Biology subjects

Luke, S.

Publications and source records attributed to Luke, S..

3 recordsLinked to original sources

bioRxiv2026

Retinal electrical synapse plasticity is required for optimal visual performance

Most electrical synapses in the mammalian central nervous system are composed of Connexin 36 (Cx36). Electrical synapses are functionally plastic, changing their degree of coupling based on the activity of the cell or connected cells, or based on activation of neurotransmitter or neurohormone receptors. Plasticity can reach an extreme in which electrical synapses become functionally silent, which is a normal operational condition for some circuits. Cx36 coupling is regulated by phosphorylation, which opens the channels. In retinal circuits, Cx36 is often maintained in a poorly phosphorylated, poorly coupled state. We reasoned that phosphomimetic mutants of Cx36 could remain constitutively open and maintain circuits in a well-coupled state that will interrogate the need for plasticity. We developed a constitutively open Cx36 mutant by systematically replacing phosphorylatable residues that regulate coupling with acidic residues. Single mutants of serine 315 significantly modified functional regulation of coupling in HeLa cells, but mutation of four residues was required to produce a mutant that was constitutively open. This mutant, Cx36-S110D, T111E, S293D, S315D, called Cx36-DEDD, displayed high coupling in control conditions and only modest changes under phosphorylating and dephosphorylating conditions. We developed a conditional knockin mouse that expresses Cx36-DEDD and cytoplasmic tdTomato in cells that expressed Cre recombinase. When crossed with Six3-Cre mice, Cx36-DEDD expressed widely in the retina including in photoreceptors, bipolar, amacrine and ganglion cells. Rod-cone electrical coupling displayed the maximum of its physiological dynamic range, and photopic visual acuity and contrast sensitivity were significantly reduced in Cx36-DEDD homozygous animals. We conclude that reduction of coupling in some retinal circuits is required for optimal daylight vision. Significance StatementTwo types of synapses, chemical and electrical, work together throughout the central nervous system to perform neurological functions. While it is widely understood for chemical synapses that plasticity, changing the strength of synaptic connections, plays critical roles in many processes, this is far less understood for electrical synapses. By developing an electrical synapse protein mutant that locks channels in an open state, we have investigated retinal circuits that retain functional electrical synapses but lack their latitude for plasticity. This perturbation significantly compromises visual acuity and contrast sensitivity in the daylight, revealing that electrical synapse plasticity is necessary to tune retinal functions for optimal performance. Thus, electrical synapse plasticity along with chemical synapse plasticity is required for neural function.

neuroscience↗

bioRxiv2024

Sex differences in deep brain shape and asymmetry persist across schizophrenia and healthy individuals: A meta-analysis from the ENIGMA-Schizophrenia Working Group

BackgroundSchizophrenia (SCZ) is characterized by a disconnect from reality that manifests as various clinical and cognitive symptoms, and persistent neurobiological abnormalities. Sex-related differences in clinical presentation imply separate brain substrates. The present study characterized deep brain morphology using shape features to understand the independent effects of diagnosis and sex on the brain, and to determine whether the neurobiology of schizophrenia varies as a function of sex. MethodsThis study analyzed multi-site archival data from 1,871 male (M) and 955 female (F) participants with SCZ, and 2,158 male and 1,877 female healthy controls (CON) from twenty-three cross-sectional samples from the ENIGMA Schizophrenia Workgroup. Harmonized shape analysis protocols were applied to each sites data for seven deep brain regions obtained from T1-weighted structural MRI scans. Effect sizes were calculated for the following main contrasts: 1) Sex effects;2) Diagnosis-by-Sex interaction; 3) within sex tests of diagnosis; 4) within diagnosis tests of sex differences. Meta-regression models between brain structure and clinical variables were also computed separately in men and women with schizophrenia. ResultsMass univariate meta-analyses revealed more concave-than-convex shape differences in all regions for women relative to men, across diagnostic groups (d = -0.35 to 0.20, SE = 0.02 to 0.07); there were no significant diagnosis-by-sex interaction effects. Within men and women separately, we identified more-concave-than-convex shape differences for the hippocampus, amygdala, accumbens, and thalamus, with more-convex-than-concave differences in the putamen and pallidum in SCZ (d = -0.30 to 0.30, SE = 0.03 to 0.10). Within CON and SZ separately, we found more-concave-than-convex shape differences in the thalamus, pallidum, putamen, and amygdala among females compared to males, with mixed findings in the hippocampus and caudate (d = -0.30 to 0.20, SE = 0.03 to 0.09). Meta-regression models revealed similarly small, but significant relationships, with medication and positive symptoms in both SCZ-M and SCZ-F. ConclusionsSex-specific variation is an overriding feature of deep brain shape regardless of disease status, underscoring persistent patterns of sex differences observed both within and across diagnostic categories, and highlighting the importance of including it as a critical variable in studies of neurobiology. Future work should continue to explore these dimensions independently to determine whether these patterns of brain morphology extend to other aspects of neurobiology in schizophrenia, potentially uncovering broader implications for diagnosis and treatment. Key PointsO_LIStatistical analyses revealed significant main effects for diagnosis and sex in deep brain shape morphology. Among patients with schizophrenia, there was a pattern of thinning and surface contraction in the bilateral hippocampus, amygdala, accumbens, and thalamus, and a pattern of significant thickening and surface expansion in the bilateral putamen and pallidum compared to healthy control participants. Between males and females, there was a pattern of significant thinning and surface contraction in the bilateral thalamus, pallidum, putamen, and amygdala in females compared to males. C_LIO_LIThere was no significant interaction between diagnosis and biological sex, suggesting that sex differences in deep brain shape and asymmetry among patients with schizophrenia reflect those observed in healthy individuals. C_LIO_LISmall but statistically significant relationships exist between brain structure and clinical correlates of schizophrenia were similar for both men and women with the disease, such that higher CPZ was associated with shape-derived thinning and surface contraction in the caudate, accumbens, hippocampus, amygdala, and thalamus, and elevated positive symptoms were associated with shape-derived thinning and surface contraction in the bilateral caudate, right hippocampus, and right amygdala. C_LI

neuroscience↗

bioRxiv2019

Generation and characterisation of an estrogen receptor-positive GEMM-derived Pten p53 null transplantable breast tumour model for therapeutic testing

Assessing the signalling pathway dependencies of tumours that arise autochthonously in genetically engineered mouse models (GEMMs) of breast cancer is particularly challenging due to the high degree of intra- and inter-tumour heterogeneity, as well as the long latency of tumour development in such models. Use of transplantable tumour lines derived from autochthonous tumours ( Mouse Derived Xenografts or MDXs) is one possible solution and has been used successfully in models of BRCA1-associated triple negative breast cancer. However, their potential in ER+ breast cancer models has not been addressed. Here, we assess the utility of orthotopic transplantable tumour lines derived from an autochthonous ER+ Blg-cre Ptenfl/fl p53fl/fl breast cancer model. We show that initial tumour implantation and early passage results in the development of lines of progeny with heterogeneous histopathological phenotypes which is coincident with an accumulation of, or selection for, de novo mutations. Importantly, these lines also display different dependencies on the key pathways that drive tumourigenesis, which can lead to inherent resistance to treatment with pharmacological agents targeting these pathways and makes them important models to test strategies to overcome such resistance.

cancer biology↗