Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model.

Among systemic lupus erythematosus (SLE) patients, neuropsychiatric symptoms are highly prevalent, being observed in up to 80% of adult and 95% of pediatric patients. Type 1 interferons, particularly interferon alpha (IFNα), have been implicated in the pathogenesis of SLE and its associated neuropsychiatric symptoms (NPSLE). However, it remains unclear how type 1 interferon signaling in the central nervous system (CNS) might result in neuropsychiatric sequelae. In this study, we validate an NPSLE mouse model and find an elevated peripheral type 1 interferon signature alongside clinically relevant NPSLE symptoms such as anxiety and fatigue. Unbiased single-nucleus sequencing of the hindbrain and hippocampus revealed that interferon-stimulated genes (ISGs) were among the most highly upregulated genes in both regions and that gene pathways involved in cellular interaction and neuronal development were generally repressed among astrocytes, oligodendrocytes, and neurons. Using image-based spatial transcriptomics, we found that the type 1 interferon signature is enriched as spatially distinct patches within the brain parenchyma of these mice. Our results suggest that type 1 interferon in the CNS may play an important mechanistic role in mediating NPSLE behavioral phenotypes by repressing general cellular communication pathways, and that type 1 interferon signaling modulators are a potential therapeutic option for NPSLE.

[WITHDRAWN] Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model.

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Neuropsychiatric disorders: An immunological perspective.

Neuropsychiatric diseases have traditionally been studied from brain, and mind-centric perspectives. However, mounting epidemiological and clinical evidence shows a strong correlation of neuropsychiatric manifestations with immune system activation, suggesting a likely mechanistic interaction between the immune and nervous systems in mediating neuropsychiatric disease. Indeed, immune mediators such as cytokines, antibodies, and complement proteins have been shown to affect various cellular members of the central nervous system in multitudinous ways, such as by modulating neuronal firing rates, inducing cellular apoptosis, or triggering synaptic pruning. These observations have in turn led to the exciting development of clinical therapies aiming to harness this neuro-immune interaction for the treatment of neuropsychiatric disease and symptoms. Besides the clinic, important theoretical fundamentals can be drawn from the immune system and applied to our understanding of the brain and neuropsychiatric disease. These new frameworks could lead to novel insights in the field and further potentiate the development of future therapies to treat neuropsychiatric disease.

Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice.

The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.

Microglial responses to peripheral type 1 interferon.

BACKGROUND: Interferon α (IFNα) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFNα signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFNα signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFNα modulates these functions are not well defined. METHODS: Using a model of peripheral IFNα administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFNα and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFNα on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry. RESULTS: We found that IFNα exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFNα-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region-specific differences. Finally, by specifically knocking down expression of IFNAR1 on microglia, we show that these changes are largely attributable to direct IFNAR signalling on microglia and not from indirect signalling effects through other CNS parenchymal cell types which are capable of IFNα-IFNAR signal transduction. CONCLUSIONS: Peripheral IFNα induces unique genetic and phenotypic changes in microglia that are largely dependent on direct signalling through microglial IFNAR. The IFNα-induced upregulation of C4b could play important roles in the context of aberrant synaptic pruning in neuropsychiatric disease.

How does mutation affect the distribution of phenotypes?

The potential for mutational processes to influence patterns of neutral or adaptive phenotypic evolution is not well understood. If mutations are directionally biased, shifting trait means in a particular direction, or if mutation generates more variance in some directions of multivariate trait space than others, mutation itself might be a source of bias in phenotypic evolution. Here, we use mutagenesis to investigate the affect of mutation on trait mean and (co)variances in zebrafish, Danio rerio. Mutation altered the relationship between age and both prolonged swimming speed and body shape. These observations suggest that mutational effects on ontogeny or aging have the potential to generate variance across the phenome. Mutations had a far greater effect in males than females, although whether this is a reflection of sex-specific ontogeny or aging remains to be determined. In males, mutations generated positive covariance between swimming speed, size, and body shape suggesting the potential for mutation to affect the evolutionary covariation of these traits. Overall, our observations suggest that mutation does not generate equal variance in all directions of phenotypic space or in each sex, and that pervasive variation in ontogeny or aging within a cohort could affect the variation available to evolution.