Biology subjects

Seguela, P.

Publications and source records attributed to Seguela, P..

6 recordsLinked to original sources

bioRxiv2025

Transient Early Postnatal Neuronal Hyperexcitation Results in Lasting Social Preference Deficits

Perturbations during critical periods of neurodevelopment are implicated in the etiology of autism spectrum disorder (ASD), a condition marked by considerable heterogeneity and prevalent comorbidities. One such comorbidity is epilepsy, with approximately 30% of children with ASD experiencing seizures and a similar proportion of children with epilepsy displaying ASD-like symptoms. Both conditions have been associated with disruptions in the brains excitation-to-inhibition (E/I) balance. Although early-life seizures in rodents have been linked to social impairments, direct causal evidence connecting E/I imbalance, interneuron development, and social behavior remains limited. To address this gap, we induced transient, brain-wide hyperexcitation in neonatal mice using pentylenetetrazol (PTZ), a GABA_A receptor antagonist. We administered both convulsive and subconvulsive doses and assessed long-term effects on social behavior, cortical E/I balance, and parvalbumin (PV) interneuron development. PTZ-treated groups displayed impaired social preference as measured in the 3-chamber test and increased PV interneuron density within the medial prefrontal cortex. These findings highlight a critical developmental window during which E/I imbalance leads to social deficits characteristic of ASD and epilepsy. They also reveal dose-dependent neurobiological changes, underscoring the importance of early-life neural activity in shaping social circuitry.

neuroscience↗

bioRxiv2025

Cerebrospinal fluid-driven ependymal motile cilia defects are implicated in multiple sclerosis pathophysiology

BackgroundMultiple sclerosis is a neurodegenerative autoimmune disorder of the central nervous system (CNS) in which autoreactive immune cells migrate through a damaged blood brain barrier, resulting in focal demyelinating lesions of both the white and grey matter. Of increasing interest is the repeated observation that beyond focal lesions, there are also diffuse, surface-in gradients of pathology in MS, wherein damage is most severe directly adjacent to cerebrospinal fluid (CSF)-contacting surfaces, such as the subpial and periventricular areas. This observation suggests that toxic factors within MS CSF may be contributing to the emergence and/or evolution of surface-in gradients. Directly separating the CSF from the periventricular parenchyma are ependymal cells - a glial epithelium that are equipped with tufts of motile cilia which are critical for circulating CSF solutes and regulating local fluid flow. While damage to ependymal cilia has the potential to drastically modify CSF homeostasis and thus contribute to the damage of CSF exposed regions, these motile cellular structures have yet to be investigated in the context of MS. MethodsWe first conducted single cell RNA sequencing of fresh human periventricular brain tissue containing ependymal cells from MS patients and non-MS disease controls. We subsequently collected CSF from MS patients and exposed cultured rodent ependymal cells to this CSF in order to evaluate impact on ependymal ciliary function. To complement our direct evaluation of cilia in the context of MS, we also confirmed whether cilia were altered in a classic animal model of MS, experimental autoimmune encephalomyelitis (EAE), and also designed a novel transgenic animal model to evaluate the cellular and behavioural effect(s) of adult ependymal ciliary disruption. ResultsSingle cell RNA sequencing analysis of human ependymal cells in MS demonstrated largescale dysregulation of ciliary genes and in situ stains of MS brain tissue confirmed a loss of ependymal cilia. Exposure of ependymal cells to MS CSF led to transcriptional modification of ciliary gene and protein expression and reduced ciliary beating frequency. Likewise, analysis of ependymal cells in EAE also demonstrated altered cilia gene and protein expression. Conditional knockout in adult mice, of the critical cilia-associated gene Ccdc39 in ependymal cells led to transient ventricular enlargement, increased periventricular microglial density, and alterations in nesting behaviour. ConclusionThese data suggest that motile cilia in ependymal cells are dysregulated in CNS autoimmunity. More importantly, however, they provide evidence to suggest that ependymal cilia disruption could play an active role in the development of periventricular pathology in MS and can lead to behavioural deficits that may underlie aspects non-motor MS symptomatology.

neuroscience↗

bioRxiv2023

Gut microbiota promotes pain in fibromyalgia

Fibromyalgia is a chronic syndrome characterized by widespread pain in the absence of evident tissue injury or pathology, making it one of the most mysterious chronic pain conditions. Despite affecting 2-4% of the population, primarily women1, the cause and underlying mechanisms of fibromyalgia remain elusive, and effective targeted treatments are currently unavailable. The gut microbiota of women with fibromyalgia differs from healthy controls2,3. However, it is unknown whether changes in gut microbiota have a causal role in mediating pain and other symptoms of fibromyalgia. Here, we show that fecal microbiota transplantation (FMT) from individuals with fibromyalgia, but not from healthy controls, into germ-free mice induces persistent pain hypersensitivity. FMT from fibromyalgia patients led to a reduction in intraepidermal nerve fiber density and alterations in the peripheral immune profile, and induced activation of spinal microglia, which contributed to the development of pain in mice. Notably, the pain hypersensitivity in mice that were administered microbiota from fibromyalgia patients resolved after FMT from healthy controls. Consistent with these findings, an open-label pilot study showed that transplanting microbiota from healthy individuals to humans with fibromyalgia alleviated pain and reduced overall symptom severity. Thus, altered gut microbiota has a causal role in fibromyalgia pain, highlighting it as a promising target for therapeutic interventions.

neuroscience↗

bioRxiv2020

Neuropathic Pain Linked to Defective Dopaminergic Inhibition in Anterior Cingulate Cortex

Pyramidal neurons in the anterior cingulate cortex (ACC), a prefrontal region involved in processing the affective components of pain, display hyperexcitability in chronic neuropathic conditions and their silencing abolishes hyperalgesia in rodents. We show here that dopamine, through D1-like receptor signaling, inhibits layer 2/3 pyramidal neurons of mouse ACC. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control the firing activity of these pyramidal neurons. Through Gs-coupled D1-like receptors, dopamine induces the opening of HCN channels at physiological membrane potentials, driving a significant decrease in input resistance and excitability. Systemic L-DOPA rescues HCN channel activity, pyramidal excitability in ACC as well as sensory phenotype in neuropathic mice while microinjection of a selective D1-like agonist in ACC induces relief of ongoing pain in neuropathic animals. We conclude that decreased dopaminergic inhibition in ACC plays a critical role in an abnormal top-down modulation leading to neuropathic pain.

neuroscience↗

bioRxiv2019

Pre- and post-synaptic roles for DCC in memory consolidation in the adult mouse hippocampus.

The receptor deleted in colorectal cancer (DCC) and its ligand netrin-1 are essential for axon guidance during development and are expressed by neurons in the mature brain. Netrin-1 recruits GluA1-containing -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and is critical for long-term potentiation (LTP) at CA3-CA1 hippocampal Schaffer collateral synapses, while conditional DCC deletion from glutamatergic neurons impairs hippocampal-dependent spatial memory and severely disrupts LTP induction. DCC co-fractionates with the detergent-resistant component of the postsynaptic density, yet is enriched in axonal growth cones that differentiate into presynaptic terminals during development. Specific presynaptic and postsynaptic contributions of DCC to the function of mature neural circuits have yet to be identified. Employing hippocampal subregion-specific conditional deletion of DCC, we show that DCC loss from CA1 hippocampal pyramidal neurons results in deficits in spatial memory, increased resting membrane potential, abnormal dendritic spine morphology, and weaker spontaneous excitatory postsynaptic activity. In contrast, deletion of DCC from CA3 neurons did not induce detectable changes in spine morphology or intrinsic electrophysiological properties of CA1 pyramidal neurons, but resulted in impaired performance on the novel object place recognition task as well as compromised excitatory synaptic transmission and long-term potentiation (LTP) at the Schaffer collateral synapse. Together, these findings reveal that DCC makes specific pre- and post-synaptic contributions to hippocampal synaptic plasticity underlying spatial memory.

neuroscience↗

bioRxiv2018

Activity-dependent netrin-1 secretion drives synaptic insertion of GluA1-containing AMPA receptors in the hippocampus.

Dynamic trafficking of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) to synapses is critical for activity-dependent synaptic plasticity underlying learning and memory, however the identity of key molecular effectors remains elusive. Here, we demonstrate that membrane depolarization and N-methyl-D-aspartate receptor (NMDAR) activation triggers secretion of the chemotropic guidance cue netrin-1 from dendrites. Using selective genetic deletion, we show that netrin-1 expression by excitatory neurons is required for NMDAR-dependent long-term potentiation (LTP) in the adult hippocampus. Further, we demonstrate that application of exogenous netrin-1 is sufficient to trigger the potentiation of excitatory glutamatergic transmission at hippocampal Schaffer collateral synapses via Ca2+-dependent recruitment of GluA1-containing AMPARs, promoting the maturation of immature or nascent synapses. These findings identify a central role for activity-dependent release of netrin-1 as a critical effector of synaptic plasticity in the adult hippocampus.

neuroscience↗