Epilepsies are a group of chronic neurological disorders characterized by spontaneous recurrent seizures caused by abnormal synchronous firing of neurons and transient brain dysfunction. The underlying mechanisms are complex and not yet fully understood. Endoplasmic reticulum (ER) stress, as a condition of excessive accumulation of unfolded and/or misfolded proteins in the ER lumen, has been considered as a pathophysiological mechanism of epilepsy in recent years. ER stress can enhance the protein processing capacity of the ER to restore protein homeostasis through unfolded protein response, which may inhibit protein translation and promote misfolded protein degradation through the ubiquitin-proteasome system. However, persistent ER stress can also cause neuronal apoptosis and loss, which may aggravate the brain damage and epilepsy. This review has summarized the role of ER stress in the pathogenesis of genetic epilepsy.
Humans ; Endoplasmic Reticulum Stress/genetics* ; Unfolded Protein Response ; Endoplasmic Reticulum/pathology* ; Apoptosis ; Epilepsy/genetics*

Inhibitory GABAergic interneurons are fundamental elements of cortical circuits and play critical roles in shaping network activity. Dysfunction of interneurons can lead to various brain disorders, including epilepsy, schizophrenia, and anxiety. Based on the electrophysiological properties, cell morphology, and molecular identity, interneurons could be classified into various subgroups. In this study, we investigated the density and laminar distribution of different interneuron types and the co-expression of molecular markers in epileptic human cortex. We found that parvalbumin (PV) and somatostatin (SST) neurons were distributed in all cortical layers except layer I, while tyrosine hydroxylase (TH) and neuropeptide Y (NPY) were abundant in the deep layers and white matter. Cholecystokinin (CCK) neurons showed a high density in layers IV and VI. Neurons with these markers constituted ~7.2% (PV), 2.6% (SST), 0.5% (TH), 0.5% (NPY), and 4.4% (CCK) of the gray-matter neuron population. Double- and triple-labeling revealed that NPY neurons were also SST-immunoreactive (97.7%), and TH neurons were more likely to express SST (34.2%) than PV (14.6%). A subpopulation of CCK neurons (28.0%) also expressed PV, but none contained SST. Together, these results revealed the density and distribution patterns of different interneuron populations and the overlap between molecular markers in epileptic human cortex.
Adolescent ; Adult ; Brain Chemistry ; genetics ; physiology ; Cerebral Cortex ; metabolism ; pathology ; Child ; Cholecystokinin ; metabolism ; Epilepsy ; etiology ; pathology ; Female ; Gene Expression Regulation ; physiology ; Humans ; Interneurons ; metabolism ; Male ; Middle Aged ; Neuropeptide Y ; metabolism ; Parvalbumins ; metabolism ; Phosphopyruvate Hydratase ; metabolism ; Somatostatin ; metabolism ; Tyrosine 3-Monooxygenase ; metabolism ; Young Adult

Epilepsy is a chronic neurological disorder, which is not only related to the imbalance between excitatory glutamic neurons and inhibitory GABAergic neurons, but also related to abnormal central cholinergic regulation. This article summarizes the scientific background and experimental data about cholinergic dysfunction in epilepsy from both cellular and network levels, further discusses the exact role of cholinergic system in epilepsy. In the cellular level, several types of epilepsy are believed to be associated with aberrant metabotropic muscarinic receptors in several different brain areas, while the mutations of ionotropic nicotinic receptors have been reported to result in a specific type of epilepsy-autosomal dominant nocturnal frontal lobe epilepsy. In the network level, cholinergic projection neurons as well as their interaction with other neurons may regulate the development of epilepsy, especially the cholinergic circuit from basal forebrain to hippocampus, while cholinergic local interneurons have not been reported to be associated with epilepsy. With the development of optogenetics and other techniques, dissect and regulate cholinergic related epilepsy circuit has become a hotspot of epilepsy research.
Acetylcholine ; physiology ; Basal Forebrain ; pathology ; Brain Chemistry ; genetics ; physiology ; Cholinergic Neurons ; chemistry ; classification ; pathology ; physiology ; Epilepsy ; genetics ; pathology ; physiopathology ; Epilepsy, Frontal Lobe ; genetics ; GABAergic Neurons ; physiology ; Hippocampus ; pathology ; Humans ; Mutation ; genetics ; physiology ; Neurons ; Non-Neuronal Cholinergic System ; genetics ; physiology ; Receptors, Muscarinic ; genetics ; physiology ; Receptors, Nicotinic ; genetics ; physiology ; Synaptic Transmission ; genetics ; physiology

Synaptic vesicle protein 2A (SV2A) involvement has been reported in the animal models of epilepsy and in human intractable epilepsy. The difference between pharmacosensitive epilepsy and pharmacoresistant epilepsy remains poorly understood. The present study aimed to observe the hippocampus SV2A protein expression in amygdale-kindling pharmacoresistant epileptic rats. The pharmacosensitive epileptic rats served as control. Amygdaloid-kindling model of epilepsy was established in 100 healthy adult male Sprague-Dawley rats. The kindled rat model of epilepsy was used to select pharmacoresistance by testing their seizure response to phenytoin and phenobarbital. The selected pharmacoresistant rats were assigned to a pharmacoresistant epileptic group (PRE group). Another 12 pharmacosensitive epileptic rats (PSE group) served as control. Immunohistochemistry, real-time PCR and Western blotting were used to determine SV2A expression in the hippocampus tissue samples from both the PRE and the PSE rats. Immunohistochemistry staining showed that SV2A was mainly accumulated in the cytoplasm of the neurons, as well as along their dendrites throughout all subfields of the hippocampus. Immunoreactive staining level of SV2A-positive cells was 0.483 ± 0.304 in the PRE group and 0.866 ± 0.090 in the PSE group (P < 0.05). Real-time PCR analysis demonstrated that 2(-ΔΔCt) value of SV2A mRNA was 0.30 ± 0.43 in the PRE group and 0.76 ± 0.18 in the PSE group (P < 0.05). Western blotting analysis obtained the similar findings (0.27 ± 0.21 versus 1.12 ± 0.21, P < 0.05). PRE rats displayed a significant decrease of SV2A in the brain. SV2A may be associated with the pathogenesis of intractable epilepsy of the amygdaloid-kindling rats.
Amygdala ; drug effects ; metabolism ; physiopathology ; Animals ; Anticonvulsants ; pharmacology ; Disease Models, Animal ; Drug Resistance ; Electric Stimulation ; Epilepsy ; drug therapy ; genetics ; metabolism ; pathology ; Gene Expression Regulation ; Hippocampus ; drug effects ; metabolism ; physiopathology ; Kindling, Neurologic ; drug effects ; genetics ; metabolism ; pathology ; Male ; Membrane Glycoproteins ; genetics ; metabolism ; Nerve Tissue Proteins ; genetics ; metabolism ; Phenobarbital ; pharmacology ; Phenytoin ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Synaptic Transmission ; Synaptic Vesicles ; drug effects ; metabolism ; pathology

Previous studies have reported the association of prodynorphin (PDYN) promoter polymorphism with temporal lobe epilepsy (TLE) susceptibility, but the results remain inconclusive. To further precisely evaluate this association, we performed a meta-analysis. Published studies of TLE and PDYN polymorphism up to February 2015 were identified. Subgroup analysis by TLE subtype was performed. Moreover, sensitivity, heterogeneity, and publication bias were also analyzed. Seven case-control studies were finally included in this meta-analysis with 875 TLE cases and 1426 controls. We did not find synthetic evidence of association between PDYN promoter polymorphism and TLE susceptibility (OR=1.184, 95% CI: 0.873-1.606, P=0.277). Similar results were also obtained in non-familial-risk TLE subgroup. However, in the familial-risk TLE subgroup analysis, a significant association was observed (OR=1.739, 95% CI: 1.154-2.619, P=0.008). In summary, this meta-analysis suggests that PDYN gene promoter polymorphism might contribute to familial-risk TLE.
Case-Control Studies ; Enkephalins ; genetics ; Epilepsy, Temporal Lobe ; diagnosis ; genetics ; pathology ; Family ; Gene Expression ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Inheritance Patterns ; Odds Ratio ; Polymorphism, Genetic ; Prognosis ; Promoter Regions, Genetic ; Protein Precursors ; genetics

Adult ; Epilepsy ; genetics ; Humans ; Hyperhomocysteinemia ; genetics ; Hypogonadism ; genetics ; Intellectual Disability ; genetics ; Male ; White Matter ; pathology

2-Aminoadipic Acid ; analogs & derivatives ; analysis ; Aldehyde Dehydrogenase ; genetics ; Anticonvulsants ; therapeutic use ; Biomarkers ; analysis ; Brain ; pathology ; DNA Mutational Analysis ; Electroencephalography ; Epilepsy ; diagnosis ; drug therapy ; genetics ; Genetic Association Studies ; Humans ; Infant ; Infant, Newborn ; Magnetic Resonance Imaging ; Mutation, Missense ; Prognosis ; Pyridoxine ; therapeutic use ; Seizures ; diagnosis ; drug therapy ; genetics ; Status Epilepticus ; diagnosis ; drug therapy ; genetics

OBJECTIVETo detect potential mutation of Doublecortin (DCX) gene in a patient featuring X-linked subcortical laminar heterotopia (X-SCLH) and epilepsy.

METHODSMutation of the DCX gene was screened by PCR and direct sequencing. Pathogenicity of the mutation was analyzed with a PolyPhen-2 software.

RESULTSA de novo missense mutation c.971T>C (p.Phe324Ser) was discovered.

CONCLUSIONA diagnostic method for X-SCLH has been established, which may facilitate diagnosis and genetic counseling of patients featuring this disease.

Agenesis of Corpus Callosum ; diagnosis ; genetics ; Base Sequence ; Brain ; pathology ; Child ; Classical Lissencephalies and Subcortical Band Heterotopias ; diagnosis ; genetics ; Electroencephalography ; Epilepsy ; diagnosis ; genetics ; Exons ; Female ; Humans ; Magnetic Resonance Imaging ; Microtubule-Associated Proteins ; genetics ; Mutation ; Neuropeptides ; genetics

OBJECTIVETo analyze the clinical and SLC2A1 gene mutation characteristics of glucose transporter type 1 deficiency syndrome.

METHODThe detailed clinical manifestations of six cases were recorded. The laboratory tests including EEG, MRI, blood chemistry, and lumbar puncture were performed. SLC2A1 gene mutations were analyzed by PCR, DNA sequencing and multiplex ligation-dependent probe amplification (MLPA).

RESULTPatient 1, 2 and 3 had classical clinical symptoms including infantile onset seizures, development delay. Patient 4, 5 and 6 had non-classical clinical symptoms including paroxysmal behavior disturbance, weakness, ataxia, lethargy, especially after fasting or exercise, without severe seizures. The plasma glucose levels were normal. The CSF glucose levels decreased in all the six cases, ranged from 1.10 mmol/L to 2.45 mmol/L, the mean level was 1.68 mmol/L. The CSF glucose/plasma glucose ratios decreased, ranged from 0.16 to 0.51, the mean ratio was 0.34. Four patients had normal EEG. Two patients had focal and diffuse epileptiform discharge, and one of them also had paroxysmal occipital or generalized high-amplitude slow waves during awake and sleep time. MRI abnormalities were found in three patients, patient 1 with mild brain atrophy, patient 3 with bilateral ventricle plump, and patient 4 with high signals in T2 in the frontal and occipital white matter, interpreted as hypomyelination. SLC2A1 gene mutations were found in six cases. Patient 1 has large scale deletion in exon 2. In patient 2 to 6, the mutations were c.741 G>A (E247K), 599delA, 761delA, c.1148 C>A (P383H), c.1198 C>T (R400C) respectively. Two patients were treated with ketogenic diet. The seizures disappeared and development became normal. Three patients responded to frequent meals with snacks. One patient refused any treatments, the symptoms continued to exist.

CONCLUSIONThe clinical manifestations of glucose transporter type 1 deficiency syndrome are varied. The common symptoms included infantile onset seizures and various paroxysmal events. These neurologic symptoms generally fluctuated and were influenced by factors such as fasting or fatigue. This feature could be a very important clue for the diagnosis of GLUT1-DS. Lumbar puncture is recommended in patients with episodic CNS symptoms especially after fasting. GLUT1-DS is a treatable neurometabolic disorder, early diagnosis and treatment may improve the prognosis of the patients.

Biomarkers ; analysis ; Brain ; diagnostic imaging ; pathology ; Carbohydrate Metabolism, Inborn Errors ; diagnosis ; genetics ; therapy ; Child ; Child, Preschool ; DNA Mutational Analysis ; Diet, Ketogenic ; Electroencephalography ; Epilepsy ; diagnosis ; genetics ; therapy ; Female ; Follow-Up Studies ; Glucose Transporter Type 1 ; genetics ; Humans ; Infant ; Magnetic Resonance Imaging ; Male ; Monosaccharide Transport Proteins ; deficiency ; genetics ; Movement Disorders ; diagnosis ; genetics ; therapy ; Mutation ; genetics ; Radiography

OBJECTIVE: To examine the changes of morphology and differentially expressed proteins in hippocampus at the latent stage of chronic mesial temporal lobe epilepsy (MTLE) in immature rats, and to explore the global mechanism of chronic MTLE at a new point. METHODS: MTLE models of immature rats were induced by lithium-pilocarpine. The rats were divided into 2 groups randomly: a control group (n=20) and an MTLE model group (n=20). At the latent stage, nissl and Timm staining were performed to evaluate the cell loss and mossy fiber sprouting. The differentially expressed proteins were separated by 2-dimensional polyacrylamide gel electrophoresis (2-DE) combined with matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF-MS) technology. Western blot was used to determine the differentially expression levels of partial proteins. RESULTS: Neuron loss and abnormal mossy fiber sprouting were obviously observed in the hippocampus in the MTLE model group; 2-DE patterns of hippocampus of the MTLE model group in latent stage and the control group were established. Thirty-one differential proteins were identified by MALDI-TOF-MS, which were categorized into several groups by biological functions: synaptic and neurotransmitter release related proteins, cytoskeletal proteins, cell junctions proteins, energy metabolism and mitochondrial proteins, biological enzymes, cellular structure related proteins, signal regulating molecular and others. The expression levels of partial proteins determined by Western blot were similar to the changes of proteomics. CONCLUSION The differentially expressed proteins of synapse-related proteins such as dynamin-1, neurogranin and ubiquitin, which cause the synapse reorganization and mossy fiber terminal sprouting related to the formation of abnormal excitatory network, probably play critic roles in the mechanism of MTLE.
Animals ; Epilepsy, Temporal Lobe ; chemically induced ; metabolism ; pathology ; Female ; Hippocampus ; metabolism ; pathology ; Male ; Pilocarpine ; Proteins ; genetics ; metabolism ; Proteomics ; methods ; Rats ; Rats, Sprague-Dawley