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KCNH2-3.1 mediates aberrant complement activation to impair hippocampal-medial prefrontal pathway associated with schizophrenia

ABSTRACT: Although elevated KCNH2-3.1 potassium channel expression is associated with cognitive dysfunctions and with schizophrenia, little is known about the pathophysiology of synapses in patient neurons and how elevated levels of KCNH2-3.1 potassium channel could lead to synaptic deficits in humans. Here, we identified specific and delayed disruption of hippocampal-mPFC synaptic transmission and connection unexpectedly associated with age-dependent reduction of SERPING1, CFH and CD74 in the KCNH2-3.1 overexpression transgenic mice, and dysfunctional interactions between hippocampus and prefrontal cortex in the fMRI coupling signal during working memory encoding in healthy subjects carrying schizophrenia-associated risk alleles of KCNH2 potassium channel. These three genes are enriched in neurons or microglia, and reduced expression of these genes dysregulates the complement cascade activation underlying impaired synaptic connectivity of hippocampal-mPFC projections. Knockdown of these genes’ expression impairs synapse formation, and replenishing reduced CFH gene expression rescues KCNH2-3.1-induced impaired synaptogenesis. Our results uncover a previously unrecognized role of truncated KCNH2-3.1 potassium channel mediating reduced expression of three genes mentioned above, which enhances aberrant complement cascade activation during development. These results direct an important conceptual advance that truncated KCNH2-3.1 causes synapse loss mediated by abnormally activated complement system, rather than aberrant neuronal firing, may represent the therapeutic targets for a number of patients with schizophrenia.

ORGANISM(S): Mus musculus

PROVIDER: GSE118989 | GEO | 2019/08/23

REPOSITORIES: GEO

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KCNH2-3.1 mediates aberrant complement activation to impair hippocampal-medial prefrontal pathway associated with schizophrenia

Project description:KCNH2-3.1 mediates aberrant complement activation to impair hippocampal-medial prefrontal pathway associated with schizophrenia

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Inhibition of BET proteins during adolescence affects prefrontal cortex development: relevance to schizophrenia

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2021-09-07 | PXD027050 | Pride

Complement Factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice.

Project description:Purpose: The complement system is closely linked to the pathogenesis of age-related macular degeneration (AMD). Several complement genes are expressed in retinal pigment epithelium (RPE), and complement proteins accumulate in drusen. Further, a common variant of complement factor H (CFH) confers increased risk of developing AMD. Because the mechanisms by which changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods: Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- C57BL/6J mice was analysed by microarrays. Expression of a wide range of complement genes was compared to expression in splenocytes and in liver tissue by qRT-PCR. Results: An age-associated increased expression of complement, particularly C1q, C3 and Factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Both hepatic and splenic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions: While the connection between CFH deficiency and failure to up-regulate CD59a remains unknown, these results suggest that expression of CD59 is tissue-specific and that neuroretinal regulation depends on CFH. This could contribute to the visual functional deficits and morphological changes in the Cfh-/- mouse retina that occur with age, and further suggests that deficient neuroretinal regulation of complement could represent an early event in AMD.

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Complement Factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice.

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Project description:Chronic administration of lysergic acid diethylamide (LSD) every other day to rats results in a variety of abnormal behaviors. These build over the 90 day course of treatment and can persist at full strength for at least several months after cessation of treatment. The behaviors are consistent with those observed in animal models of schizophrenia and include hyperactivity, reduced sucrose-preference, and decreased social interaction. In order to elucidate molecular changes that underlie these aberrant behaviors, we chronically treated rats with LSD and performed RNA-sequencing on the medial prefrontal cortex (mPFC), an area highly associated with both the actions of LSD and the pathophysiology of schizophrenia and other psychiatric illnesses. Results: We observed widespread changes in the neurogenetic state of treated animals four weeks after cessation of LSD treatment. QPCR was used to validate a subset of gene expression changes observed with RNA-Seq, and confirmed a significant correlation between the two methods. Functional clustering analysis indicates differentially expressed genes are enriched in pathways involving neurotransmission (Drd2, Gabrb1), synaptic plasticity (Nr2a, Krox20), energy metabolism (Atp5d, Ndufa1) and neuropeptide signaling (Npy, Bdnf), among others. Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia, and genes affected by LSD are enriched with putative schizophrenia genes. Our results provide a relatively comprehensive analysis of mPFC transcriptional regulation in response to chronic LSD, and indicate that the long-term effects of LSD may bear relevance to psychiatric illnesses, including schizophrenia.

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Project description:Nitrosative stress has been implicated in the pathogenesis of age related macular degeneration (AMD). Tyrosine nitration is a unique type of post translational modification that occurs in the setting of inflammation and nitrosative stress. To date, the significance and functional implications of tyrosine nitration of complement factor H (CFH), a key complement regulator in the eye has not been explored, and is examined in this study in the context of AMD pathogenesis. Sections of eyes from deceased individuals with AMD (n = 5) demonstrated the presence of immunoreactive nitrotyrosine CFH. We purified nitrated CFH from retinae from 2 AMD patients. Mass spectrometry of CFH isolated from AMD eyes revealed residues in domains critical for binding to heparan sulphate glycosaminoglycans (GAGs), lipid peroxidation by-products and complement (C) 3b were nitrated. Functional studies revealed that nitrated CFH did not bind to lipid peroxidation products, nor to the GAG of perlecan nor to C3b. There was loss of cofactor activity for Factor I mediated cleavage of C3b with nitrated CFH compared to non-nitrated CFH. CFH inhibits, but nitrated CFH significantly potentiates, the secretion of the pro-inflammatory and angiogenic cytokine IL-8 from monocytes that have been stimulated with lipid peroxidation by-products. AMD patients (n = 30) and controls (n = 30) were used to measure plasma nitrated CFH using a novel ELISA. AMD patients had significantly elevated nitrated CFH levels compared to controls (p = 0.0117). These findings strongly suggest that nitrated CFH contributes to AMD progression, and is a target for therapeutic intervention.

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