Biology subjects

Wilson, M. A.

Publications and source records attributed to Wilson, M. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Conformational flexibility of soybean lipoxygenase is coupled to crystal solvent content in serial crystallography

X-ray crystallography is increasingly employed to study protein conformational ensembles under physiological conditions, but the effects of the crystal lattice on protein motions remains understudied. Here, we report the structure determination of soybean lipoxygenase-1 (SLO) from microcrystal slurries using serial femtosecond crystallography (SFX) at the Linac Coherent Light Source. During data analysis, we observed unexpected polymorphism in SLOs unit-cell parameters, arising from two compounding factors: indexing ambiguities caused by the pseudo-tetragonal symmetry of the SLO crystal lattice, and true non-isomorphism between individual crystal populations consistent with different solvent content. By combining unit-cell clustering with systematic reindexing, we resolved two distinct polymorphs and determined two independent structures from a single experiment. The two structures exhibit a small overall RMSD (0.34 [A]), yet a difference distance matrix reveals coordinated rearrangements that are not readily apparent from simple structural overlays. Furthermore, a difference of approximately 8.5% in crystal solvent content produces measurable differences in crystal contacts and conformational flexibility. The more hydrated (large-cell) polymorph exhibits greater inter-domain flexibility, as well as higher B-factors in key hydrophobic core residues. In the dehydrated (small-cell) polymorph, which shows less interdomain flexibility, these same residues adopt discrete alternative conformations resolvable in the electron density. Our results highlight that subtle changes in crystal packing can give rise to distinct conformational landscapes for crystallized proteins, with potential implications for the interpretation of protein intramolecular dynamics from crystallographic data. SynopsisUsing soybean lipoxygenase-1 as a model system, we determine two independent structures within a single experiment that differ in crystal solvent content. Despite a small overall RMSD, a detailed analysis reveals coordinated domain-level rearrangements and shows that conformational flexibility is sensitive to crystal packing, a consideration of broad relevance for the study of protein dynamics using X-ray crystallography.

biochemistry↗

bioRxiv2026

PP2A-dependent internalisation of GABAB receptors in somatostatin interneurons regulates function and plasticity.

Cortical circuits rely on a precise balance of inhibitory and excitatory neurotransmission to encode information reliably and prevent pathology. Metabotropic GABAB receptors (GABABRs) are key regulators of inhibitory signalling in mammalian neurons. In GABAergic interneurons (INs), GABABR activation reduces inhibition overall, leading to disinhibitory mechanisms. In the hippocampus, somatostatin-expressing (SST) INs form a major subtype that provides feedback inhibition to the distal dendrites of principal cells (PCs) and other INs. Plasticity of SST INs is well established as a mechanism controlling hippocampal circuit function through both inhibitory and disinhibitory pathways and depends on metabotropic glutamate receptors (mGluRs) and GABABRs. However, whether activation of GABABRs induces metaplastic changes in SST INs, and how this influences circuit function and behaviour, remains unclear. Here, we combined quantitative SDS-digested freeze-fracture replica immunoelectron microscopy, ex vivo electrophysiology, in vivo behavioural testing, and pharmacological manipulation of GABABRs. We show that receptor activation directly regulates SST IN plasticity via protein phosphatase 2A (PP2A)-dependent internalisation. GABABR activation not only controls its own surface expression but also regulates membrane levels of mGluR1 and high-voltage-activated Cav1.2 (L-type) Ca2+ channels. This GABABR-dependent metaplasticity shifts circuit plasticity toward greater enhancement of long-range inputs to the CA1 region and disrupts contextual memory formation. These findings demonstrate that receptor-mediated surface dynamics in SST INs are critical for maintaining physiological neurotransmission and proper hippocampal microcircuit function.

neuroscience↗

bioRxiv2026

Time-frequency embedding with contrastive pre-training allows sub-second seizure detection

Rapid and accurate detection of electrographic seizures is critical for both clinical diagnosis and neuroscience research. Although seizure identification is commonly performed in the time domain, analysis in the time-frequency domain provides a more comprehensive representation of seizure characteristics. In this study, we present a 3D convolutional neural network (CNN) that incorporates a trainable continuous wavelet transform (CWT) layer, enabling adaptive time-frequency feature learning directly from raw EEG. To address common data challenges, we augment the 3D CNN for pre-training with contrastive learning, comparing contrastive predictive coding (CPC) against bidirectional contrastive learning (BiCL). On single-channel and multi-channel data, the standard 3D CNN outperformed both a 2D CNN with pre-computed CWT and a 1D CNN that processes raw signals, achieving >95% accuracy down to 0.5-second segments. Compared to the standard 3D CNN, the 3D CNN with BiCL pre-training showed superior performance in both low-data and class imbalance scenarios. Further experiments involving band-pass filtering and temporal shuffling revealed that classification is driven primarily by low-frequency patterns and statistical features rather than temporal dependencies. The proposed framework also maintained >90% accuracy with moderate noise and downsampling applied to inputs, as well as when cross-subject generalization was evaluated using held-out subjects. We show that a 3D CNN with a trainable CWT layer and BiCL pre-training enables accurate sub-second seizure detection and effectively mitigates data limitations common in clinical settings. This work demonstrates that time-frequency embedding within CNNs, augmented by self-supervised pre-training, offers a promising path toward architectures for sub-second seizure detection in the presence of practical limitations of real-world scenarios.

neuroscience↗

bioRxiv2025

Origin and evolution of acrocentric chromosomes in human and great apes

The short arms of human acrocentric chromosomes are characterized by nucleolar organizer regions essential for ribosome biogenesis, but their highly repetitive nature has hindered genomic analysis. Leveraging the recently completed genomes of all major ape lineages, we identified recurrent features of their acrocentrics, including enriched repeat classes, centromere repositioning by whole-arm inversion, interchromosomal sequence exchange, and birth-and-death evolution of multiple gene families. Together, these processes have enabled the repeated amplification and diversification of the FRG1 gene family over 25 million years of ape evolution, and, in gorilla, the formation and amplification of a novel IGSF3-GGT fusion gene under positive selection. Similar evolutionary events also explain the distribution of segmental duplications and heterochromatin in the modern human genome, predisposing it to karyotypic abnormalities such as Robertsonian translocations. Our findings highlight acrocentric chromosomes as key drivers of evolution in the great apes, with implications for speciation, adaptation, and clinical genomics.

genomics↗

bioRxiv2025

Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds

Hydrogen bonds (H-bonds) are central to biomolecular structure and dynamics. Although H-bonds are typically characterized by well-defined proton positions, proton delocalization can play a key role in facilitating enzyme catalysis and allostery in some systems. Experimentally locating protons is difficult, hampering the study of the proton mobility in H-bonds. We used neutron crystallography and large quantum mechanics/molecular mechanics-Born Oppenheimer molecular dynamics (QM/MM-BOMD) simulations of human DJ-1 and its bacterial homolog YajL to validate atomic resolution X-ray crystallographic bond length analysis, directly visualizing the shared deuteron in a low-barrier hydrogen bond (LBHB) between Glu14-Asp23 in YajL that is a conventional H-bond in DJ-1. In addition, X-ray bond length analysis of protiated and perdeuterated DJ-1 and YajL shows no significant effect of deuteron substitution on these carboxylic acid-carboxylate H-bonds but does reveal an effect at the active site glutamic acid. Residues in the vicinity of Glu14-Asp23 that might favor LBHB formation in YajL were interrogated by mutagenesis of homologous residues in DJ-1. X-ray bond length analysis and QM/MM-BOMD simulations demonstrate that a distal I21T DJ-1 substitution increases proton delocalization in the Glu-Asp H-bond. In addition, simulations show that the extent of proton mobility in the H-bond influences correlated dimer-spanning motions in YajL and DJ-1. In total, we show that mutations within extended H-bonding networks can modulate proton transfer barriers in carboxylic acid-carboxylate H-bonds, allowing proton delocalization to be engineered using combined bioinformatic, structural, and computational information.

biochemistry↗

bioRxiv2025

FMRP regulates adult human cortical excitability via cyclic-AMP signalling

Fragile X Syndrome (FXS) is a common inherited neurodevelopmental condition, resulting from loss of Fragile X Messenger Ribonuclear Protein (FMRP). Rodent models of FXS display cellular hyperexcitability, but it is not known to what extent this is the case in intact human neurons. Depleting FMRP in human brain slice cultures reveals cyclic-AMP-dependent cellular hyperexcitability which is corrected by phosphodiesterase 4D inhibition and may be independent of neurodevelopment.

neuroscience↗

bioRxiv2025

Reproducible autosomal gene expression changes with loss of typical X and Y complement across tumor types

Although there are known sex differences in cancer incidence, severity, and treatment, the sex chromosomes are typically excluded from genomic analyses because of the unique technical challenges associated with assessing their copy number, sequence variation, and expression. Here we assess sex chromosome complement in three widely-used human genomics datasets from normal (non-cancerous) tissues, primary tumors, and cancer cell lines and study the effects on genome-wide gene expression. Expected sex chromosome complements based on reported patient sex were observed in non-cancerous tissues, but about half of tumors and cancer cell lines showed loss of typical sex chromosome gene expression across tissue types with three categories: loss of chromosome Y (LOY), loss of chromosome X (LOX) and reactivation of the inactive X chromosome (XaXa). Genes consistently differentially expressed in tumors with loss of chromosome X, loss of chromosome Y, or loss of X chromosome inactivation are associated with the hallmarks of cancer and include both sex-linked and autosomal genes from nearly all chromosomes, druggable genes, and genes with molecular functions relevant to cancer signaling, such as kinase activity. Strikingly, tumors that are X0, including tumors from female patients that have lost an X chromosome and tumors from male patients that have lost a Y chromosome, cluster together by gene expression profile. Patients with tumors that have LOX or LOY had poorer survival outcomes compared to those with tumors that had maintained their sex chromosome complement. Further, LOX and LOY eliminates nearly all of the differential gene expression between tumors from different patient sexes, affecting sex chromosomal and autosomal gene expression. Going forward, considering patient sex as well as the entire genome, including assessment of the sex chromosome complement, will provide additional insights into personalized tumor etiology, progression, treatment, and patient outcome. TeaserLoss of typical sex chromosome complement is present in primary tumors and cancer cell lines across tissue types. We identify consistent autosomal gene expression changes across multiple cancers when the sex chromosome complement is altered, and show that loss of sex chromosomes reduces tumor gene expression differences between patient sexes. We show that loss of sex chromosomes is also associated with poorer patient survival.

cancer biology↗

bioRxiv2025

Comparative genomic insights into the action of suicide Thi4 thiazole synthases

Suicide thiazole synthases (Thi4) are mononuclear metal enzymes that form the thiazole moiety of thiamin from NAD+, glycine, and a sulfur atom that is stripped from an active-site cysteine residue, causing enzyme inactivation. Comparative genomic analysis indicates that prokaryotic Thi4 genes often cluster on the chromosomal regions encoding ThiS, ThiF, and other proteins that can produce, relay, or use persulfide or thiocarboxylate sulfur. This genomic evidence suggests that certain suicide Thi4s might use a persulfide or thiocarboxylate as sulfur donor instead of the active-site cysteine - i.e., that they can operate in a non-suicide mode - and that a metal cofactor reservoir supports Thi4 function. To explore these possibilities, we performed proof-of-concept experiments using Escherichia coli as a heterologous platform. A representative bacterial Thi4 that clustered with thiS and thiF complemented an E. coli {Delta}thiG (thiazole auxotroph) single mutant better than a {Delta}thiG {Delta}thiF {Delta}thiS triple mutant, consistent with predicted interactions with the host sulfide transfer chain. Collectively, this evidence indicates that suicide Thi4s may not necessarily operate suicidally and highlights genomic and structural clues that warrant deeper biochemical investigation.

biochemistry↗

bioRxiv2025

Genome Report: De novo genome assembly of the greater Bermuda land snail, Poecilozonites bermudensis (Mollusca:Gastropoda), confirms ancestral genome duplication

Poecilozonites bermudensis, the greater Bermuda land snail, is a critically endangered species and one of only two extant members in its genus. These snails are one of Bermudas few endemic animal clades and their rich fossil record was the basis for the punctuated equilibria model of speciation. Once thought extinct, recent conservation efforts have focused on the recovery of the species, yet no genomic information or other molecular sequences have been available to inform these initiatives. We present a high-quality, annotated genome for P. bermudensis generated using PacBio long read and Omni-C short read sequencing. The resulting assembly is approximately 1.36 Gb with a scaffold N50 of 44.t Mb and 31 chromosome-length scaffolds. Nearly 43 percent of the genome was identified as repeat content. This assembly will serve as a resource for the conservation and study of P. bermudensis, and its only close extant and also critically endangered relative, P. circumfirmatus. Additionally, this genome adds to the growing body of data needed for a more complete understanding of gastropod evolution and for evolutionary processes in general. Article summaryThis paper is aimed primarily at researchers studying genomic evolution and phylogenetics of mollusks, and secondarily researchers studying evolution and conservation of Bermuda land snails. It reports not only the first genome sequence for the Bermuda land snails, but the first sequence of any kind from the group and the first genome from the larger clade to which they belong. The paper presents a complete de novo genome annotation and first order analyses. The results support previous hypotheses that a genome duplication occurred at the base of land snails, and they facilitate future molecular work on Bermudian and other snails.

genomics↗

bioRxiv2025

Sex chromosome identification and genome curation, at scale, from a single individual with SCINKD

In most animal species, the sex determining pathway is typically initiated by the presence/absence of a primary genetic cue at a critical point during development. This primary genetic cue is often located on a single locus--referred to as sex chromosomes--and can be limited to females (in a ZZ/ZW system) or males (in an XX/XY system). One trademark of sex chromosomes is a restriction or cessation of recombination surrounding the sex-limited region (to prevent its inheritance in the homogametic sex). This may lead to--through a variety of mechanisms--higher amounts of genetic divergence within this region, i.e. between the X/Z and Y/W chromosomes, especially when compared to their autosomal counterparts. Recent advances in genome sequencing and computation have brought with them the ability to resolve haplotypes within a diploid individual, permitting assembly of previously challenging genomic regions like sex chromosomes. Leveraging these advances, we identified replicable diagnostic characteristics between typical autosomes and sex chromosomes (within a single genome assembly). Under this framework, we can use this information to identify putative sex chromosome linkage groups across divergent vertebrate taxa and simultaneously curate misassembled regions on autosomes. Here, we present this conceptual framework and associated tool for identifying candidate sex chromosome linkage groups from a single, diploid individual dubbed Sex Chromosome Identification by Negating Kmer Densities, or SCINKD.

genomics↗

bioRxiv2025

Best practices for improving alignment and variant calling on human sex chromosomes

Sex chromosome complement is the largest karyotypic variation observed in humans. X and Y chromosomes were once a pair of homologous autosomes. Although chromosome X and Y differentiated from one another, they still share high levels of sequence similarity in some regions, like the pseudoautosomal regions (PARs) and the X-transposed region (XTR). The sex chromosomes violate some assumptions of autosomal pairs, but are not always processed separately in genomics analyses. Here, we undertook a simulation study to assess the effects of standard autosomal versus sex chromosome complement-informed alignment, variant calling, and variant filtering strategies on variants detected on the human sex chromosomes. We find that aligning samples to a reference genome informed by the sex chromosome complement of the sample increases the number of true positives called in the PARs, and, in XX-samples only, also the XTR. In contrast, in XY-samples, masking the XTR during alignment results in a ten-fold higher rate of false positives. We further find that haploid calling on the sex chromosomes in XY-samples reduces the number of false positives compared to diploid calling, but does not decrease the number of false negatives. Improving the accuracy of variant calling results in detection of variants that could be relevant to studies of health and disease, including variants we recovered in genes implicated in cardiomyopathy, immunodeficiency, and Alzheirmers disease, among others. We recommend future genomic analyses implement the following best practices for detecting variants: aligning samples to versions of the human reference genome informed by the sex chromosome complement of the sample and using accurate ploidy parameters when calling variants.

genomics↗

bioRxiv2025

Harnessing Mass Spectrometry-Based Proteomics for Continuous Directed Evolution

Continuous directed evolution is a powerful Synthetic Biology tool to engineer proteins with desired functions in vivo. Mimicking natural evolution, it involves repeated cycles of high-frequency mutagenesis, selection, and replication within platform cells, where the function of the target gene is tightly linked to the host cells fitness. However, cells might escape the selection pressure due to the inherent flexibility of their metabolism, which allows for adaptation. Whole-proteome analysis as well as targeted proteomics offer valuable insights into global and specific cellular changes. They can identify modifications in the target protein and its interactors to help understand its evolution and network integration. Using the continuous evolution of the Arabidopsis methionine synthases AtMS1 and AtMS2 as an example, we demonstrate how mass spectrometry-based proteomics can be applied in CDE, propose specific checkpoints for its integration and illustrate its role in informed decision making.

synthetic biology↗

bioRxiv2024

A threshold level of JNK activates damage-responsive enhancers via JAK/STAT to promote tissue regeneration

Tissue regeneration requires precise activation and coordination of genes, many of which are reused from development. While key factors have been identified, how their expression is initiated and spatially regulated after injury remains unclear. The stress-activated MAP kinase JNK is a conserved driver of regeneration and promotes expression of genes involved in proliferation, growth, and cell fate changes in Drosophila. However, how JNK selectively activates its targets in damaged tissue is not well understood. We previously identified Damage-Responsive, Maturity-Silenced (DRMS) enhancers as JNK-activated elements critical for regeneration. Here, we show that cell death is dispensable for the activation of these enhancers, which only depends on JNK and its immediate downstream effectors. One of these is JAK/STAT, which acts as a direct, additional input necessary to expand enhancer activity into the wound periphery where JNK alone is insufficient. Furthermore, we demonstrate that a threshold level of JNK is required to initiate enhancer activation. Together, our findings reveal how JNK and JAK/STAT signaling cooperate to drive spatially and temporally regulated gene expression through damage-responsive enhancers, ensuring proper regenerative outcomes.

genetics↗

bioRxiv2024

Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH)

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by poor drug-like properties of lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher antimalarial potency than their parent compounds (1). However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH) is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a novel fluorogenic ester library, we characterize the structure activity relationship of APEH, and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a novel mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance (2-4). Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance. SignificanceRising antimalarial drug resistance threatens current gains in malaria control. New antimalarial drugs are urgently needed. Unfortunately, many drug candidates have poor drug-like properties, such as poor absorbability in the gastrointestinal tract, or poor accumulation at the site of action. This can be overcome by prodrugging, the addition of prodrug groups which mask poor drug features until they are removed by an activating enzyme. Here, we show that a red blood cell enzyme, acylpeptide hydrolase, is taken up by malaria parasites and serves as the activating enzyme for multiple lipophilic ester prodrugs. Our findings highlight a novel mechanism for prodrug activation, which could be leveraged to design novel prodrugs with high barriers to drug resistance.

microbiology↗

bioRxiv2024

Scaling and Merging Time-Resolved Laue Data with Variational Inference

Time-resolved X-ray crystallography (TR-X) at synchrotrons and free electron lasers is a promising technique for recording dynamics of molecules at atomic resolution. While experimental methods for TR-X have proliferated and matured, data analysis is often difficult. Extracting small, time-dependent changes in signal is frequently a bottleneck for practitioners. Recent work demonstrated this challenge can be addressed when merging redundant observations by a statistical technique known as variational inference (VI). However, the variational approach to time-resolved data analysis requires identification of successful hyperparameters in order to optimally extract signal. In this case study, we present a successful application of VI to time-resolved changes in an enzyme, DJ-1, upon mixing with a substrate molecule, methylglyoxal. We present a strategy to extract high signal-to-noise changes in electron density from these data. Furthermore, we conduct an ablation study, in which we systematically remove one hyperparameter at a time to demonstrate the impact of each hyperparameter choice on the success of our model. We expect this case study will serve as a practical example for how others may deploy VI in order to analyze their time-resolved diffraction data.

biophysics↗

bioRxiv2024

Resolving DJ-1 Glyoxalase Catalysis Using Mix-and-Inject Serial Crystallography at a Synchrotron

DJ-1 (PARK7) is an intensively studied protein whose cytoprotective activities are dysregulated in multiple diseases. DJ-1 has been reported as having two distinct enzymatic activities in defense against reactive carbonyl species that are difficult to distinguish in conventional biochemical experiments. Here, we establish the mechanism of DJ-1 using a synchrotron-compatible version of mix-and-inject-serial crystallography (MISC), which was previously performed only at XFELs, to directly observe DJ-1 catalysis. We designed and used new diffusive mixers to collect time-resolved Laue diffraction data of DJ-1 catalysis at a pink beam synchrotron beamline. Analysis of structurally similar methylglyoxal-derived intermediates formed through the DJ-1 catalytic cycle shows that the enzyme catalyzes nearly two turnovers in the crystal and defines key aspects of its glyoxalase mechanism. In addition, DJ-1 shows allosteric communication between a distal site at the dimer interface and the active site that changes during catalysis. Our results rule out the widely cited deglycase mechanism for DJ-1 action and provide an explanation for how DJ-1 produces L-lactate with high chiral purity.

biochemistry↗

bioRxiv2024

HCV- and HBV-mediated liver cancer converge on similar transcriptomic landscapes and immune profiles.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, and a large proportion of HCC is attributable to viral causes including hepatitis B (HBV) and C virus (HCV). The pathogenesis of viral-mediated HCC can differ between HBV and HCV, but it is unclear how much these differences influence the tumors final molecular and immune profiles. Additionally, there are known sex differences in the molecular etiology of HCC, but sex differences have not been explored in the context of viral-mediated HCC. To determine the extent to which the viral status and sex impact the molecular and immune profiles of HCC, we performed differential expression and immune cell deconvolution analyses. We identified a large number of differentially expressed genes unique to the HBV or HCV tumor:tumor-adjacent comparison. Pathway enrichment analyses demonstrated that the changes unique to the HCV tumor:tumor-adjacent tissue were predominated by changes in the immune pathways. Immune cell deconvolution demonstrated that HCV tumor-adjacent tissue had the largest immune cell infiltrate, with no difference in the immune profiles within HBV and HCV tumor samples. We subsequently segregated the differential expression analyses by sex, but demonstrated that the low number of female samples led to an overestimate of differentially expressed genes unique to male tumors. This limitation highlights the importance of additional sampling of female HCC tumors to allow for a more complete analysis of the sex differences in HCC. Overall, this work demonstrates the convergence of HBV- and HCV-mediated HCC on a similar transcriptomic landscape and immune profile despite differences in the surrounding tissue. Author SummaryHepatocellular carcinoma (HCC) is a significant worldwide health challenge. The majority of cases are attributable to infection with hepatitis B (HBV) or C (HCV). HBV and HCV differ in their methods of transmission and how they cause cancer. Despite these differences, most treatment guidelines are ambivalent to the underlying viral etiology of the tumor. In the age of personalized medicine, we sought to determine how similar or different HCC was when mediated by HBV or HCV. Additionally, since previous work has demonstrated biological differences in the tumors between males and females, we sought to characterize the sex differences within viral-mediated HCC. We found that, although there are several genes with differences in HBV- and HCV-mediated tumors, the tumors appear to be more biologically similar than the corresponding tumor-adjacent tissue. This suggests a convergence on common pathways toward cancers even when the starting point differs. The lower number of female samples inhibits a full understanding of the biological differences between HCC in males and females. This presents a critical need in the field to increase the sampling of female cancers to enable a full understanding of the sex differences in HCC.

genetics↗

bioRxiv2024

Phylogenetic divergence of GABAB receptor signalling in neocortical networks over adult life.

Cortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. Much is known about fast GABA currents, GABAB receptor (GABABR) signalling exerts powerful slow inhibition that controls synaptic, dendritic and neuronal activity. However, little is known about how GABABRs contribute to circuit-level inhibition over the lifespan of rodents and humans. In this study, we quantitatively determine the functional contribution of GABABR signalling to pre- and postsynaptic domains in rat and human cortical principal cells (PC). We find that postsynaptic GABABR differentially control pyramidal cell activity within the cortical column as a function of age and species, and that these receptors contribute to co-ordination of local information processing in a layer- and species-dependent manner. These data directly increase our knowledge of translationally relevant local circuit dynamics, with direct impact on understanding the role of GABABRs in the treatment of seizure disorders. HighlightsO_LIGABAB receptor signalling displays age and species differences in cortex C_LIO_LIGABAB receptor presynaptic inhibition is stronger in humans than rodents C_LIO_LIIn vitro oscillations in human cortex are strongly regulated by GABABRs C_LIO_LILevetiracetam enhances endogenous GABABR signalling in human cortex C_LI

neuroscience↗