Biology subjects

Crunelli, V.

Publications and source records attributed to Crunelli, V..

10 recordsLinked to original sources

bioRxiv2026

Biphasic Modulation of Absence Seizures by Lisuride in GAERS: Dissecting the Role of 5-HT2A Receptors

BackgroundSerotonergic signaling plays an important role in the modulation of absence seizures (ASs), and activation of serotonin 2A receptors (5-HT2ARs) with TCB-2 suppresses spontaneous absence seizures (ASs) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Lisuride is a pharmacologically complex serotonergic and dopaminergic ligand with low 5-HT2AR signaling efficacy and a receptor profile distinct from that of TCB-2. We therefore investigated its effects on spontaneous ASs and the contribution of 5-HT2ARs to its actions. MethodsThe effects of systemic lisuride (0.1 and 0.5 mg/kg) on spontaneous ASs were examined in freely moving GAERS over 120 min by quantifying time spent in seizure, mean seizure duration and seizure number. The contribution of 5-HT2ARs was investigated by administering lisuride (0.5 mg/kg) following pretreatment with the selective 5-HT2AR antagonist MDL11,939 (0.5 mg/kg). ResultsLisuride produced marked dose- and time-dependent effects on ASs. At 0.1 mg/kg, lisuride elicited modest pro-absence effect. In contrast, 0.5 mg/kg produced a pronounced biphasic response, with a marked reduction in seizure activity during the first 40 min, followed by rebound increase during the second hour. The early suppression involved reductions in both seizure number and duration, whereas the delayed pro-absence effect was predominantly associated with prolonged ASs. MDL11,939 did not prevent the early seizure suppression but blocked the increase in seizure duration while producing a transient increase in seizure number. ConclusionsLisuride is a dose- and time-dependent bidirectional modulator of ASs in GAERS. The persistence of the profound early anti-absence effect during 5-HT2AR blockade indicates that this response does not require 5-HT2AR activation, whereas the modification of the delayed response by MDL11,939 supports a 5-HT2AR-dependent component in the later phase. These findings distinguish lisuride pharmacologically from TCB-2 and suggest that its biphasic effects arise from the dynamic engagement of multiple receptor mechanisms, potentially including dopaminergic signaling.

neuroscience↗

bioRxiv2026

Block of Thalamic 5-HT2A Receptors modulates Tonic GABA-A Inhibition but not Absence Seizures

Absence epilepsy is a generalized non-convulsive epilepsy characterized by recurrent absence seizures (ASs) and enhanced GABAA receptor-mediated tonic inhibition of thalamocortical (TC) neurons has been shown to lead to ASs. Serotonergic signalling is an important modulator of these seizures, yet the contribution of specific 5-HT receptor subtypes remains incompletely understood. Here, we investigated whether endogenous serotonergic signalling through 5-HT2A receptors (5-HT2ARs) contributes to pathological tonic inhibition and ASs expression. Patch-clamp recordings were obtained from ventrobasal (VB) TC neurons of Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and non-epileptic control (NEC) rats. The selective 5-HT2AR antagonist MDL11,939 had no effect on tonic GABA-A currents in NEC TC neurons but significantly reduced the enhanced tonic current in GAERS neurons, revealing a disease-dependent contribution of endogenous 5-HT2AR signalling. MDL11,939 administered bilaterally into the VB of freely moving GAERS by reverse microdialysis did not alter ASs. This dissociation between the modulation of a disease-associated cellular mechanism and seizure outcome suggests that the previously reported reduction of ASs by systemic 5-HT2AR blockade may involve mechanisms outside the VB.

neuroscience↗

bioRxiv2025

Heterogeneity of ictal firing during generalized seizures in the awake cortex

Cortico-thalamo-cortical oscillations are central to both normal and pathological brain activities and emerge from complex cortical and thalamic interactions. However, the specific activity of identified cortical neurons during the paroxysmal oscillations associated with absence seizures (ASs) in awake animals remains underexplored. The dominant narrative suggests that seizures indiscriminately disrupt cortical activity through generalized hyperexcitability, but direct evidence supporting this view is lacking. Here, we recorded single units from pyramidal neurons and different interneuron subtypes in the neocortex of two validated rodent models of absence epilepsy under awake, behaving conditions. We find that neurons maintain their firing rank order across interictal and ictal states, regardless of whether their ictal firing rate increases, decreases, or remains stable compared to the interictal phase. Rather than a random cortical takeover, ictal activity represents a scalable modulation of pre-existing network states. These results challenge the generalized hyperexcitability model and highlight the structured, heterogeneous nature of cortical activity during ASs, with implications for mechanistic understanding and targeted therapies.

neuroscience↗

bioRxiv2022

Higher-order thalamic nuclei facilitate the generalization and maintenance of spike-and-wave discharges in absence seizures

Spike-and-wave discharges (SWDs), generated by the cortico-thalamo-cortical (CTC) network, are pathological, large amplitude oscillations and the hallmark of absence seizures (ASs). SWDs begin in a cortical initiation network in both humans and animal models, including the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), where it is located in the primary somatosensory cortex (S1). The behavioral manifestation of an AS occurs when SWDs spread from the cortical initiation site to the whole brain, however, the mechanisms behind this rapid propagation remain unclear. Here we investigated these processes beyond the principal CTC network, in higher-order (HO) thalamic nuclei (lateral posterior (LP) and posterior (PO) nuclei) since their diffuse connectivity and known facilitation of intracortical communications make these nuclei key candidates to support SWD generation and maintenance. In freely moving GAERS, multi-site LFP in LP, PO and multiple cortical regions revealed a novel feature of SWDs: during SWDs there are short periods (named SWD-breaks) when cortical regions far from S1, such the primary visual cortex (V1), become transiently unsynchronized from the ongoing EEG rhythm. Inactivation of HO nuclei with local muscimol injections or optogenetic perturbation of HO nuclei activity increased the occurrence of SWD-breaks and the former intervention also increased the SWD propagation-time from S1. The neural underpinnings of these findings were explored further by silicon probe recordings from single units of PO which uncovered two previously unknown groups of excitatory neurons based on their burst firing dynamics at SWD onset. Moreover, a switch from tonic to burst firing at SWD onset was shown to be an important feature since it was much less prominent for non-generalized events, i.e. SWDs that remained local to S1. Additionally, one group of neurons showed a reverse of this switch during SWD-breaks, demonstrating the importance of this firing pattern throughout the SWD. In summary, these results support the view that multiple HO thalamic nuclei are utilized at SWD onset and contribute to cortical synchrony throughout the paroxysmal discharge.

neuroscience↗

bioRxiv2022

Sleep waves in a large-scale corticothalamic model constrained by activities intrinsic to neocortical networks and single thalamic neurons

AimMany biophysical and non-biophysical models have been able to reproduce the corticothalamic activities underlying different EEG sleep rhythms but none of them included the known ability of neocortical networks and single thalamic neurons to generate some of these waves intrinsically. MethodsWe built a large-scale corticothalamic model with a high fidelity in anatomical connectivity consisting of a single cortical column and first- and higher-order thalamic nuclei. The model is constrained by different neocortical excitatory and inhibitory neuronal populations eliciting slow (<1 Hz) oscillations and by thalamic neurons generating sleep waves when isolated from the neocortex. ResultsOur model faithfully reproduces all EEG sleep waves and the transition from a desynchronized EEG to spindles, slow (<1 Hz) oscillations and delta waves by progressively increasing neuronal membrane hyperpolarization as it occurs in the intact brain. Moreover, our model shows that slow (<1 Hz) waves most often start in a small assembly of thalamocortical neurons though occasionally they originate in cortical layer 5. Moreover, thalamocortical neuron input increases the frequency of slow (<1 Hz) waves compared to those generated by isolated cortical networks. ConclusionOur simulations challenge current mechanistic understanding of the temporal dynamics of sleep wave generation and suggest testable predictions.

neuroscience↗

bioRxiv2022

Spike-and-wave discharges of absence seizures in a sleep waves-constrained corticothalamic model

AimsRecurrent network activity in corticothalamic circuits generates physiological and pathological EEG waves. Many computer models have simulated spike-and-wave discharges (SWDs), the EEG hallmark of absence seizures (ASs). However, these models either provided detailed simulated activity only in a selected territory (i.e. cortical or thalamic) or did not test whether their corticothalamic networks could reproduce the physiological activities that are generated by these circuits. MethodsUsing a biophysical large-scale corticothalamic model that reproduces the full extent of EEG sleep waves, including sleep spindles, delta and slow (<0.1 Hz) waves, here we investigated how single abnormalities in voltage- or transmitter-gated channels in the neocortex or thalamus lead to SWDs. ResultsWe found that a selective increase in the tonic {gamma}-aminobutyric acid type A receptor (GABA-A) inhibition of first order thalamocortical (TC) neurons or a selective decrease in cortical phasic GABA-A inhibition are sufficient to generate [~]4 Hz SWDs (as in humans) that invariably start in neocortical territories. Decreasing the leak conductance of higher order TC neurons leads to [~]7 Hz SWDs (as in rodent models) while maintaining sleep spindles at 7-14 Hz. ConclusionBy challenging key features of current mechanistic views, this simulated ictal corticothalamic activity provides novel understanding of ASs and makes key testable predictions.

neuroscience↗

bioRxiv2022

Cannabinoid 1/2 Receptor Activation Induces Strain-Dependent Behavioral and Neurochemical Changes in GAERS and NEC rats

Childhood absence epilepsy (CAE) is characterized by absence seizures which are episodes of lack of consciousness accompanied by electrographic spike-wave discharges. About 60% of children and adolescents with ASs are affected by major neuropsychological comorbidities, including anxiety. Endocannabinoids and monoamines are likely involved in the pathophysiology of these CAE psychiatric comorbidities. Here, we show that the synthetic cannabinoid receptor type 1/2 (CB1/2R) agonist WIN 55,212-2 (2 mg/kg, i.p.) has a strain-dependent effect on anxiety-like and motor behavior and cerebral monoaminergic levels in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and their non-epileptic control (NEC) rat strain. Using quantitative and Temporal-Pattern analysis, we found that WIN 55,212-2 did not affect the emotional status of GAERS but it was anxiolytic in NEC. Conversely, WIN 55,212-2 had a sedative effect in GAERS but was ineffective in NEC. Moreover, vehicle-treated GAERS are more motivated to explore by implementing more complex and articulated strategies. These behavioral changes correlate with the reduction of 5-HT in the hippocampus and substantia nigra (SN) and noradrenaline (NA) in the entopeduncular nucleus (EPN) in vehicle-treated GAERS compared to NEC rats which could contribute to their low anxiety status and hypermotility, respectively. On the other hand, the increased level of NA in the EPN and 5-HT in the SN is consistent with an activation of the basal ganglia output-mediated motor suppression observed in WIN 55,212-2-treated GAERS rats. These data support the view of a strain-dependent alteration of the endocannabinoid system by adding evidence of lower emotional responsiveness and a basal ganglia hypersensitivity to cannabinoids in GAERS compared to NEC rats.

neuroscience↗

bioRxiv2021

Decreased overall neuronal activity in a rodent model of impaired consciousness during absence seizures

Absence seizures are characterized by a brief behavioural impairment including apparent loss of consciousness. Neuronal mechanisms determining the behavioural impairment of absence seizures remain unknown, and their elucidation might highlight therapeutic options for reducing seizure severity. However, recent studies have questioned the similarity of animal spike-wave-discharges (SWD) to human absence seizures both behaviourally and neuronally. Here, we report that Genetic Absence Epilepsy Rats from Strasbourg recapitulate the decreased neuroimaging signals and loss of consciousness characteristic of human absence seizures. Overall neuronal firing is decreased but rhythmic in the somatosensory cortex and thalamus during these seizures. Interestingly, individual neurons in both regions tend to consistently express one of four distinct patterns of seizure-associated activity. These patterns differ in firing rate dynamics and in rhythmicity during seizure. One group of neurons showed a transient initial peak in firing at SWD onset, accounting for the brief initial increase in overall neuronal firing seen in cortex and thalamus. The largest group of neurons in both cortex and thalamus showed sustained decreases in firing during SWD. Other neurons showed either sustained increases or no change in firing. These findings suggest that certain classes of cortical and thalamic neurons may be particularly responsible for the paroxysmal oscillations and consequent loss of consciousness in absence epilepsy.

neuroscience↗

bioRxiv2021

Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures

ObjectiveHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a pro-absence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, that is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection in the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. MethodsWe used EEG recordings in freely moving Genetic Absence Epilepsy from Strasbourg Rats (GAERS) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected in the CIN and VB of GAERS in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical layer 5/6 and thalamocortical neurons, respectively. ResultsOral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection in CIN abolished ASs and elicited small-amplitude 4-7 Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN-channel-dependent properties of cortical layer 5/6 pyramidal and thalamocortical neurons, respectively. SignificanceThese results provide the first demonstration of the anti-absence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.

neuroscience↗

bioRxiv2018

Ehmt1 forebrain haploinsufficiency leads to impaired memory, sensory gating and information processing

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders (NDDs). Haploinsufficiency of EHMT1, encoding a histone methyl-transferase, is associated with several NDDs, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency (Ehmt1D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to NDDs. Specifically, we show that Ehmt1D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity (MMN). The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in Ehmt1D6Cre/+ matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of Grin1 mRNA expression in Ehmt1D6Cre/+ hippocampus, suggests that Ehmt1 haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced Ehmt1 dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the NDDs associated with EHMT1 haploinsufficiency.

neuroscience↗