CASPR2-IgG-associated autoimmune seizures.

Objective: This study was undertaken to report clinical presentations and outcomes of CASPR2-IgG-associated seizures.

Methods: Mayo Clinic Neuroimmunology database was queried to identify CASPR2-IgG-seropositive (CASPR2-IgG+) patients evaluated at our institution (2009-2019).

Results: Of the 53 CASPR2-IgG+ patients (titer ≥ 1:10), 20 had seizures (38%).

Two decades of research towards a potential first anti-epileptic drug.

The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g.

PspA facilitates evasion of pneumococci from bactericidal activity of neutrophil extracellular traps (NETs).

Pneumococcal strains are variably resistant to killing by neutrophil extracellular traps (NETs). We hypothesize that this variability in resistance is due to heterogeneity in pneumococcal surface protein A (PspA), a structurally diverse virulence factor of Streptococcus pneumoniae. Pneumococcal strains showed variability in induction of NETs and in susceptibility to killing by NETs.

Nanotherapeutics for Gene Modulation that Prevents Apoptosis in the Brain and Fatal Neuroinflammation.

The failure of therapeutic agents to cross the blood-brain barrier (BBB) has been a major impediment in the treatment of neurological disorders and brain tumors. We have addressed this issue using an immunoliposome nanocomplex (designated scL) that delivers therapeutic nucleic acids across the BBB into the deep brain via transcytosis mediated by transferrin receptors. We validated brain delivery of payloads after systemic administration by monitoring uptake of fluorescently labeled payloads and by confirming up- or down-modulation of specific target gene expression in the brain, mainly in neuronal cells.

Altered neurotransmitter release, vesicle recycling and presynaptic structure in the pilocarpine model of temporal lobe epilepsy.

In searching for persistent seizure-induced alterations in brain function that might be causally related to epilepsy, presynaptic transmitter release has relatively been neglected. To measure directly the long-term effects of pilocarpine-induced status epilepticus on vesicular release and recycling in hippocampal mossy fibre presynaptic boutons, we used (i) two-photon imaging of FM1-43 vesicular release in rat hippocampal slices; and (ii) transgenic mice expressing the genetically encoded pH-sensitive fluorescent reporter synaptopHluorin preferentially at glutamatergic synapses. In this study we found that, 1-2 months after pilocarpine-induced status epilepticus, there were significant increases in mossy fibre bouton size, faster rates of action potential-driven vesicular release and endocytosis.

Metabolic gene expression changes in the hippocampus of obese epileptic male rats in the pilocarpine model of temporal lobe epilepsy.

Chronically epileptic male adult rats in the pilocarpine model of temporal lobe epilepsy (TLE), exhibited gross expansion of abdominal fat mass and significant weight gain several months after induction of status epilepticus (SE) when compared to control rats. We hypothesized that epileptogenesis can induce molecular changes in the hippocampus that may be associated with metabolism. We determined the expression levels of genes Hsd11b1, Nr3c1, Abcc8, Kcnj11, Mc4r, Npy, Lepr, Bdnf, and Drd2 that are involved in regulation of energy metabolism, in the hippocampus of age-matched control and chronic epileptic animals.

Differential expression of voltage-gated K+ currents in medial septum/diagonal band complex neurons exhibiting distinct firing phenotypes.

The medial septum/diagonal band complex (MSDB) controls hippocampal excitability, rhythms and plastic processes. Medial septal neuronal populations display heterogeneous firing patterns. In addition, some of these populations degenerate during age-related disorders (e.

Epileptiform activity in the limbic system.

Mesial temporal lobe epilepsy (MTLE) is a common neurological disorder characterized by hyperexcitability of limbic structures. Studies in epileptic patients and animal models of MTLE indicate that epileptiform activity arise primarily from limbic areas (e.g.

Activation of D1/D5 dopamine receptors protects neurons from synapse dysfunction induced by amyloid-beta oligomers.

Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of Alzheimer disease (AD) patients and are implicated in synapse failure and early memory loss in AD. AβOs have been shown to impact synapse function by inhibiting long term potentiation, facilitating the induction of long term depression and inducing internalization of both AMPA and NMDA glutamate receptors, critical players in plasticity mechanisms. Because activation of dopamine D1/D5 receptors plays important roles in memory circuits by increasing the insertion of AMPA and NMDA receptors at synapses, we hypothesized that selective activation of D1/D5 receptors could protect synapses from the deleterious action of AβOs.

Chronic deficit in the expression of voltage-gated potassium channel Kv3.4 subunit in the hippocampus of pilocarpine-treated epileptic rats.

Voltage gated K(+) channels (Kv) are a highly diverse group of channels critical in determining neuronal excitability. Deficits of Kv channel subunit expression and function have been implicated in the pathogenesis of epilepsy. In this study, we investigate whether the expression of the specific subunit Kv3.

Upregulation of STREX splice variant of the large conductance Ca2+-activated potassium (BK) channel in a rat model of mesial temporal lobe epilepsy.

Functional properties of large conductance Ca(2+) activated potassium (BK) channels are determined by complex alternative splicing of the Kcnma1 gene encoding the alpha pore-forming subunit. Inclusion of the STREX exon in a C-terminal splice site is dynamically regulated and confers enhanced Ca(2+) sensitivity and channel inhibition via cAMP-dependent phosphorylation. Here, we describe a real time quantitative PCR (qPCR) approach to investigate relative changes in the expression of STREX and ZERO splice variants using a newly designed set of probes and primers for TaqMan-based qPCR analysis of cDNA from the rat dentate gyrus at different time points following pilocarpine-induced status epilepticus.

Altered expression and function of small-conductance (SK) Ca(2+)-activated K+ channels in pilocarpine-treated epileptic rats.

Small conductance calcium (Ca(2+)) activated SK channels are critical regulators of neuronal excitability in hippocampus. Accordingly, these channels are thought to play a key role in controlling neuronal activity in acute models of epilepsy. In this study, we investigate the expression and function of SK channels in the pilocarpine model of mesial temporal lobe epilepsy.

Prostaglandin E2 modulates Na+,K+-ATPase activity in rat hippocampus: implications for neurological diseases.

Prostaglandin E(2) (PGE(2)) is quantitatively one of the major prostaglandins synthesized in mammalian brain, and there is evidence that it facilitates seizures and neuronal death. However, little is known about the molecular mechanisms involved in such excitatory effects. Na(+),K(+)-ATPase is a membrane protein which plays a key role in electrolyte homeostasis maintenance and, therefore, regulates neuronal excitability.

Impaired expression and function of group II metabotropic glutamate receptors in pilocarpine-treated chronically epileptic rats.

Group II metabotropic (mGlu II) receptor subtypes mGlu2 and mGlu3 are important modulators of synaptic plasticity and glutamate release in the brain. Accordingly, several pharmacological ligands have been designed to target these receptors for the treatment of neurological disorders characterized by anomalous glutamate regulation including epilepsy. In this study, we examine whether the expression level and function of mGlu2 and mGlu3 are altered in experimental epilepsy by using immunohistochemistry, Western blot analysis, RT-PCR and extracellular recordings.

Deficit of Kcnma1 mRNA expression in the dentate gyrus of epileptic rats.

Epileptogenesis in mesial temporal lobe epilepsy is determined by several factors including abnormalities in the expression and function of ion channels. Here, we report a long-lasting deficit in gene expression of Kcnma1 coding for the large-conductance calcium-activated potassium (BK, MaxiK) channel alpha-subunits after pilocarpine-induced status epilepticus. By using comparative real-time PCR, Taqman gene expression assays, and the delta-delta comparative threshold method we detected a significant reduction in Kcnma1 expression in microdissected dentate gyrus at different intervals after status epilepticus (24 h, 10 days, 1 month, and more than 2 months).

Differential changes in mGlu2 and mGlu3 gene expression following pilocarpine-induced status epilepticus: a comparative real-time PCR analysis.

Group II metabotropic glutamate (mGlu II) receptors subtype 2 and 3 (mGlu2 and mGlu3) are subtle regulators of neuronal excitability and synaptic plasticity in the hippocampus. In recent years, researchers have investigated the potential neuroprotective and anticonvulsant effects of compounds acting on mGlu II receptors. However, abnormal expression and function of mGlu2 and mGlu3 have been reported in temporal lobe epilepsy, a phenomena that may limit the therapeutic effectiveness of these potentially new antiepileptic drugs.

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy.

In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown.

Modulation of normal and altered hippocampal excitability states by septal networks.

The septal region of the basal forebrain plays a dual role: 1) It modulates hippocampal excitability, facilitating synaptic plasticity within hippocampal circuits. Through this mechanism, the septum facilitates diverse cognitive processes that involve hippocampal circuits. 2) Additionally, the septum maintains the hippocampal networks working within normal ranges, decreasing the probability of abnormal excitability states.

Selective vulnerability of hippocampal NAAGergic neurons in experimental temporal lobe epilepsy.

The dipeptide N-acetylaspartylglutamate (NAAG) has been recently implicated in numerous neurological disorders. NAAG binds and stimulates group II metabotropic glutamate receptors producing a down-modulation of synaptic glutamate release. In the present immunohistochemical study, we compare the distribution of NAAG-containing (NAAGergic) neurons between the hippocampus of control and chronic epileptic rats obtained with the pilocarpine model of temporal lobe epilepsy.

Abnormal mGluR2/3 expression in the perforant path termination zones and mossy fibers of chronically epileptic rats.

Epilepsy is characterized by hyperexcitability of hippocampal networks, excessive release of glutamate, and progressive neurodegeneration. Presynaptic group II metabotropic receptors (mGluR2 and mGluR3) are among different mechanisms that modulate presynaptic release of glutamate, especially at the mossy fibers in the hippocampus. Here, we explore whether mGluR2/3 expression is affected in a rat model of temporal lobe epilepsy obtained via pilocarpine-induced status epilepticus (SE).

Septo-hippocampal networks in chronically epileptic rats: potential antiepileptic effects of theta rhythm generation.

A series of experiments was carried out testing the hypothesis that the septal region decreases the hippocampal susceptibility to hyperexcitability states through theta rhythm generation. Medial septal neurons were simultaneously recorded with hippocampal field potentials to investigate the septo-hippocampal function in the pilocarpine model of chronic epilepsy. The theta rhythm from chronically epileptic rats had lower amplitude (20% less) and higher frequency than controls (from 3.

Characterization of medial septal glutamatergic neurons and their projection to the hippocampus.

The two neuronal populations that have been typically investigated in the septum use acetylcholine and GABA as neurotransmitters. The existence of noncholinergic, non-GABAergic, most likely glutamatergic septal neurons has recently been reported. However, their morphological characteristics, numbers, distribution, and connectivity have not been determined.

Immunohistochemical study of six cases of Taylor's type focal cortical dysplasia: correlation with electroclinical data.

Purpose: Cortical specimens from six patients operated on for drug-resistant epilepsy diagnosed as Taylor's type focal cortical dysplasia were submitted to neuropathological and immunohistochemical studies.

Methods: All patients were submitted to presurgical investigations including clinical and neuropsychological evaluations, EEG/video telemetry of ictal and interictal events, magnetic resonance imaging, and ictal and interictal single-photon emission computed tomography (SPECT). Recordings from electrocorticography (ECoG) were obtained in four cases and from subdural electrode implantation in two.