Biology subjects

Madison, J.

Publications and source records attributed to Madison, J..

3 recordsLinked to original sources

bioRxiv2026

Discovery of GluA3 preferring AMPA receptor positive allosteric modulator BRD3290

Schizophrenia is a debilitating neuropsychiatric disease that lacks effective treatments for many symptom domains including negative, cognitive and sleep disturbances. Lack of clear disease etiology has hampered the development of new, effective treatments for the unmet needs of people with schizophrenia. Large scale human genetics have identified rare loss of function mutations that substantially increase risk of developing schizophrenia, including in GRIA3, the gene that encodes the GluA3 receptor subunit of the AMPA receptor (AMPAR). Several drug discovery programs have been aimed at developing AMPAR positive allosteric modulators (PAMs) as a novel treatment for schizophrenia. Despite intense drug discovery efforts, there are no FDA approved AMPAR PAMs. We therefore hypothesized that selectively targeting GluA3, the AMPAR subunit implicated by human genetics, could yield a safer and more effective AMPAR PAM for the potential treatment of schizophrenia. Using a combination of medicinal chemistry, in vitro, and in vivo studies, we discovered BRD3290, a GluA3-preferring AMPAR PAM with reasonable potency in heterologous cells, as well as favorable tolerability and brain exposure. Peripheral administration of BRD3290 engaged an established AMPAR PAM target engagement biomarker but did not improve performance of wildtype mice in the novel object recognition task (NOR), in contrast to the nonselective AMPAR PAM PF-4778574, which improved mouse NOR. These findings suggest that the GluA3 selectivity profile of BRD3290 was insufficient to enhance cognitive function in this mouse NOR paradigm. This work highlights the challenges of AMPAR subtype-selective modulation and provides molecular insights into the ability to develop subtype-selective AMPAR PAMs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/740780v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1577f62org.highwire.dtl.DTLVardef@16c1750org.highwire.dtl.DTLVardef@16eaef3org.highwire.dtl.DTLVardef@19fdb6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Host population structure and rare dispersal events drive leptospirosis transmission patterns among Rattus norvegicus in Boston, Massachusetts, US

Leptospirosis (caused by pathogenic bacteria in the genus Leptospira) is prevalent worldwide but more common in tropical and subtropical regions. Transmission can occur following direct exposure to infected urine from reservoir hosts, such as rats, or a urine-contaminated environment, which then can serve as an infection source for additional rats and other mammals, including humans. The brown rat, Rattus norvegicus, is an important reservoir of leptospirosis in urban settings. We investigated leptospirosis among brown rats in Boston, Massachusetts and hypothesized that rat dispersal in this urban setting influences the movement, persistence, and diversity of Leptospira. We analyzed DNA from 328 rat kidney samples collected from 17 sites in Boston over a seven-year period (2016-2022); 59 rats representing 12 of 17 sites were positive for Leptospira. We used 21 neutral microsatellite loci to genotype 311 rats and utilized the resulting data to investigate genetic connectivity among sampling sites. We generated whole genome sequences for 28 Leptospira isolates obtained from frozen and fresh tissue from some of the 59 Leptospira-positive rat kidneys. When isolates were not obtained, we attempted Leptospira genomic DNA capture and enrichment, which yielded 14 additional Leptospira genomes from rats. We also generated an enriched Leptospira genome from a 2018 human case in Boston. We found evidence of high genetic structure and limited dispersal among rat populations that is likely influenced by major roads and/or other unknown dispersal barriers, resulting in distinct rat population groups within the city; at certain sites these groups persisted for multiple years. We identified multiple distinct phylogenetic clades of L. interrogans among rats, with specific clades tightly linked to distinct rat populations. This pattern suggests L. interrogans persists in local rat populations and movement of leptospirosis in this urban rat community is driven by rat dispersal. Finally, our genomic analyses of the 2018 human leptospirosis case in Boston suggests a link to rats as the source. These findings will be useful for guiding rat control and human leptospirosis mitigation efforts in this and other urban settings.

molecular biology↗

bioRxiv2021

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

To study how the 22q11.2 deletion predisposes to psychiatric disease, we generated induced pluripotent stem cells from deletion carriers and controls, as well as utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Upon differentiation into neural progenitor cells, we found the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including Autism Spectrum Disorder. In more differentiated excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common (per-SNP heritability p ({tau}c)= 4.2 x 10-6) and rare, loss of function variants (p = 1.29x10-12). These findings suggest a potential relationship between cellular states, developmental windows and susceptibility to psychiatric conditions with different ages of onset. To understand how the deletion contributed to these observed changes in gene expression, we developed and applied PPItools, which identifies the minimal protein-protein interaction network that best explains an observed set of gene expression alterations. We found that many of the genes in the 22q11.2 interval interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways that underlie the broader alterations in psychiatric risk gene expression we identified. Our findings suggest that the 22q11.2 deletion impacts genes and pathways that may converge with risk loci implicated by psychiatric genetic studies to influence disease manifestation in each deletion carrier.

neuroscience↗