Cannabidiol (CBD) improves survival and behavioural comorbidities of Dravet syndrome in mice

Background and Purpose Dravet syndrome is a severe, genetic form of paediatric epilepsy associated with premature mortality and comorbidities such as anxiety, depression, autism, motor dysfunction, and memory deficits. Cannabidiol is an approved anticonvulsive drug in USA and Europe for seizures associated with Dravet syndrome therapy in patients 2 years of age and older; we investigated its potential to prevent premature mortality and improve associated comorbidities. Experimental Approach The efficacy of sub-chronic cannabidiol administration in two mouse models which reproduce characteristics of Dravet syndrome was investigated. The effect of cannabidiol on neonatal welfare and survival was studied using Scn1a-/- mice. We then used a hybrid, heterozygote Scn1a+/- mouse model to study the effect of cannabidiol on survival and behavioural comorbidities; motor deficits (rotarod and static-beam test), gait abnormality (gait test), social anxiety (social interaction test), anxiety-like (elevated plus maze) and depressive-like behaviours (sucrose preference test) and cognitive impairment (radial arm maze test). Key Results In Scn1a-/- mice, cannabidiol increased survival and delayed worsening of neonatal welfare. In Scn1a+/- mice chronic cannabidiol administration did not show any adverse effect on motor function and gait, reduced premature mortality, improved social behaviour and memory function, and reduced anxiety-like and depressive-like behaviours. Conclusion and Implications We are the first to demonstrate a potential disease-modifying effect of cannabidiol in animal models of Dravet syndrome. cannabidiol treatment reduced premature mortality and improved several behavioural comorbidities in Dravet syndrome mice. These crucial findings may be translated into human therapy to address behavioural comorbidities associated with Dravet syndrome

Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in the TSC1 or TSC2 genes and is characterized by widespread tumour growth, intractable epilepsy, cognitive deficits and autistic behaviour. CBD has been reported to decrease seizures and inhibit tumour cell progression, therefore we sought to determine the influence of CBD on TSC pathology in zebrafish carrying a nonsense mutation in the tsc2 gene. CBD treatment from 6 to 7 days post-fertilization (dpf) induced significant anxiolytic actions without causing sedation. Furthermore, CBD treatment from 3 dpf had no impact on tsc2-/- larvae motility nor their survival. CBD treatment did, however, reduce the number of phosphorylated rpS6 positive cells, and their cross-sectional cell size. This suggests a CBD mediated suppression of mechanistic target of rapamycin (mTOR) activity in the tsc2-/- larval brain. Taken together, these data suggest that CBD selectively modulates levels of phosphorylated rpS6 in the brain and additionally provides an anxiolytic effect. This is pertinent given the alterations in mTOR signalling in experimental models of TSC. Additional work is necessary to identify upstream signal modulation and to further justify the use of CBD as a possible therapeutic strategy to manage TSC

Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

Objective Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol (CBD), in a battery of acute seizure models. Additionally, we defined the disease-modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus-spontaneous recurrent seizure (RISE-SRS) model of temporal lobe epilepsy (TLE). Methods We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure (MES), 6 Hz psychomotor seizure, and pentylenetetrazol (PTZ) acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective (ED50) or behavioral toxic dose (TD50) was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg, single dose) in a rat model of pilocarpine-induced status epilepticus. We defined the effect of chronic CBD administration (200mg/kg, orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE-SRS model of TLE. Results CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD’s acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time-dependent increase in seizure burden and improved TLE-associated motor comorbidities of epileptic rats in the RISE-SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task. Significance The present study illustrates that CBD is a well-tolerated and effective antiseizure agent and illustrates a potential disease-modifying effect of CBD on both reducing seizure burden and associated comorbidities well-after the onset of symptomatic seizures in a model of TLE

Self-sustained activity of low firing rate in balanced networks

Self-sustained activity in the brain is observed in the absence of external stimuli and contributes to signal propagation, neural coding, and dynamic stability. It also plays an important role in cognitive processes. In this work, by means of studying intracellular recordings from CA1 neurons in rats and results from numerical simulations, we demonstrate that self-sustained activity presents high variability of patterns, such as low neural firing rates and activity in the form of small-bursts in distinct neurons. In our numerical simulations, we consider random networks composed of coupled, adaptive exponential integrate-and-fire neurons. The neural dynamics in the random networks simulates regular spiking (excitatory) and fast spiking (inhibitory) neurons. We show that both the connection probability and network size are fundamental properties that give rise to self-sustained activity in qualitative agreement with our experimental results. Finally, we provide a more detailed description of self-sustained activity in terms of lifetime distributions, synaptic conductances, and synaptic currents

Origine des potentiels de champ unitaires et macroscopiques dans la région CA3 de l'hippocampe

L électroencéphalogramme (EEG) est largement utilisé comme mesure de l activité des populations de neurones. Néanmoins, les mécanismes gouvernant se genèse restent peu connus. La première étude a confirmé que les cellules inhibitrices génèrent un champ monosynaptique détectable. Nous avons utilisé des faisceaux d électrodes extracellulaires disposées le long du stratum pyramidale ou dans l axe somato-dendritique des cellules pyramidales de CA3 afin d étudier le patron spatial des événements. La technique de clusterisation par la méthode k-means nous a permis d'isoler l'activité d'interneurones innervant des zones distinctes de la membrane somato-dendritique ou d'interneurones innervant des zones périsomatiques diverses. La seconde étude a eu pour but de déterminer les altérations de la région CA3 de l hippocampe des souris KO pour la doublecortine. Lorsque cette protéine est mutée chez la souris, la migration neuronale est désorganisée. Les tranches d hippocampes issues des animaux KO sont spontanément épileptiques. Il se produit une augmentation de l activité des interneurones, et ceux-ci semblent innerver à la fois les deux couches de cellules pyramidales. Nous avons enfin mis en évidence que les cellules pyramidales de CA3 sont également capables d initier un potentiel de champ extracellulaire. Les mécanismes contribuant à la genèse des sharp-waves ne sont pas complètement connus. Nos données suggèrent que (1) les sharp-waves sont initiées au niveau de sites qui varient lors d un enregistrement, (2) se propagent au sein même de CA3 et (3) comprennent des champs initiés par les interneurones périsomatiques de la région CA3PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Hippocampal theta input to the amygdala shapes feedforward inhibition to gate heterosynaptic plasticity

The dynamic interactions between hippocampus and amygdala are critical for emotional memory. Theta synchrony between these structures occurs during fear memory retrieval and may facilitate synaptic plasticity, but the cellular mechanisms are unknown. We report that interneurons of the mouse basal amygdala are activated during theta network activity or optogenetic stimulation of ventral CA1 pyramidal cell axons, whereas principal neurons are inhibited. Interneurons provide feedforward inhibition that transiently hyperpolarizes principal neurons. However, synaptic inhibition attenuates during theta frequency stimulation of ventral CA1 fibers, and this broadens excitatory postsynaptic potentials. These effects are mediated by GABAB receptors and change in the Cl(-) driving force. Pairing theta frequency stimulation of ventral CA1 fibers with coincident stimuli of the lateral amygdala induces long-term potentiation of lateral-basal amygdala excitatory synapses. Hence, feedforward inhibition, known to enforce temporal fidelity of excitatory inputs, dominates hippocampus-amygdala interactions to gate heterosynaptic plasticity. VIDEO ABSTRACT

Unitary inhibitory field potentials in the CA3 region of rat hippocampus

Glickfeld and colleagues (2009) suggested that single hippocampal interneurones generate field potentials at monosynaptic latencies. We pursued this obervation in simultaneous intracellular and multiple extracellular records from the CA3 region of rat hippocampal slices. We confirmed that interneurones evoked field potentials at monosynaptic latencies. Pyramidal cells initiated disynaptic inhibitory field potentials, but did not initiate detectable monosynaptic excitatory fields. We confirmed that inhibitory fields were GABAergic in nature and showed they were suppressed at low external Cl−, suggesting they originate at postsynaptic sites. Field potentials generated by a single interneurone were detected at multiple sites over distances of more than 800 μm along the stratum pyramidale of the CA3 region. We used arrays of extracellular electrodes to examine amplitude distributions of spontaneous inhibitory fields recorded at sites orthogonal to or along the CA3 stratum pyramidale. Cluster analysis of spatially distributed inhibitory field events let us separate events generated by interneurones terminating on distinct zones of somato-dendritic axis. Events generated at dendritic sites had similar amplitudes but occurred less frequently and had somewhat slower kinetics than perisomatic events generated near the stratum pyramidale. In records from multiple sites in the CA3 stratum pyramidale, we distinguished inhibitory fields that seemed to be initiated by interneurones with spatially distinct axonal arborisations