Biology subjects

Figiel, I.

Publications and source records attributed to Figiel, I..

6 recordsLinked to original sources

bioRxiv2026

Primate Astrocyte Evolution Controls the Tempo of Neuronal Development

Prolonged neuronal maturation, also referred to as neoteny, constitutes a hallmark of human brain evolution. Yet, the mechanisms controlling neotenic brain development remain poorly understood, and have been defined as neuron-intrinsic. Astrocytes shape synapse formation, activity, and elimination, and have changed substantially between humans and other species. Yet, whether the evolutionary divergence in astrocytes shapes the timing of neuronal maturation is unknown. Here, we show that astrocytes from humans and their closest living relatives, chimpanzees, exert contrasting effects on neuronal maturation: chimpanzee astrocytes accelerate it, whereas human astrocytes delay it, without affecting neuronal survival. Through comparative transcriptomics and epigenomics, we find that evolutionarily reduced APOE expression in human astrocytes underlies the observed delay in neuronal maturation: restoring APOE levels in human astrocytes accelerates neuronal development. We further establish that the Hippo-TEAD signaling represses APOE expression in human astrocytes, revealing a link between the enhanced morphological complexity of human astrocytes and the observed reduced tempo of neuronal development in their presence. Strikingly, neuronal genes differentially impacted by human and chimpanzee astrocytes are associated with schizophrenia, Alzheimers disease, and epilepsy, linking astrocyte evolution to disease vulnerability. Altogether, these findings establish that brain neoteny is partly a glial phenomenon, revealing that understanding the pace of human brain development requires understanding how astrocytes, not only neurons, have evolved.

neuroscience↗

bioRxiv2025

Temporal and protein-specific S-palmitoylation supports synaptic and neural network plasticity

S-palmitoylation, a dynamic post-translational modification, has long been suggested to play a pivotal role in synaptic plasticity, learning, and memory. However, its precise impact on synaptic proteins and function remains unclear. In this study, we show that acute protein depalmitoylation in the hippocampus differentially affects short- and long-term synaptic plasticity, depending on synapse type. Strikingly, depalmitoylation also reprograms neuronal spiking timing following associative network activation. Our research identifies pre- and postsynaptic proteins dynamically regulated by S-palmitoylation during synaptic plasticity and suggests this modification occurs in isolated excitatory synapses. We also demonstrate that S-palmitoylation targets specific proteins within minutes and is not proteome-wide. These findings mark a significant advance in understanding how lipid modifications drive neural adaptability, memory, and learning.

neuroscience↗

bioRxiv2023

Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to the human brain evolution

Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, the molecular signature of foetal astrocyte evolution in primates is unknown. Here, to address this question, we use human, chimpanzee, and macaque induced pluripotent stem cell-derived foetal astrocytes (iAstrocytes). Human iAstrocytes are bigger and more complex than the non-human primate iAstrocytes. We find loci related to the regulation of cell size with increased expression in the human lineage. Likewise, we uncover that genes and mechanisms implicated in long-range intercellular signalling are activated in the human iAstrocytes. Strikingly, loci downregulated in the human lineage frequently relate to intellectual disability raising new questions on the trade-offs associated with the evolution of the human mind. Using our system, through a multilevel regulome analysis and machine learning, we uncover that functional activation of enhancers coincides with a previously unappreciated, pervasive gain of binding sites of stripe transcription factors. In summary, we shed new light on a mechanism driving the acquisition of the regulatory potential of enhancers.

neuroscience↗

bioRxiv2022

The molecular fingerprint of stress resilience

Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we here investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods. Our results indicate that stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. We reveal that chronic stress influences palmitoylation of synaptic proteins, whose profiles differ between resilient and anhedonic animals. The changes in palmitoylation are predominantly related with the glutamate receptor signaling thus affects synaptic transmission and associated structures of dendritic spines. We show that stress resilience is associated with structural compensatory plasticity of the postsynaptic parts of synapses in CA1 subfield of the hippocampus. One Sentence SummaryCompensatory remodeling of dendritic spines at the structural and molecular levels underlies stress resilience.

neuroscience↗

bioRxiv2021

Plasmin-mediated cleavage of EphA4 at central amygdala inhibitory synapses controls anxiety

Severe stress can trigger complex behavioural changes such as high anxiety (1). Inhibitory GABA-ergic interneurons in the lateral division of the central amygdala (CEl) control anxiety through feedforward inhibition of their target cells in the medial division (CEm) (2, 3). In particular, PKC{delta}-positive (PKC{delta}+) interneurons in CEl are critical elements of the neuronal circuitry of fear and anxiety (3-5), but the molecular mechanisms they employ are poorly understood. Here, we show that, during stress, GABA-ergic synapses of amygdala PKC{delta}+ interneurons are regulated by a serine protease plasmin. On stress, plasmin cleaves the extracellular portion of the tyrosine kinase receptor EphA4 triggering its dissociation from gephyrin, a postsynaptic GABA-receptor anchoring protein. Dynamic EphA4/gephyrin interaction leads to modification of dendritic spine morphology and synaptic GABA-receptor expression profile. Consistent with the critical role for the plasmin/EphA4/gephyrin signalling axis in anxiogenesis, viral delivery of plasmin-resistant (prEphA4) form of EphA4 into the central amygdala prevents the development of stress-induced anxiety in mice, while the delivery of plasmin-truncated EphA4 (tEphA4) dramatically enhances this effect. Thus, our studies identify a novel, critical molecular cascade regulating GABA-ergic signalling in the central amygdala synapses that allows bidirectional switching of animal behaviour from high to low anxiety states.

neuroscience↗

bioRxiv2018

Stress-induced changes in the S-palmitoylation and S-nitrosylation of synaptic proteins

The precise regulation of synaptic integrity is critical for neuronal network connectivity and proper brain function. Essential aspects of the activity and localization of synaptic proteins are regulated by posttranslational modifications. S-palmitoylation is a reversible covalent modification of the cysteine with palmitate. It modulates affinity of the protein for cell membranes and membranous compartments. Intracellular palmitoylation dynamics are regulated by other posttranslational modifications, such as S-nitrosylation. Still unclear, however, are the ways in which this crosstalk is affected in brain pathology, such as stress-related disorders. Using a newly developed mass spectrometry-based approach (Palmitoylation And Nitrosylation Interplay Monitoring), we analyzed the endogenous S-palmitoylation and S-nitrosylation of postsynaptic density proteins at the level of specific single cysteines in a mouse model of chronic stress. Our results suggest that atypical mechanism of crosstalk between the S-palmitoylation and S-nitrosylation of synaptic proteins might be one of the major events associated with chronic stress disorders.

neuroscience↗