Biology subjects

Khazipov, R.

Publications and source records attributed to Khazipov, R..

3 recordsLinked to original sources

bioRxiv2025

Dual role of Spreading Depolarization in the epileptic focus

Spreading Depolarizations (SDs) are often associated with epileptic discharges. While SDs are traditionally thought contributing to the postictal depression and termination of epileptic discharges, seizures may also occur during SDs or may even follow SDs suggesting that interactions between SD and seizures are more complex. Here, we examined the interactions between SD and epileptic activity by spatially separating the epileptic focus and the site of SD initiation. Epileptic focus was induced by local intracortical injection of the potassium channel blocker 4-AP combined with the GABA(A) receptor antagonist gabazine, whereas extrinsic SDs were evoked by distal high potassium application. We found that extrinsic SDs promoted seizure-like events (SLEs) when the SD wave approached the epileptic focus, followed by suppression of epileptic activity when SD spread through the focus. The timing of SLE relatively SD varied at different recordings sites, with SLEs occurring before, during or after SD arrival depending on electrode position along the trajectory of SD propagation between the SD initiation site and the epileptic focus. During intracortical recordings, the proconvulsive effects of SD were associated with a wave of pre-SD neuronal excitation reaching the epileptic focus. The epileptic focus per se also demonstrated a resistance to the SD invasion. Thus, the interactions between SD and epileptic focus are not limited to postictal depression, and SDs may also promote epileptic activity in the hyperexcitable cortex. Key pointsO_LIEffects of SD on epileptic focus are dual: both pro- and anticonvulsive C_LIO_LISDs promote epileptic discharges upon approaching the epileptic focus C_LIO_LIThe timing of epileptic discharges relatively SD varies along the SD trajectory C_LIO_LIProconvulsive effects of SD align with the pre-SD excitation C_LIO_LIEpileptic focus resists the SD propagation C_LI

neuroscience↗

bioRxiv2023

GluK2 is a target for gene therapy in drug-resistant Temporal Lobe Epilepsy

ObjectiveTemporal 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) creates 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. Previously we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE. MethodsWe combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE. ResultsHere we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated Interictal-like Epileptiform Discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti-grik2 miRNA was designed to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs. InterpretationOur gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients.

neuroscience↗

bioRxiv2022

Vibrissae-evoked activity in the somatosensory thalamus of rat pups: an intracellular study

Spontaneous and sensory-evoked neuronal activity plays a decisive role in network formation during postnatal development. The thalamus is a major gateway for sensory outputs to the cortex, so that thalamic neuronal activity in newborn animals might be crucial for maturation of the thalamocortical network. The sensory-evoked intracellular thalamic activity and signal propagation in newborn animals remain largely unknown. Here we performed local field potential (LFP), juxtacellular, and patch clamp recordings in the somatosensory thalamus of urethane anesthetized rats at postnatal days 6-7 (P6-7, both sexes) with one whisker stimulation. To reach the thalamus with the electrodes the majority of the overlying cortex and hippocampus were removed. Deflection of only one (the principal) whisker induced spikes in a particular thalamic cell. Sensory stimulation evoked excitatory and inhibitory postsynaptic events in thalamocortical cells. Up to 5-10 sensory-evoked large-amplitude excitatory events followed with 100-200 ms inter-event intervals, while multiple inhibitory events tended to form 20-40 ms inter-event intervals. Large-amplitude excitatory events produced spike bursts with an intraburst frequency of 50-100 Hz and/or short plateau potentials in thalamocortical cells. Inhibitory events could down-modulate evoked spiking or prevented a depolarization block. Juxtacellular recordings confirmed the partial inactivation of spikes during short plateau potentials. Excitatory events evoked low-threshold spikes (LTS) in thalamocortical cells, but, in agreement with previously reported results, hyperpolarizing current pulses generated weak LTS without spike bursts. We conclude that thalamic neuronal activity in rat pups is determined by relatively weak and slow intrinsic membrane currents and relatively strong synapses that might underlay immature forms of thalamocortical synchrony and signal propagation.

physiology↗