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NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models.

ABSTRACT: Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.

SUBMITTER: Ghatak S

PROVIDER: S-EPMC7704704 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Modeling the developmental etiology of viable human aneuploidies can be challenging in rodent models, where synteny with human chromosomes is affected, or primate-specific biology is implicated. In humans, monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which remain largely unaffected in 39,X-mice. We derived human 45,X and isogenic euploid induced pluripotent stem cells (hiPSCs) from male and female mosaics to model how human monosomy-X may impact early embryonic development. Because several neural crest (NC) derived cell types are hypothesized to underpin craniofacial and cardiovascular changes in TS, we derived anterior neural crest from our hiPSCs and performed a highly-powered and extensive differential expression study. Across all three isogenic panels, 45,X neural crest cells (NCCs) show impaired acquisition of the PAX7/SOX10 double-positive NC state relative to euploid 46,XY controls. Monosomy-X NCCs also share similarly disrupted expression of NC-specific genes relative to their isogenic euploid control regardless of whether the latter carry an inactive X or Y. Gene-set enrichment analyses indicate monosomy-X NCCs increase cholesterol biosynthesis genes while dampening ribosomal protein and nuclear-encoded mitochondrial genes. These metabolic pathways are also over-represented in gene modules that are preserved in monogenic conditions involving neurocristopathy. Importantly, these gene modules are also significantly enriched in 28% of all TS-associated terms of the human phenotype ontology, and point to specific sex-linked genes that are expressed from two copies in euploid males and females alike, which may qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. Our study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as a powerful model of early NC development in TS, and provides euploid and X-monosomic transcriptomic datasets relevant to exploration of TS and NC biology.

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NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models.

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