Biology subjects

Powell, S. B.

Publications and source records attributed to Powell, S. B..

6 recordsLinked to original sources

bioRxiv2026

Pro-Cognitive Effects of IgM Isotype Anti-NMDAR1 Autoantibodies in Mice

Natural anti-NMDAR1 autoantibodies are present at varying levels in the general human population, but their effects on cognitive function remain unclear. Recent human studies reported significant associations between higher blood levels of natural anti-NMDAR1 autoantibodies and potential neuroprotective outcomes in Alzheimers disease, traumatic brain injury-associated depression and PTSD symptoms, and schizophrenia. However, whether these natural autoantibodies play a causal role in emotional and cognitive function has not been investigated. Since natural autoantibodies in human blood are predominantly of the IgM isotype, we immunized Aicda mutant mice to produce only IgM isotype anti-NMDAR1 autoantibodies without IgG and IgA isotypes. Mice were tested for sensorimotor gating and conditioned fear and extinction, cross species measures of information processing and emotional memory, respectively. Mice with higher levels of IgM anti-NMDAR1 autoantibodies exhibited significantly increased sensorimotor gating and improved fear extinction recall compared with mice with baseline levels of these autoantibodies. These findings indicate that IgM anti-NMDAR1 autoantibodies are pro-cognitive, unlike previous reports of poor cognition associated with IgG anti-NMDAR1 autoantibodies. Together, these studies suggest that IgM may hold therapeutic potential for a range of neurodegenerative, neurological, and psychiatric disorders.

neuroscience↗

bioRxiv2025

Maternal Immune Activation Disrupts Epigenomic and Functional Maturation of Cortical Excitatory Neurons

Elevated levels of maternal pro-inflammatory cytokines during gestation can disrupt offspring neural development, increasing the risk of neurodevelopmental disorders. We studied the effects of Poly(I:C)-induced maternal immune activation (PIC-MIA) during mid-gestation on developing cortical excitatory neurons DNA methylation and transcriptome. PIC-MIA disrupted the developmental regulation of synapse-related genes and of genes implicated in autism spectrum disorders. Genomic regions that gain or lose DNA methylation during normal development were altered following PIC-MIA, including neurodevelopmental transcription factor binding sites. The DNA methylation and transcriptional changes were consistent with a delay in excitatory neuron maturation. Whole-cell recordings showed that PIC-MIA preferentially altered the physiological development of layer 5 excitatory neurons. Taken together, present results suggest that alterations in the epigenome, through the disruption of circuit formation, may drive the long-term consequences of maternal infection during gestation.

neuroscience↗

bioRxiv2023

In vivo mapping of protein-protein interactions of schizophrenia risk factors generates an interconnected disease network.

Genetic analyses of Schizophrenia (SCZ) patients have identified thousands of risk factors. In silico protein-protein interaction (PPI) network analysis has provided strong evidence that disrupted PPI networks underlie SCZ pathogenesis. In this study, we performed in vivo PPI analysis of several SCZ risk factors in the rodent brain. Using endogenous antibody immunoprecipitations coupled to mass spectrometry (MS) analysis, we constructed a SCZ network comprising 1612 unique PPI with a 5% FDR. Over 90% of the PPI were novel, reflecting the lack of previous PPI MS studies in brain tissue. Our SCZ PPI network was enriched with known SCZ risk factors, which supports the hypothesis that an accumulation of disturbances in selected PPI networks underlies SCZ. We used Stable Isotope Labeling in Mammals (SILAM) to quantitate phencyclidine (PCP) perturbations in the SCZ network and found that PCP weakened most PPI but also led to some enhanced or new PPI. These findings demonstrate that quantitating PPI in perturbed biological states can reveal alterations to network biology.

neuroscience↗

bioRxiv2021

MicroPET evidence for a hypersensitive neuroinflammatory profile of gp120 mouse model of HIV

Despite increased survivability for people living with HIV (PLWH), HIV-related cognitive and behavioral abnormalities persist. Determining the biological mechanism(s) underlying these abnormalities is critical to minimize the long-term impact of HIV. Human positron emission tomography (PET) studies reveal that PLWH exhibit higher neuroinflammation, which may contribute to cognitive and behavioral problems. PLWH are hypersensitive to environmental insults that drive elevated inflammatory profiles. Gp120 is an envelope glycoprotein exposed on the surface of the HIV envelope which enables HIV virus entry into a cell and contributes to HIV-related neurotoxicity. Gp120 overexpression in mice enables delineating its impact, including on neuroinflammation. In vivo evidence for gp120 transgenic (Tg) mice exhibiting neuroinflammation has yet to be determined. Here, we conducted microPET imaging in male gp120 Tg and wildtype mice, using the radiotracer [(18)F]FEPPA which binds to the translocator protein expressed by activated microglial and serves as a marker of neuroinflammation. Imaging was performed at baseline and 24 hours after treatment with lipopolysaccharide (LPS; 5 mg/kg), endotoxin that triggers an immune response. Gp120 Tg mice exhibited elevated [(18F)]FEPPA in response to LPS vs. wildtype mice throughout the brain including dorsal and ventral striata, hypothalamus, and hippocampus, but not prefrontal cortex. Gp120 Tg mice are hypersensitive to environmental inflammatory insults, consistent with PLWH, measurable in vivo. It remains to-be-determined whether this heightened sensitivity is connected to the behavioral abnormalities of these mice or is sensitive to antiretroviral or other treatments.

neuroscience↗

bioRxiv2021

Nicotine-mediated recruitment of GABAergic neurons to a dopaminergic phenotype attenuates motor deficits in alpha-synuclein Parkinson's model.

BACKGROUNDPrevious work revealed an inverse correlation between smoking and Parkinsons disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. We investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. METHODSWild-type and -syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in-situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. RESULTSNicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of -syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1 in non-DA neurons. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. CONCLUSIONSNicotine exposure initiates neuroprotective mechanisms counteracting the neurodegenerative effects of -syn accumulation in DA neurons and contributing to Nurr1-mediated therapeutic effects. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.

neuroscience↗

bioRxiv2019

Polycomb-mediated repression compensates for loss of postnatal DNA methylation in excitatory neurons

Two epigenetic pathways of repression, DNA methylation and Polycomb repressive complex 2 (PRC2) mediated gene silencing, regulate neuron development and function, but their respective contributions are unknown. We found that conditional loss of the de novo DNA methyltransferase Dnmt3a in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. Loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving neurons with an unmethylated, fetal-like epigenomic pattern at -140,000 genomic regions. The PRC2-associated histone modification H3K27me3 increased at many of these sites, partially compensating for the loss of DNA methylation. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

neuroscience↗