Biology subjects

Sullivan, M. T.

Publications and source records attributed to Sullivan, M. T..

4 recordsLinked to original sources

bioRxiv2026

Characterization of the Grin1Q536R/+ mouse: a preclinical model for GRIN1-related neurodevelopmental disorder

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors playing critical roles in brain development, synaptic plasticity, and cognition. GRIN1-Related Neurodevelopmental Disorder (GRIN1-NDD) is a rare genetic condition caused by pathogenic variations in the GRIN1 gene, which encodes the obligatory subunit of NMDARs. The spectrum of GRIN1 clinical symptoms is hypothesized to result from the functional consequences that different missense variants have on NMDARs. To investigate the disease mechanism in vivo, we generated a novel heterozygous Grin1Q536R/+ knock-in mouse model that carries the identical variation as an adolescent male patient. We describe the clinical presentation of this patient and conduct comprehensive molecular, morphological, electrophysiological, and behavioural characterization in the juvenile, adult, and aging mice. Compared to wildtype littermates, Grin1Q536R/+ mice displayed reduced whole-cell NMDA-induced currents in cortical pyramidal neurons, and reduced NMDAR-mediated synaptic transmission, decreased long-term potentiation, but intact depotentiation at the hippocampal CA1 synapses. Morphological change was observed in the dentate gyrus region of the Grin1Q536R/+ mice. Behavioral phenotyping revealed age- and sex-dependent differences from controls, including hyperlocomotion, reduced muscle strength, and spatial learning deficits. These phenotypes are in line with the clinical manifestations and the relative disease severity of the male patient. The age-dependent phenotypic shift in Grin1Q536R/+ mice highlights the model's value for investigating GRIN1-NDD disease progression and informing longitudinal monitoring as well as potential therapeutic adjustments with age. Taken together, our findings establish a novel and robust in vivo model for studying NMDAR mechanisms and disease pathology in GRIN1-NDD, while supporting the preclinical development of new therapeutic strategies.

neuroscience↗

bioRxiv2024

Context matters: Integrative NMDA receptor dysfunction reveals effective seizure treatment in mice with a human patient GluN1 variant

Mutations in N-Methyl D-Aspartate receptors (NMDARs) cause epilepsy and profound cognitive impairment, though the underlying subunit-specific vulnerabilities remain unclear. We investigate the impact of a severe human variant in the lurcher motif of obligate GluN1 NMDAR subunit using transgenic mice, leveraging context-specific dysfunction to devise a surprising treatment. We show that the GluN1 Y647S variant significantly reduces current flow through isolated NMDARs in the mouse brain. However, this loss-of-function paradoxically extends NMDAR-dependent dendritic integration, causing prolonged circuit-wide excitation that promotes seizures. Mutant receptors fail to sufficiently engage opposing dendritic ion channels that normally prevent NMDAR overactivation. Boosting negative feedback restores normal dendritic integration and successfully treats seizures in vivo, despite loss-of-function of isolated NMDARs. We demonstrate how seizures arise from loss-of-function NMDARs and target the interaction between a GluN1 variants receptor-level effects and its dendritic environment to treat them effectively.

neuroscience↗

bioRxiv2024

Grin1Y647S/+ Mice: A Preclinical Model of GRIN1-Related Neurodevelopmental Disorder

GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by clinically significant variation in the GRIN1 gene, which encodes the obligatory GluN1 subunit of N-methyl-D-aspartate receptors (NMDARs). The identified p.Tyr647Ser (Y647S) variant is carried by a 34-year-old female with seizures and intellectual disability. This study builds upon initial in vitro investigations of the functional impacts of this variant in the SYTANLAAF domain of the GluN1 M3 helix and examines its in vivo consequences in a mouse model. To investigate in vitro functional impacts of NMDARs containing GluN1-Y647S variant subunits, GluN1-Y647S was co-expressed with wildtype GluN2A or GluN2B subunits in Xenopus laevis oocytes and HEK cells. Grin1Y647S/+ mice were created by CRISPR-Cas9 endonuclease-mediated transgenesis and the molecular, electrophysiological, and behavioural consequences of the variant were examined. Additionally, de-identified patient data were collected to examine the representative nature of Grin1Y647S/+ mice in modelling specific aspects of patient symptomology. In vitro, NMDARs containing GluN1-Y647S showed altered sensitivity to endogenous agonists and negative allosteric modulators, and reduced cell surface trafficking. Ex vivo, Grin1Y647S/+ mice displayed a reduction in whole brain GluN1 levels and a deficiency in NMDAR-mediated synaptic transmission in the hippocampus. Behaviourally, Grin1Y647S/+ mice exhibited altered vocalizations, muscle strength, sociability, and problem-solving, as well as spontaneous convulsions that were ameliorated with supplementation of {beta}-hydroxybutyrate (BHB), an endogenously produced ketone body. The Y647S variant confers a complex in vivo phenotype, which reflects largely diminished properties of NMDAR function. As a result, Grin1Y647S/+ mice display atypical behaviour in domains relevant to the clinical characteristics of GRIN1-NDD and the individual carrying the variant, which allowed for the identification of BHB supplementation as a potential anti-convulsant treatment. Ultimately, the characterization of Grin1Y647S/+ mice accomplished in the present work, expands our understanding of the mechanisms underlying GRIN1-NDD and provides a foundation for the continued development of novel therapeutics.

neuroscience↗

bioRxiv2021

Deciphering the potential niche of novel black yeast fungal isolates in a biological soil crust based on genomes, phenotyping, and melanin regulation

Black yeasts are polyextremotolerant fungi that contain high amounts of melanin in their cell wall and maintain a primarily yeast form. These fungi grow in xeric, nutrient deplete environments which implies that they require highly flexible metabolisms and have been suggested to contain the ability to form lichen-like mutualisms with nearby algae and bacteria. However, the exact ecological niche and interactions between these fungi and their surrounding community is not well understood. We have isolated two novel black yeasts from the genus Exophiala that were recovered from dryland biological soil crusts. Despite notable differences in colony and cellular morphology, both fungi appear to be members of the same species, which has been named Exophiala viscosa (i.e., E. viscosa JF 03-3 Goopy and E. viscosa JF 03-4F Slimy). A combination of whole genome sequencing, phenotypic experiments, and melanin regulation experiments have been performed on these isolates to fully characterize these fungi and help decipher their fundamental niches within the biological soil crust consortium. Our results reveal that E. viscosa is capable of utilizing a wide variety of carbon and nitrogen sources potentially derived from symbiotic microbes, can withstand many forms of abiotic stresses, and excrete melanin that can potentially provide UV resistance to the biological soil crust community. Besides the identification of a novel species within the genus Exophiala, our study also provides new insight into the regulation of melanin production in polyextremotolerant fungi.

microbiology↗