Biology subjects

Mantegazza, M.

Publications and source records attributed to Mantegazza, M..

10 recordsLinked to original sources

bioRxiv2026

An astro-neural-field model with application to cortical spreading depolarization

We present a novel astro-neural-field population model with application to migraine-related cortical spreading depolarization. The model is composed of four spatio-temporal state variables: excitatory and inhibitory membrane potentials, astrocytic potassium uptake recruitment, and extracellular potassium concentration. Extending a previous neural field model, we incorporate activity-dependent astrocytic potassium clearance via a nonlinear term coupled to astrocyte dynamics. The astrocyte transfer function, like its neural counterpart, exhibits three regimes governed by extracellular potassium, capturing its effect on clearance. This yields a more comprehensive framework, better fits experimental data, and provides new insights into the mechanisms of cortical spreading depolarization.

neuroscience↗

bioRxiv2026

Non-syndromic autism-associated SCN2A variants selectively exert dominant-negative effects on NaV1.2 channels.

The voltage-gated Na+ channel Nav1.2 has a key role for the initiation and propagation of action potentials and therefore in neuronal excitability in brain development and function. Genetic variants of the encoding gene SCN2A cause various neurodevelopmental phenotypes with infantile-childhood onset. Here, we investigated the functional impact on hNav1.2 function of 15 variants associated with pure non-syndromic ASD (nsASD), ASD with epileptic activity, developmental and epileptic encephalopathy or schizophrenia. Only nsASD variants caused a complete loss of function hNav1.2 channels when expressed alone in tsA-201 cells and cultured neocortical neurons. Co-expression of the WT and mutant channels mimicking heterozygosis revealed that ASD mutants induce a dominant negative effect. Using different strategies to impair the domains of the channels that have been suggested to be implicated in the interaction of two Nav subunits, we reversed the dominant negative effect of ASD mutants on WT channels. These findings identify in heterologous systems a mechanistically distinct class of SCN2A variants implicated in nsASD, defined by dominant-negative loss of Nav1.2 function, with potential utility as a biomarker for genetic counseling, patient stratification, and the development of precision therapeutic strategies.

neuroscience↗

bioRxiv2026

Long-lasting astrocyte remodeling in Dravet Syndrome Scn1a+/- mouse model.

BackgroundDravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by SCN1A gene mutations leading to NaV1.1 loss of function. The latter causes early-onset drug-resistant seizures and enduring cognitive and behavioral deficits. In this pathological context, the implication of astrocytes remains insufficiently explored. MethodsUsing a heterozygous Scn1a knock-out (Scn1a/-) mouse model that recapitulates the DS-human phenotype, we examine astrocyte remodeling at landmark disease stages, as defined by video-EEG and behavioral read-outs. ResultsFrom initial disease aggravation (PN20-35) to long-term stabilization (up to PN90), Scn1a/- mice showed increased hippocampal and cortical GFAP transcript and protein levels, compared to age-matched control littermates and to an earlier presymptomatic (<PN20) time point. During the aggravation phase in Scn1a/- mice, astrocyte branching, revealed by GFAP histological analysis and by intracellular delivery of Alexa Fluor 488 in hippocampal slices was increased but not sustained long-term. These disease-stage-dependent astrocyte modifications were not associated with macroscopic hippocampal sclerosis or cortical atrophy. To further study astrocyte remodeling during disease progression, we used biocytin diffusion following single-astrocyte loading to reveal an expanded astrocyte-astrocyte network in Scn1a/- mice long-term, along with increased Cx30 and Cx43 protein levels. An ethidium bromide uptake assay indicated impaired astrocytic hemichannel function in Scn1a/- mice long-term. Regionally, these long-term cellular and network astrocyte modifications coincided with augmented post-tetanic synaptic potentiation. DiscussionIn DS, astrocytes undergo a long-lasting network remodeling. We discuss how this astrocyte remodeling may be related to seizures as well as synaptic and cognitive deficits.

neuroscience↗

bioRxiv2024

GABAergic neurons can facilitate the propagation of cortical spreading depolarization: experiments in mouse neocortical slices and a novel neural field computational model

Cortical spreading depolarization (CSD) is a wave of depolarization with local onset and extended propagation implicated in several pathological conditions. Its mechanisms have been extensively investigated, including our recent studies showing with experimental and computational approaches that the hyperactivity of GABAergic neurons can initiate migraine-related CSD because of spiking-generated extracellular potassium (K+) build-up. However, less is known about the role played by GABAergic neurons in CSD propagation. Here we studied mechanisms of CSD propagation, focusing on the role of GABAergic neurons, with experiments performed in mouse brain slices and with a new spatially extended neural field computational model. Experimentally, we induced CSD by applying brief puffs of potassium chloride (KCl) in somatosensory cortex slices from wild type and VGAT-ChR2-tdtomato mice, which specifically express the excitatory opsin channelrhodopsin (ChR2) in GABAergic neurons. We evaluated the role of GABAergic neurons in CSD propagation by modulating their activity with optogenetic illumination and their synaptic connections with pharmacological tools. We have developed the computational model to obtain realistic simulations of both initiation and propagation of CSD. It includes large populations of interconnected excitatory and inhibitory neurons, as well as the effect of extracellular ion concentrations on their features. We found that the decrease of the synaptic activity of GABAergic neurons can enhance CSD propagation, because of the reduction of the inhibitory synaptic weight, whereas their spiking activity can enhance CSD propagation because of extracellular K+ upload. However, differently than for CSD initiation, the latter effect is normally hidden by the action of GABAergic synaptic transmission. A reduction of GABAergic synaptic transmission, which can be observed in pathological states, can reveal the potentiating effect of the K+ upload induced by GABAergic activation. The neural field model that we implemented can generate accurate simulations of CSD, providing testable hypotheses on mechanisms, and can also be used for modeling other (patho)-physiological activities of neuronal networks.

neuroscience↗

bioRxiv2024

Neurodevelopmental defects in Dravet syndrome Scn1a+/- mice: selective rescue of behavioral alterations but not seizures by targeting GABA-switch.

Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the SCN1A gene (NaV1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression, as well as the role of the mutation in inducing early neurodevelopmental defects before symptoms onset, are not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) was reported in models of DS, but its effects on the phenotype have not been investigated. Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21 Scn1a+/- DS mouse model. Bumetanide also improves spatial working memory defects. Importantly, neither KU nor bumetanide have effect on seizures or mortality rate. Also, we disclose early behavioral defects and delayed neurodevelopmental milestones well before seizure onset, at the beginning of NaV1.1 expression. We thus reveal that neurodevelopmental components in DS, in particular GABA switch, selectively underlie some cognitive/behavioral defects, but not seizures. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies.

neuroscience↗

bioRxiv2023

Gender-specific behavioral features of juvenile and adult haploinsufficient Scn2a+/- female mice, model of Autism Spectrum Disorder

Variants of the SCN2A gene, encoding the NaV1.2 sodium channel, cause a spectrum of neurodevelopmental and epileptic disorders, and are among those that show the strongest association with Autism Spectrum Disorder (ASD). ASD has a male-bias prevalence, but several studies have proposed that female prevalence may be underestimated due to different symptomatic expression compared with males. However, it is unclear whether this is related to actual different pathological features or to greater masking abilities in females. Studies on Scn2a+/- mice, a model of SCN2A haploinsufficiency and ASD, have shown an age-dependent ASD-like phenotype attenuated at adulthood in males. However, little is known about the behavioral features of Scn2a+/- female mice. We performed a battery of behavioral tests that are relevant for assessing ASD-like features, investigating juvenile and adult Scn2a+/- female mice. Our results demonstrate that female Scn2a+/- mice exhibit an overall milder phenotype than males, showing increased sociability and increased risk taking in juveniles, hyper-reactivity to cold stimuli in adults, altered decision-making related behaviors in both. Thus, this is consistent with the male-bias prevalence of ASD and the existence of different ASD phenotypic features in males and females. Both genders should be investigated in studies of mouse models of ASD.

neuroscience↗

bioRxiv2023

Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to Low-Voltage-Fast onset seizures in Dravet syndrome.

Epilepsies have numerous specific mechanisms. Understanding neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing targeted therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials and hippocampal single-unit neuronal activities in Scn1a+/- knock-out and Scn1aRH/+ knock-in DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal period) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients EEG, which are consistent with the dysfunctions that we observed in single neurons. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Spectral features may be used as predictive seizure biomarker. Significance statementDravet syndrome (DS) is caused by mutations of the NaV1.1 sodium channel (SCN1A gene) leading to hypoexcitability of GABAergic interneurons. We found that most of the seizures in both DS patients and mouse models have low-voltage-fast onset, which is instead thought to be generated by hyperactivity of GABAergic neurons. We disclosed a disorganization in the temporal pattern of the firing of single interneurons before the seizure (preictal period), and a rebound hyperactivity at seizure onset. Consistently, the electrographic signal showed a decrease of fast oscillations in the preictal period. Thus, perturbed interneurons preictal activity, consistent with the main mechanism of DS, leads to their hyperactivity at seizure onset and induces specific electrographic signatures that may be exploited for seizure prediction.

neuroscience↗

bioRxiv2021

Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eEF2K

Dravet Syndrome is a severe childhood pharmacoresistant epileptic disorder caused mainly by mutations in the SCN1A gene, which encodes for the 1 subunit of the type I voltage-gated sodium channel (NaV1.1), that cause imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhanced GABAergic transmission and tonic inhibition and were less susceptible to epileptic seizures. In Scn1a+/- mice, a mouse model of the Dravet syndrome, we found that the activity of eEF2K/eEF2 pathway was enhanced. Then, we demonstrated that both genetic deletion and pharmacological inhibition of eEF2K were able to reduce the epileptic phenotype of Scn1a+/- mice. Interestingly we also found that motor coordination defect, memory impairments, and stereotyped behavior of the Scn1a+/- mice were reverted by eEF2K deletion. The analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) suggested that the rescue of the pathological phenotype was driven by the potentiation of GABAergic synapses. Our data indicate that pharmacological inhibition of eEF2K could represent a novel therapeutic intervention for treating epilepsy and related comorbidities in the Dravet syndrome.

neuroscience↗

bioRxiv2020

GABAergic neurons and Nav1.1 channel hyperactivity: a novel neocortex-specific mechanism of cortical spreading depression.

Cortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel neocortex-specific mechanism of CSD initiation and a novel pathological role of GABAergic neurons. Mutations of the NaV1.1 sodium channel (the SCN1A gene), which is particularly important for GABAergic neurons excitability, cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura. They induce gain-of-function of NaV1.1 and hyperexcitability of GABAergic interneurons in culture. However, the mechanism linking these dysfunctions to CSD and FHM3 has not been elucidated. Here, we show that NaV1.1 gain-of-function, induced by the specific activator Hm1a, or mimicked by optogenetic-induced hyperactivity of cortical GABAergic neurons, is sufficient to ignite CSD by spiking-generated extracellular K+ build-up. This mechanism is neocortex specific because, with these approaches, CSD was not generated in other brain areas. GABAergic and glutamatergic synaptic transmission is not required for optogenetic CSD initiation, but glutamatergic transmission is implicated in CSD propagation. Thus, our results reveal the key role of hyper-activation of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which is relevant for FHM3 and possibly also for other types of migraine.

neuroscience↗

bioRxiv2019

SULTA4A1 modulates synaptic development and function by promoting the formation of PSD-95/NMDAR complex

Sulfotransferase 4A1 (SULT4A1) is a cytosolic sulfotransferase, that is highly conserved across species and extensively expressed in the brain. However, the biological function of SULT4A1 is unclear. SULT4A1 has been implicated in several neuropsychiatric disorders, such as Phelan-McDermid Syndrome and schizophrenia. Here, we investigate the role of SULT4A1 within neuron development and function. Our data demonstrate that SULT4A1 modulates neuronal branching complexity and dendritic spines formation. Moreover, we show that SULT4A1, by negatively regulating the catalytic activity of Pin1 towards PSD-95, facilitates NMDAR synaptic expression and function. Finally, we demonstrate that the pharmacological inhibition of Pin1 reverses the pathological phenotypes of SULT4A1 knockdown neurons by specifically restoring dendritic spine density and rescuing NMDAR-mediated synaptic transmission. Together, these findings identify SULT4A1 as a novel player in neuron development and function by modulating dendritic morphology and synaptic activity.

neuroscience↗