Biology subjects

Sweet, R.

Publications and source records attributed to Sweet, R..

5 recordsLinked to original sources

bioRxiv2026

A Key Regulator of Dendritic Morphology in Supragranular Neocortex Impacts Mismatch Negativity

BackgroundCytoskeletal structure and neuronal function are heavily intertwined, and altered pyramidal neuron morphology (e.g., reduced dendritic arbors) has been consistently identified in the neocortex of individuals with psychiatric disorders. A missense mutation in Kalrn (Kalrn-PT) enhances activation of RhoA, a cytoskeletal regulator, and leads to adolescent-onset dendritic regression in supragranular auditory cortex. To investigate the relationship between this spatiotemporally altered cytoskeletal structure and psychiatric-relevant dysfunction, we examine the functional impacts of this genetic mutation, focusing on mismatch negativity - a common biomarker of altered sensory integration that matures across adolescence. MethodsIn Kalrn-PT and littermate wild-type mice, pyramidal dendritic morphology was assessed across primary visual cortex (V1) layers using Golgi staining (n=172 neurons/26 mice). Local field potentials (LFPs) and neuronal spiking were recorded during a visual oddball sequence (n=25 mice). Deviance detection - the rodent neural analogue of mismatch negativity - was analyzed across V1 layers. ResultsKalrn-PT mice exhibit reductions in V1 dendritic length specific to layer 2/3, mirroring observations in post-mortem samples from people with psychiatric disorders. Deviance detection was reduced in LFPs from Kalrn-PT mice and absent in layer 2/3 neurons, despite typical feature selectivity and firing rates. These deficits were accompanied by reduced functional connectivity between visual and frontal areas. ConclusionsThese results highlight alterations in higher-level sensory cortical integration in Kalrn-PT mice and demonstrate that adolescent-onset, disease-relevant structural and functional phenotypes can be linked by a common upstream effector. Further, these alterations appear restricted to supragranular layers, demonstrating an outsized role for Kalrn, particularly longer isoforms, in superficial neocortex.

neuroscience↗

bioRxiv2025

Tissue destruction during food spoilage is associated with the formation of biofilms by Pseudomonas species

Members of the Pseudomonas genus are common spoilers of a range of meat, dairy and vegetable products. While we have a good understanding of the Pseudomonas species typically responsible for spoilage, we know very little about how these bacteria interact with food surfaces during spoilage. Here we assessed the spoilage capabilities of a large panel (n=124) of Pseudomonas species food-derived isolates on meat (chicken) and leafy greens (spinach). Most isolates (71/124) were capable of spoiling both foods, but some were only capable of spoiling only chicken (21/124) or spinach (23/124), or neither (9/124). Our data also demonstrated that the type of fresh food the strain was isolated from influenced spoilage capabilities: strains isolated from meat were likely to spoil both chicken and spinach, while those isolated from leafy greens were more likely to spoil only spinach. We used fluorescence microscopy to visualise how Pseudomonas spoilage species interacted with the meat or leaf tissue and observed significant tissue destruction associated with biofilm formation. For chicken, this was associated with the formation of dense biofilm pillars that penetrated deep into the tissue. For spinach we observed biofilms on the leaf in areas of tissue degradation. Finally, we explored the correlation between potentially relevant phenotypes (in vitro biofilm, motility and secreted enzyme production) and spoilage capabilities. There was no significant correlation between any of these phenotypes and spoilage, except for secreted protease activity and chicken spoilage. Overall, this study increases our understanding of processes involved in food spoilage by Pseudomonas species.

microbiology↗

bioRxiv2025

Cellular and Regional Vulnerability Shapes the Molecular Landscape of Psychosis in Alzheimers Disease

Approximately 40 percent of Alzheimers disease patients develop psychosis (AD+P), yet the molecular and cellular basis of these symptoms remains poorly understood. Here we profiled single-nucleus transcriptomes and epigenomes from 48 postmortem Alzheimers brains stratified by psychiatric diagnosis. Across cell types, AD+P was distinguished by transcriptional programs in upper-layer cortical pyramidal neurons consistent with re-engagement of developmental and structural plasticity pathways. These neurons exhibited greater loss in AD+P cortex, indicating that such programs emerge in a context of heightened vulnerability. Integrating these findings with functional perturbation screens in stem-cell-derived brain organoids, we found that activation of these programs alters cortico-cortical network connectivity and can exacerbate network dysfunction. Our data suggest that compensatory neuronal plasticity, shaped by glial inflammatory responses, may paradoxically contribute to circuit instability and selective vulnerability underlying neuropsychiatric symptoms in dementia. HighlightsO_LICell-type- and brain-region-specific transcriptional changes in AD with psychosis (AD+P) C_LIO_LIUpper-layer pyramidal dysfunction and metabolic vulnerability marks the pathophysiology of AD+P C_LIO_LICircuit wiring programs are evoked in AD+P as maladaptive compensatory responses C_LIO_LIAD+P-associated IL-6 signaling impairs neuronal network function in brain organoids C_LI

neuroscience↗

bioRxiv2022

CACNB4 overexpression decreases dendritic spine density in sex-specific manner

The canonical voltage-gated calcium channel (VGCC) subunit complex is comprised of the 1 subunit, the ion permeable channel, plus three auxiliary subunits: {beta}, 2{delta} and {gamma}. {beta} is the most extensively studied auxiliary subunit and is necessary for proper forward trafficking of the 1 subunit to the plasma membrane. 1 subunits mediate voltagedependent movement of calcium ions into the cytoplasm of neurons, including at dendritic sites, where increased intracellular calcium initiates signaling cascades that shape structural and functional plasticity of dendritic spines. Genetic studies strongly implicate calcium signaling dysfunction in the etiology of neurodevelopmental disorders including schizophrenia. Dendritic spine density (DSD) is significantly decreased in schizophrenia in primary auditory cortex where DSD is driven by loss of small spines, and small spine loss is associated with increased peptide levels of ALFDFLK found in the VGCC {beta} subunit {beta}4. Overexpessing CACNB4 to increase {beta}4 levels selectively reduced small spine density in cortical neuron cultures. The studies described herein set out to validate this in vitro observation in an intact mammalian system within a neurodevelopmental context. We overexpressed CACNB4 in neurodevelopment and assessed DSD and morphology in cerebral cortex of male and female mice at an adult timpoint. We then characterized {beta} protein levels and {beta}4 protein-protein interactions in male and female mouse cortex. Overexpression selectively reduced small dendritic spine density but this effect was present only in female mice and did not appear to result from estrous stage. Instead, the sex-dependent effect on DSD corresponded to sex differences in the {beta}4 interactome of male versus female mice: the VGCC {beta} subunit {beta}1b was significantly enriched in the {beta}4 interactome of brain tissue of male mice, and thus may have served to mitigate VGCC overexpression-mediated spine loss in male mice.

neuroscience↗

bioRxiv2021

A Kalirin Missense Mutation Enhances Dendritic RhoA Signaling and Leads to Regression of Cortical Dendritic Arbors Across Development

Normally, dendritic size is established prior to adolescence then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor, Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wildtype KAL. In mice containing this missense mutation at the endogenous locus there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Tissue density of dendritic spines was also reduced. Early adult mice with these structural deficts exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease. SIGNIFICANCE STATEMENTDendrites are long branching processes on neurons that contain small processes called spines that are the site of connections with other neurons, establishing cortical circuitry. Dendrites have long been considered stable structures, with rapid growth prior to adolescence followed by maintenance of size into adulthood. However, schizophrenia is characterized by accelerated reductions of cortical gray matter volume and onset of clinical symptoms during adolescence, with reductions in dendritic length present when examined after death. We show that dendrites retain the capacity for regression, and that a mild genetic vulnerability in a regression pathway leads to onset of structural impairments in previously formed dendrites across adolescence. This suggests that targeting specific regression pathways could potentially lead to new therapeutics for schizophrenia.

neuroscience↗