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

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

Hippocampal Theta Input to the Amygdala Shapes Feedforward Inhibition to Gate Heterosynaptic Plasticity

SummaryThe 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 Abstrac

Molecular targets of cannabidiol in neurological disorders

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD’s beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular phar- macology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeu- tics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent with modulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug’s action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD’s effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD’s therapeutic mechanism of action