Does acquired epileptogenesis in the immature brain require neuronal death.

Because epilepsy often occurs during development, understanding the mechanisms by which this process takes place (epileptogenesis) is important. In addition, the age-specificity of seizures and epilepsies of the neonatal, infancy, and childhood periods suggests that the processes and mechanisms that culminate in epilepsy might be age specific as well. Here we provide an updated review of recent and existing literature and discuss evidence that neuronal loss may occur during epileptogenesis in the developing brain, but is not required for the epileptogenic process. We speculate about the mechanisms for the resilience of neurons in immature limbic structures to epileptogenic insults, and propose that the type, duration and severity of these insults influence the phenomenology of the resulting spontaneous seizures

Nuclear Respiratory Factor 1 (NRF-1) Controls the Activity Dependent Transcription of the GABA-A Receptor Beta 1 Subunit Gene in Neurons

While the exact role of β1 subunit-containing GABA-A receptors (GABARs) in brain function is not well understood, altered expression of the β1 subunit gene (GABRB1) is associated with neurological and neuropsychiatric disorders. In particular, down-regulation of β1 subunit levels is observed in brains of patients with epilepsy, autism, bipolar disorder and schizophrenia. A pathophysiological feature of these disease states is imbalance in energy metabolism and mitochondrial dysfunction. The transcription factor, nuclear respiratory factor 1 (NRF-1), has been shown to be a key mediator of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Using a variety of molecular approaches (including mobility shift, promoter/reporter assays, and overexpression of dominant negative NRF-1), we now report that NRF-1 regulates transcription of GABRB1 and that its core promoter contains a conserved canonical NRF-1 element responsible for sequence specific binding and transcriptional activation. Our identification of GABRB1 as a new target for NRF-1 in neurons suggests that genes coding for inhibitory neurotransmission may be coupled to cellular metabolism. This is especially meaningful as binding of NRF-1 to its element is sensitive to the kind of epigenetic changes that occur in multiple disorders associated with altered brain inhibition

Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135085/1/epi13557_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135085/2/epi13557.pd

Two tyrosine residues on the a subunit are crucial for benzodiazepine binding and allosteric modulation of g-aminobutyric acidA receptors. Mol Pharmacol 51:833–841.

SUMMARY Benzodiazepines (BZs) exert their therapeutic effects in the mammalian central nervous system at least in part by modulating the activation of ␥-aminobutyric acid (GABA)-activated chloride channels. To gain further insight into the mechanism of action of BZs on GABA receptors, we have been investigating structural determinants required for the actions of the BZ diazepam (dzp) on recombinant ␣1␤2␥2 GABA A receptors. Sitedirected mutagenesis was used to introduce point mutations into the ␣1 and ␥2 GABA A receptor subunits. Wild-type and mutant GABA A receptors were then expressed in Xenopus laevis oocytes or human embryonic kidney 293 (HEK 293) cells and studied using two-electrode voltage-clamp and ligandbinding techniques. With this approach, we identified two tyrosine residues on the ␣1 subunit (Tyr159 and Tyr209) that when mutated to serine, dramatically impaired modulation by dzp. The Y209S substitution resulted in a Ͼ7-fold increase in the EC 50 for dzp, and the Y159S substitution nearly abolished dzp-mediated potentiation. Both of these mutations abolished binding of the high affinity BZ receptor antagonist [ 3 H]Ro 15-1788 to GABA A receptors expressed in HEK 293 cells. These tyrosine residues correspond to two tyrosines of the ␤2 subunit (Tyr157 and Tyr205) previously postulated to form part of the GABA-binding site. Mutation of the corresponding tyrosine residues on the ␥2 subunit produced only a slight increase in the EC 50 for dzp (ϳ2-fold) with no significant effect on the binding affinity of [ 3 H]Ro 15-1788. These data suggest that Tyr159 and Tyr209 of the ␣1 subunit may be components of the BZ-binding site on ␣1␤2␥2 GABA A receptors. BZs are frequently prescribed as anxiolytics, sedatives, anticonvulsants, and muscle relaxants (1-3). It is now generally accepted that these compounds exert their therapeutic effects, at least partly, by interacting with GABA A receptors in the brain (2-8). Thus, a substantial effort has been directed at understanding the molecular mechanism by which BZs modulate GABA A receptor function (9 -12). Molecular cloning studies (13-15) have revealed multiple classes and isoforms of GABA A receptor subunits in the mammalian brain (␣1-6, ␤1-4, ␥1-3, ␦). This diversity of ␣, ␤, and ␥ subunits allows the expression of a vast number of structurally unique GABA A receptor subtypes with distinct pharmacologies. Studies using exogenous expression, photoaffinity labeling, chimeric subunits, and site-directed mutagenesis have indicated that the ␣ subunit contributes a major component of the BZ-binding site and, depending on the subtype, can confer either BZ1 or BZ2 pharmacology on the GABA A receptor (16 -23). In particular, a histidine residue at position 101 (22) and a glycine residue at position 200 (21) have been implicated in BZ binding to the GABA receptor complex Although the ␣ subunit seems to form part of the BZbinding site, the presence of a ␥ subunit is essential for the normal modulatory actions of BZs on GABA A receptors We previously identified two tyrosines at position 157 and 205 of the ␤2 subuni

Does acquired epileptogenesis in the immature brain require neuronal death.

Because epilepsy often occurs during development, understanding the mechanisms by which this process takes place (epileptogenesis) is important. In addition, the age-specificity of seizures and epilepsies of the neonatal, infancy, and childhood periods suggests that the processes and mechanisms that culminate in epilepsy might be age specific as well. Here we provide an updated review of recent and existing literature and discuss evidence that neuronal loss may occur during epileptogenesis in the developing brain, but is not required for the epileptogenic process. We speculate about the mechanisms for the resilience of neurons in immature limbic structures to epileptogenic insults, and propose that the type, duration and severity of these insults influence the phenomenology of the resulting spontaneous seizures

Neonatal Seizures.

Neonatal seizures are common among patients with acute brain injury or critical illness and can be difficult to diagnose and treat. The most common etiology of neonatal seizures is hypoxic-ischemic encephalopathy, with other common causes including ischemic stroke and intracranial hemorrhage. Neonatal clinicians can use a standardized approach to patients with suspected or confirmed neonatal seizures that entails laboratory testing, neuromonitoring, and brain imaging. The primary goals of management of neonatal seizures are to identify the underlying cause, correct it if possible, and prevent further brain injury. This article reviews recent evidence-based guidelines for the treatment of neonatal seizures and discusses the long-term outcomes of patients with neonatal seizures

Evidence for a non-canonical JAK/STAT signaling pathway in the synthesis of the brain's major ion channels and neurotransmitter receptors.

BackgroundBrain-derived neurotrophic factor (BDNF) is a major signaling molecule that the brain uses to control a vast network of intracellular cascades fundamental to properties of learning and memory, and cognition. While much is known about BDNF signaling in the healthy nervous system where it controls the mitogen activated protein kinase (MAPK) and cyclic-AMP pathways, less is known about its role in multiple brain disorders where it contributes to the dysregulated neuroplasticity seen in epilepsy and traumatic brain injury (TBI). We previously found that neurons respond to prolonged BDNF exposure (both in vivo (in models of epilepsy and TBI) and in vitro (in BDNF treated primary neuronal cultures)) by activating the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway. This pathway is best known for its association with inflammatory cytokines in non-neuronal cells.ResultsHere, using deep RNA-sequencing of neurons exposed to BDNF in the presence and absence of well characterized JAK/STAT inhibitors, and without non-neuronal cells, we determine the BDNF transcriptome that is specifically regulated by agents that inhibit JAK/STAT signaling. Surprisingly, the BDNF-induced JAK/STAT transcriptome contains ion channels and neurotransmitter receptors coming from all the major classes expressed in the brain, along with key modulators of synaptic plasticity, neurogenesis, and axonal remodeling. Analysis of this dataset has revealed a unique non-canonical mechanism of JAK/STATs in neurons as differential gene expression mediated by STAT3 is not solely dependent upon phosphorylation at residue 705 and may involve a BDNF-induced interaction of STAT3 with Heterochromatin Protein 1 alpha (HP1α).ConclusionsThese findings suggest that the neuronal BDNF-induced JAK/STAT pathway involves more than STAT3 phosphorylation at 705, providing the first evidence for a non-canonical mechanism that may involve HP1α. Our analysis reveals that JAK/STAT signaling regulates many of the genes associated with epilepsy syndromes where BDNF levels are markedly elevated. Uncovering the mechanism of this novel form of BDNF signaling in the brain may provide a new direction for epilepsy therapeutics and open a window into the complex mechanisms of STAT3 transcriptional regulation in neurological disease