Epileptogenesis

About: Epileptogenesis is a research topic. Over the lifetime, 4218 publications have been published within this topic receiving 170809 citations.

Spatiotemporal characteristics of astroglial death in the rat hippocampo-entorhinal complex following pilocarpine-induced status epilepticus.

Abstract: Recently we reported that astroglial loss and subsequent gliogenesis in the dentate gyrus play a role in epileptogenesis following pilocarpine-induced status epilepticus (SE). In the present study we investigated whether astroglial damages in the hippocampo-entorhinal complex following SE are relevant to pathological or electrophysiological properties of temporal lobe epilepsy. Astroglial loss/damage was observed in the entorhinal cortex and the CA1 region at 4 weeks and 8 weeks after SE, respectively. These astroglial responses in the hippocampo-entorhinal cortex were accompanied by hyperexcitability of the CA1 region (impairment of paired-pulse inhibition and increase in excitability ratio). Unlike the dentate gyrus and the entorhinal cortex, CA1 astroglial damage was protected by conventional anti-epileptic drugs. alpha-Aminoadipic acid (a specific astroglial toxin) infusion into the entorhinal cortex induced astroglial damage and changed the electrophysiological properties in the CA1 region. Astroglial regeneration in the dentate gyrus and the stratum oriens of the CA1 region was found to originate from gliogenesis, while that in the entorhinal cortex and stratum radiatum of the CA1 region originated from in situ proliferation. These findings suggest that regional specific astroglial death/regeneration patterns may play an important role in the pathogenesis of temporal lobe epilepsy.

Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Abstract: Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy. The pathophysiology of epilepsy is unclear. Here, the authors present single-nuclei transcriptomic profiling of human temporal lobe epilepsy from patients. They identified epilepsy-associated neuronal subtypes, and a panel of dysregulated genes, predicting neuronal circuits contributing to epilepsy.

Traumatic brain injury causes an FK506-sensitive loss and an overgrowth of dendritic spines in rat forebrain.

Abstract: Traumatic brain injury (TBI) causes both an acute loss of tissue and a progressive injury through reactive processes such as excitotoxicity and inflammation. These processes may worsen neural dysfunction by altering neuronal circuitry beyond the focally-damaged tissue. One means of circuit alteration may involve dendritic spines, micron-sized protuberances of dendritic membrane that support most of the excitatory synapses in the brain. This study used a modified Golgi-Cox technique to track changes in spine density on the proximal dendrites of principal cells in rat forebrain regions. Spine density was assessed at 1 h, 24 h, and 1 week after a lateral fluid percussion TBI of moderate severity. At 1 h after TBI, no changes in spine density were observed in any of the brain regions examined. By 24 h after TBI, however, spine density had decreased in ipsilateral neocortex in layer II and III and dorsal dentate gyrus (dDG). This apparent loss of spines was prevented by a single, post-injury administr...

Disruption of TrkB-mediated phospholipase Cgamma signaling inhibits limbic epileptogenesis.

Abstract: The BDNF receptor, TrkB, is critical to limbic epileptogenesis, but the responsible downstream signaling pathways are unknown. We hypothesized that TrkB-dependent activation of phospholipase Cγ1 (PLCγ1) signaling is the key pathway and tested this in trkBPLC/PLC mice carrying a mutation (Y816F) that uncouples TrkB from PLCγ1. Biochemical measures revealed activation of both TrkB and PLCγ1 in hippocampi in the pilocarpine and kindling models in wild-type mice. PLCγ1 activation was decreased in hippocampi isolated from trkBPLC/PLC compared with control mice. Epileptogenesis assessed by development of kindling was inhibited in trkBPLC/PLC compared with control mice. Long-term potentiation of the mossy fiber-CA3 pyramid synapse was impaired in slices of trkBPLC/PLC mice. We conclude that TrkB-dependent activation of PLCγ1 signaling is an important molecular mechanism of limbic epileptogenesis. Elucidating signaling pathways activated by a cell membrane receptor in animal models of CNS disorders promises to reveal novel targets for specific and effective therapeutic intervention.

Transplants of cells engineered to produce GABA suppress spontaneous seizures.

Abstract: Summary: Purpose: Cell transplantation into the brain is an aggressive clinical alternative. The hopes of treating diseases like intractable temporal lobe epilepsy have been subdued because the preclinical successes thus far have shown only slowing of epileptogenesis, or suppression of electrically induced seizures. Because the hallmark of epilepsy is spontaneous seizures, the clinical relevance of these studies has been questioned. The purpose of this study was to establish that cells genetically engineered to produce γ-aminobutyric acid (GABA) could suppress spontaneous seizures in an accepted model of temporal lobe epilepsy. Methods: Conditionally immortalized neurons were engineered to produce GABA under the control of tetracycline. These cells were transplanted into the substantia nigra of spontaneously seizing animals. After transplantation, the animals were monitored for 3 days immediately after surgery and again for 3 days beginning 7–8 days after surgery. Seizures and epileptiform spikes were recorded and later analyzed with detection software combined with video monitoring. Results: Animals that received genetically engineered GABA-producing cells had significantly fewer spontaneous seizures than did animals that received control cells, or animals that received GABA-producing cells plus doxycycline at the observation period starting 1 week after transplantation. A significant suppression of epileptiform spikes also was noted between the group that received GABA-producing cells and the group that received the same cells but were given doxycycline. The engineered cells show evidence of integration with the host but limited survival. Conclusions: These data demonstrate that genetically engineered cells have the ability to suppress spontaneous seizures when transplanted into seizure-modulating nuclei. This is an important step toward defining a clinical potential for this approach in epilepsy. The fact that the gene of interest can be regulated suggests that individualizing transplant therapy may be possible.