinant NXN. Proteomics revealed reduced oxidation in the hippocampus of Nestin-NXN^-/- deficient mice, including Camk2a, further synaptic and mitochondrial proteins, and was associated with a reduction of mitochondrial respiration. Nestin-NXN^-/- mice were healthy and behaved normally in behavioral tests of anxiety, activity and sociability. They had no cognitive deficits in touchscreen based learning & memory tasks, but omitted more trials showing a lower interest in the reward. They also engaged less in rewarding voluntary wheel running, and in exploratory behavior in IntelliCages. Accuracy was enhanced owing to the loss of exploration. The data suggested that NXN maintained the oxidative state of Camk2a and thereby its activity. In addition, it supported oxidation of other synaptic and mitochondrial proteins, and mitochondrial respiration. The loss of NXN-dependent pro-oxidative functions manifested in a loss of exploratory drive and reduced interest in reward in behaving mice.

SUBMITTER: Tran BN

PROVIDER: S-EPMC8254043 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict.

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Protein expression and oxidation in the hippocampus of neuronal nucleoredoxin knockout (Nestin-NXN-/-) versus floxed control mice (NXN-flfl)

Project description:Nucleoredoxin (NXN) is a thioredoxin-like member of the large group of redoxins which maintain redox balances in the cell. Its primary localization is the cytoplasm, and it is highly expressed in neurons. It has been described as a redox regulator of WNT signaling via maintenance of the redox balance of Disheveled (Dvl). Previous proteomic analyses in NXN-knockdown SH-SY5Y cells found a high fraction of reduced proteins involved in development and cell differentiation. The results suggested NXN mainly acted as oxidase under the culture conditions. The functions in vivo are not known, but full deletion of NXN is embryonically lethal owing to cranial deformities. We have generated mice with a pan-neuronal Nestin-Cre driven deletion of NXN (Nestin-NXN-/-) to study its functions in neurons. Nestin-NXN-/- develop normally and are healthy up to old age. They show a loss of exploratory and playful behavior but have no deficits of cognitive functions, social behavior or readouts of anxiety. Using a Yeast-2-Hybrid screen, calcium calmodulin kinase 2a was identified as interaction partner. Camk2a is crucial for long-term potentiation and thereby learning and memory but is also associated with psychiatric diseases, and it is regulated via redox modification of cysteines that impact on the autophosphorylation status of a critical threonine. Camk2a colocalized and co-precipitated with NXN and its activity depended on the presence of NXN. To further study the functions of NXN in neurons we performed a proteomic screen of the hippocampal proteome and the redox proteome using the BIAM switch method.

2021-09-10 | PXD024624 | Pride

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Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit.

Project description:Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

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