A novel AAV9-dual microRNA-vector targeting in the hippocampus as a treatment for mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (mTLE) is the most prevalent type of epilepsy in adults. First and subsequent generations of anti-epileptic therapy regimens fail to decrease seizures in a large number of patients suffering from mTLE, leaving surgical ablation of part of the hippocampus as the only therapeutic option to potentially reach seizure freedom. GluK2 has recently been identified as a promising target for the treatment of mTLE using gene therapy.

Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitability via overactivation of neuronal GluN2C N-methyl-D-aspartate receptors.

Objective: Genetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood.

A class-specific effect of dysmyelination on the excitability of hippocampal interneurons.

The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.

Kainate receptors modulate the microstructure of synchrony during dentate gyrus epileptiform activity.

Temporal Lobe Epilepsy (TLE) is the most common form of epilepsy in adults. In TLE, recurrent mossy fiber (rMF) sprouting from dentate gyrus granule cells (DGCs) forms an aberrant epileptogenic network between dentate granule cells (DGCs) that operates via ectopically expressed kainate receptors (KARs). It was previously shown that KARs expressed at the rMF-DGC synapses play a prominent role in epileptiform network events in TLE.

GluK2 Is a Target for Gene Therapy in Drug-Resistant Temporal Lobe Epilepsy.

Objective: Temporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies.

Substantial outcome improvement using a refined pilocarpine mouse model of temporal lobe epilepsy.

Systemic pilocarpine treatment is one of the most reliable means of inducing temporal lobe epilepsy (TLE). However, the traditional pilocarpine injection protocol using mice was associated with a high death rate, possibly because of cardiorespiratory collapse following status epilepticus (SE). To prevent this, we developed a modified procedure of pilocarpine SE induction, which included a single injection of a moderate dose of caffeine during the induction phase.

A stable proportion of Purkinje cell inputs from parallel fibers are silent during cerebellar maturation.

Cerebellar Purkinje neurons integrate information transmitted at excitatory synapses formed by granule cells. Although these synapses are considered essential sites for learning, most of them appear not to transmit any detectable electrical information and have been defined as silent. It has been proposed that silent synapses are required to maximize information storage capacity and ensure its reliability, and hence to optimize cerebellar operation.

Regulation and dysregulation of neuronal circuits by KARs.

Kainate receptors (KARs) constitute a family of ionotropic glutamate receptors (iGluRs) with distinct physiological roles in synapses and neuronal circuits. Despite structural and biophysical commonalities with the other iGluRs, AMPA receptors and NMDA receptors, their role as post-synaptic receptors involved in shaping EPSCs to transmit signals across synapses is limited to a small number of synapses. On the other hand KARs regulate presynaptic release mechanisms and control ion channels and signaling pathways through non-canonical metabotropic actions.

Dentate Granule Cells Recruited in the Home Environment Display Distinctive Properties.

The dentate granule cells (DGCs) play a crucial role in learning and memory. Many studies have described the role and physiological properties of these sparsely active neurons using different behavioral contexts. However, the morpho-functional features of DGCs recruited in mice maintained in their home cage (without training), considered as a baseline condition, have not yet been established.

Selective Axonal Expression of the Kv1 Channel Complex in Pre-myelinated GABAergic Hippocampal Neurons.

In myelinated fibers, the voltage-gated sodium channels Nav1 are concentrated at the nodal gap to ensure the saltatory propagation of action potentials. The voltage-gated potassium channels Kv1 are segregated at the juxtaparanodes under the compact myelin sheath and may stabilize axonal conduction. It has been recently reported that hippocampal GABAergic neurons display high density of Nav1 channels remarkably in clusters along the axon before myelination (Freeman et al.

Serotonin Regulates the Firing of Principal Cells of the Subiculum by Inhibiting a T-type Ca Current.

The subiculum is the main output of the hippocampal formation. A high proportion of its principal neurons fire action potentials in bursts triggered by the activation of low threshold calcium currents. This firing pattern promotes synaptic release and regulates spike-timing-dependent plasticity.

Depolarizing γ-aminobutyric acid contributes to glutamatergic network rewiring in epilepsy.

Objective: Rewiring of excitatory glutamatergic neuronal circuits is a major abnormality in epilepsy. Besides the rewiring of excitatory circuits, an abnormal depolarizing γ-aminobutyric acidergic (GABAergic) drive has been hypothesized to participate in the epileptogenic processes. However, a remaining clinically relevant question is whether early post-status epilepticus (SE) evoked chloride dysregulation is important for the remodeling of aberrant glutamatergic neuronal circuits.

Abnormal UP/DOWN Membrane Potential Dynamics Coupled with the Neocortical Slow Oscillation in Dentate Granule Cells during the Latent Phase of Temporal Lobe Epilepsy.

The dentate gyrus, a major entry point to the hippocampus, gates (or filters) incoming information from the cortex. During sleep or anesthesia, the slow-wave oscillation (SWO) orchestrates hippocampus-neocortex communication, which is important for memory formation. The dentate gate is altered in temporal lobe epilepsy (TLE) early during epileptogenesis, which favors the propagation of pathological activities.

Impaired neuronal operation through aberrant intrinsic plasticity in epilepsy.

Objective: Patients with temporal lobe epilepsy often display cognitive comorbidity with recurrent seizures. However, the cellular mechanisms underlying the impairment of neuronal information processing remain poorly understood in temporal lobe epilepsy. Within the hippocampal formation neuronal networks undergo major reorganization, including the sprouting of mossy fibers in the dentate gyrus; they establish aberrant recurrent synapses between dentate granule cells and operate via postsynaptic kainate receptors.

Physiopathology of kainate receptors in epilepsy.

Kainate receptors (KARs) are tetrameric ionotropic glutamate receptors composed of the combinations of five subunits GluK1-GluK5. KARs are structurally related to AMPA receptors but they serve quite distinct functions by regulating the activity of synaptic circuits at presynaptic and postsynaptic sites, through either ionotropic or metabotropic actions. Although kainate is a potent neurotoxin known to induce acute seizures through activation of KARs, the actual role of KARs in the clinically-relevant chronic phase of temporal lobe epilepsy (TLE) has long been elusive.

Contribution of aberrant GluK2-containing kainate receptors to chronic seizures in temporal lobe epilepsy.

Kainate is a potent neurotoxin known to induce acute seizures. However, whether kainate receptors (KARs) play any role in the pathophysiology of temporal lobe epilepsy (TLE) is not known. In TLE, recurrent mossy fiber (rMF) axons form abnormal excitatory synapses onto other dentate granule cells that operate via KARs.

The information content of physiological and epileptic brain activity.

Cerebral cortex is a highly sophisticated computing machine, feeding on information provided by the senses, which is integrated with other, internally generated patterns of neural activity, to trigger behavioural outputs. Bit by bit, we are coming to understand how this may occur, but still, the nature of the 'cortical code' remains one of the greatest challenges in science. As with other great scientific challenges of the past, fresh insights have come from a coalescence of different experimental and theoretical approaches.

An epilepsy-related ARX polyalanine expansion modifies glutamatergic neurons excitability and morphology without affecting GABAergic neurons development.

Epileptic encephalopathies comprise a heterogeneous group of severe infantile disorders for which the pathophysiological basis of epilepsy is inaccurately clarified by genotype-phenotype analysis. Because a deficit of GABA neurons has been found in some of these syndromes, notably in patients with X-linked lissencephaly with abnormal genitalia, epilepsy was suggested to result from an imbalance in GABAergic inhibition, and the notion of "interneuronopathy" was proposed. Here, we studied the impact of a polyalanine expansion of aristaless-related homeobox (ARX) gene, a mutation notably found in West and Ohtahara syndromes.

Selective block of postsynaptic kainate receptors reveals their function at hippocampal mossy fiber synapses.

Progress in understanding the roles of kainate receptors (KARs) in synaptic integration, synaptic networks, and higher brain function has been hampered by the lack of selective pharmacological tools. We have found that UBP310 and related willardiine derivatives, previously characterized as selective GluK1 and GluK3 KAR antagonists, block postsynaptic KARs at hippocampal mossy fiber (MF) CA3 synapses while sparing AMPA and NMDA receptors. We further show that UBP310 is an antagonist of recombinant GluK2/GluK5 receptors, the major population of KARs in the brain.

Synaptic kainate receptors in interplay with INaP shift the sparse firing of dentate granule cells to a sustained rhythmic mode in temporal lobe epilepsy.

Dentate granule cells, at the gate of the hippocampus, use coincidence detection of synaptic inputs to code afferent information under a sparse firing regime. In both human patients and animal models of temporal lobe epilepsy, mossy fibers sprout to form an aberrant glutamatergic network between dentate granule cells. These new synapses operate via long-lasting kainate receptor-mediated events, which are not present in the naive condition.

Inhibitory actions of the gamma-aminobutyric acid in pediatric Sturge-Weber syndrome.

Objective: The mechanisms of epileptogenesis in Sturge-Weber syndrome (SWS) are unknown. We explored the properties of neurons from human pediatric SWS cortex in vitro and tested in particular whether gamma-aminobutyric acid (GABA) excites neurons in SWS cortex, as has been suggested for various types of epilepsies.

Methods: Patch-clamp and field potential recordings and dynamic biphoton imaging were used to analyze cortical tissue samples obtained from four 6- to 14-month-old pediatric SWS patients during surgery.

A selective interplay between aberrant EPSPKA and INaP reduces spike timing precision in dentate granule cells of epileptic rats.

Spike timing precision is a fundamental aspect of neuronal information processing in the brain. Here we examined the temporal precision of input-output operation of dentate granule cells (DGCs) in an animal model of temporal lobe epilepsy (TLE). In TLE, mossy fibers sprout and establish recurrent synapses on DGCs that generate aberrant slow kainate receptor-mediated excitatory postsynaptic potentials (EPSP(KA)) not observed in controls.

Abnormal network activity in a targeted genetic model of human double cortex.

In human patients, cortical dysplasia produced by Doublecortin (DCX) mutations lead to mental retardation and intractable infantile epilepsies, but the underlying mechanisms are not known. DCX(-/-) mice have been generated to investigate this issue. However, they display no neocortical abnormality, lessening their impact on the field.

Seizures beget seizures in temporal lobe epilepsies: the boomerang effects of newly formed aberrant kainatergic synapses.

Do temporal lobe epilepsy (TLE) seizures in adults promote further seizures? Clinical and experimental data suggest that new synapses are formed after an initial episode of status epilepticus, however their contribution to the transformation of a naive network to an epileptogenic one has been debated. Recent experimental data show that newly formed aberrant excitatory synapses on the granule cells of the fascia dentate operate by means of kainate receptor-operated signals that are not present on naive granule cells. Therefore, genuine epileptic networks rely on signaling cascades that differentiate them from naive networks.

Late-onset epileptogenesis and seizure genesis: lessons from models of cerebral ischemia.

Patients surviving ischemic stroke often express delayed epileptic syndromes. Late poststroke seizures occur after a latency period lasting from several months to years after the insult. These seizures might result from ischemia-induced neuronal death and associated morphological and physiological changes that are only partly elucidated.