Biology subjects

Bayes, A.

Publications and source records attributed to Bayes, A..

7 recordsLinked to original sources

bioRxiv2026

NREM Oscillations Mediate Synaptic Proteome Remodelling to Support Synapse Stabilisation

Synapses are known to remodel their proteome during sleep. However, the exact mechanisms driving this remodelling and its impact on synaptic function or cognition are not well understood. We combine 24-hour EEG recordings with time-resolved synaptic proteomics in a model of SYNGAP1-Related Disorders to reveal a mechanism by which slow-waves and spindles, two NREM sleep oscillations, mediate the remodelling of the synaptic proteome. Moreover, we uncover that this remodelling promotes synaptic stabilization, which could support sleep-dependent memory consolidation. In contrast, the increase of slow-waves and decrease of spindles found in Syngap1+/- mice would activate molecular pathways involved in synaptic weakening instead of stabilization. This is consistent with the proposed roles of slow-waves and spindles in synaptic downscaling and potentiation, respectively. Here, we provide evidence on how NREM oscillations regulate the synaptic proteome and reveal a pathological mechanism that could be of relevance to all neurodevelopmental disorders coursing with sleep disturbances.

neuroscience↗

bioRxiv2025

SynaptopathyDB: a resource for studying the genetic and synaptic basis of nervous system disorders

Synaptic dysfunction resulting from pathogenic variants in genes encoding synaptic proteins is a major contributor to brain and behavioural disorders, collectively termed synaptopathies. To facilitate research into the genetic basis and clinical manifestations of synaptopathy we have created SynaptopathyDB, an online resource that integrates data from 64 mammalian synapse proteomic studies and multiple genetic and phenotypic resources. We identified a consensus set of 3,437 mammalian synapse proteins from presynaptic and postsynaptic compartments, which have wide application in genetic and omic studies. Mutations in 954 genes encoding 28% of the consensus synapse proteome were associated with 1,266 OMIM diseases of the central and peripheral nervous system. We present findings that underscore the pervasive role of synaptic gene variants in the phenotypes of neurological, psychiatric, developmental, and systemic disorders highlighting the significant burden they impose on individuals and healthcare systems. SynaptopathyDB is a versatile platform and discovery tool for understanding the role of synapse proteins and genetic variants in human disease phenotypes.

neuroscience↗

bioRxiv2024

Synaptic proteome diversity is primarily driven by gene regulation of glutamate receptors and their regulatory proteins

Synapses formed by equivalent pairs of pre- and postsynaptic neurons have similar electrophysiological characteristics, belonging to the same type. However, these are generally confined to microscopic brain regions, precluding their proteomic analysis. This fact has greatly limited our ability to investigate the molecular basis of synaptic physiology. We introduce a procedure to characterise the synaptic proteome of microscopic brain regions and explore the molecular diversity among the synapses forming the trisynaptic circuit in the hippocampus. While we observe a remarkable proteomic diversity among these synapses, we also report that proteins involved in the regulation of the function of glutamate receptors are differentially expressed in all of them. Moreover, neuron-specific gene expression programs would contribute to their regulation. Here, we introduce a combined proteomics and transcriptomics analysis uncovering a previously unrecognised neuron-specific control of synaptic proteome diversity, directed towards the regulation of glutamate receptors and their regulatory proteins.

neuroscience↗

bioRxiv2021

Endogenous Syngap1 Alpha Splice Forms Promote Cognitive Function and Seizure Protection

Loss-of-function variants in SYNAGP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of 1/2 expression improved learning and increased seizure latency. Mice expressing 1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with 1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP- expression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.

neuroscience↗

bioRxiv2021

Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis

Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type specific vulnerability, their progression and histopathological classification remain controversial. Here using single-cell electrophysiology in vivo and immediate early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rats and mice in vivo. Bulk tissue and single-nucleus expression profiling disclosed sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage-channels, synaptic signalling and cell adhesion molecules were deregulated by epilepsy differently across sublayers, while neurodegenerative signatures primarily involved superficial cells. Pseudotime analysis of gene expression in single-nuclei and in situ validation revealed separated trajectories from health to epilepsy across cell types, and identified a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate sublayer- and cell type-specific changes associated with selective CA1 neuronal damage contributing to progression of hippocampal sclerosis.

neuroscience↗

bioRxiv2020

Splicing of the SynGAP Carboxyl-Terminus Enables Isoform-Specific Tuning of NMDA Receptor Signaling Linked to Cognitive Function

SynGAP-1 is a splice variant of the neurodevelopmental disorder risk gene, SYNGAP1/Syngap1. 1 encodes the C-terminal PDZ binding motif (PBM) that promotes liquid-liquid phase separation, a candidate process for postsynaptic density organization within excitatory synapses. However, it remains unknown how the endogenous SynGAP PBM regulates synapse properties and related cognitive functions. We found that a major PBM function in mice is to limit the mobility of SynGAP-1 in response to NMDA receptor activation. Genetic disruption of the PBM increased SynGAP-1 mobility to levels consistent with other non-PBM-containing C-terminal isoforms. This resulted in a lowering of the threshold for NMDA receptor-dependent signaling required for plasticity, leading to aberrant strengthening of excitatory synapses in spontaneously active neurons. PBM-deficient animals also exhibited a lower seizure threshold, disrupted LTP, and impaired cognition. Thus, the PBM enables isoform-specific SynGAP gating of NMDA receptor function, a mechanism linking synaptic signaling dynamics to network excitability and cognition.

neuroscience↗

bioRxiv2019

Syngap Splice Variants Display Heterogeneous Spatio-Temporal Expression And Subcellular Distribution In The Developing Mammalian Brain

The Syngap1 gene is a major regulator of synapse biology and neural circuit function. Genetic variants linked to epilepsy and intellectual disability disrupt synaptic function and neural excitability. The SynGAP protein has been involved in multiple signaling pathways and can regulate small GTPases with very different functions. Yet, the molecular bases behind this pleiotropy are poorly understood. We hypothesize that different SynGAP isoforms will mediate different sets of functions and that deciphering their spatio-temporal expression and subcellular localization will accelerate our understanding of the multiple functions performed by SynGAP. Using antibodies that detect all isoforms of SynGAP, we found that its subcellular localization changed throughout postnatal development. Consistent with previous reports, SynGAP was enriched in the postsynaptic density in the mature forebrain. However, this was age-dependent and SynGAP was predominantly found in non-synaptic locations in a period of postnatal development highly sensitive to SynGAP levels. Furthermore, we identified different expression patterns in the spatial and temporal axes for different SynGAP isoforms. Particularly noticeable was the delayed expression of SynGAP 1 isoforms, which bind to PSD-95 at the postsynaptic density, in cortex and hippocampus during the first two weeks of postnatal development. The subcellular localization of SynGAP was also isoform-dependent. While, 1 isoforms were highly enriched in the postsynaptic density, other C-terminal isoforms were less enriched or even more abundant in non-synaptic locations, particularly during the postnatal period. Thus, the regulation of expression and subcellular distribution of SynGAP isoforms may contribute to isoform-specific regulation of small GTPases, explaining SynGAP pleiotropy.

neuroscience↗