GABA is a modulator, rather than a classical transmitter, in the medial nucleus of the trapezoid body-lateral superior olive sound localization circuit.

Key Points: The lateral superior olive (LSO), a brainstem hub involved in sound localization, integrates excitatory and inhibitory inputs from the ipsilateral and the contralateral ear, respectively. In gerbils and rats, inhibition to the LSO reportedly shifts from GABAergic to glycinergic within the first three postnatal weeks. Surprisingly, we found no evidence for synaptic GABA signalling during this time window in mouse LSO principal neurons.

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society.

L-type Calcium Channel Cav1.2 Is Required for Maintenance of Auditory Brainstem Nuclei.

Cav1.2 and Cav1.3 are the major L-type voltage-gated Ca(2+) channels in the CNS.

Inhibitory glycinergic neurotransmission in the mammalian auditory brainstem upon prolonged stimulation: short-term plasticity and synaptic reliability.

Short-term plasticity plays a key role in synaptic transmission and has been extensively investigated for excitatory synapses. Much less is known about inhibitory synapses. Here we analyze the performance of glycinergic connections between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO) in the auditory brainstem, where high spike rates as well as fast and precise neurotransmission are hallmarks.

Inefficient SRP interaction with a nascent chain triggers a mRNA quality control pathway.

Misfolded proteins are often cytotoxic, unless cellular systems prevent their accumulation. Data presented here uncover a mechanism by which defects in secretory proteins lead to a dramatic reduction in their mRNAs and protein expression. When mutant signal sequences fail to bind to the signal recognition particle (SRP) at the ribosome exit site, the nascent chain instead contacts Argonaute2 (Ago2), and the mutant mRNAs are specifically degraded.

The role of phenytoin in the treatment of localization related epilepsy: an international internet-based survey of neurologists and epileptologists.

Phenytoin (PHT) has been the most widely used medication to treat both partial and generalized seizures. However, over the past twenty years, a variety of new compounds have been released with comparable efficacy, fewer adverse effects, and more predictable pharmacokinetic properties. We surveyed neurologists and epileptologists to determine current practice patterns relating to the use of PHT using an online survey instrument.

Identifying recent adaptations in large-scale genomic data.

Although several hundred regions of the human genome harbor signals of positive natural selection, few of the relevant adaptive traits and variants have been elucidated. Using full-genome sequence variation from the 1000 Genomes (1000G) Project and the composite of multiple signals (CMS) test, we investigated 412 candidate signals and leveraged functional annotation, protein structure modeling, epigenetics, and association studies to identify and extensively annotate candidate causal variants. The resulting catalog provides a tractable list for experimental follow-up; it includes 35 high-scoring nonsynonymous variants, 59 variants associated with expression levels of a nearby coding gene or lincRNA, and numerous variants associated with susceptibility to infectious disease and other phenotypes.

Synaptic refinement of an inhibitory topographic map in the auditory brainstem requires functional Cav1.3 calcium channels.

Synaptic refinement via the elimination of inappropriate synapses and strengthening of appropriate ones is crucially important for the establishment of specific, topographic neural circuits. The mechanisms driving these processes are poorly understood, particularly concerning inhibitory projections. Here, we address the refinement of an inhibitory topographic projection in the auditory brainstem in functional and anatomical mapping studies involving patch-clamp recordings in combination with minimal and maximal stimulation, caged glutamate photolysis, and single axon tracing.

Repertoire of high voltage-activated Ca2+ channels in the lateral superior olive: functional analysis in wild-type, Ca(v)1.3(-/-), and Ca(v)1.2DHP(-/-) mice.

Voltage-gated Ca(2+) (Ca(v))1.3 α-subunits of high voltage-activated Ca(2+) channels (HVACCs) are essential for Ca(2+) influx and transmitter release in cochlear inner hair cells and therefore for signal transmission into the central auditory pathway. Their absence leads to deafness and to striking structural changes in the auditory brain stem, particularly in the lateral superior olive (LSO).

Lyme neuroborreliosis presenting as Alice in Wonderland syndrome.

We describe a 7-year-old boy with Alice in Wonderland syndrome associated with Lyme disease. He presented with metamorphopsia and auditory hallucinations in the absence of previous tick bites or other signs of Lyme disease. The boy never developed clinical seizures, and electroencephalograms during these spells indicated no epileptic activity.

Urgent referrals for seizure evaluation to a tertiary care neurology center: a pilot study.

This study evaluates the outcome of urgent neurologic referrals. This was a retrospective review of all referrals to the Floating Hospital for Children in 1 month. The total number of patients referred to our center was 223.

Natural history of Christianson syndrome.

Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types. Gilfillan et al.2008] reported mutations in SLC9A6, the gene encoding the sodium/hydrogen exchanger NHE6, in the family first reported and in three others.

Thapsigargin induces expression of activating transcription factor 3 in human keratinocytes involving Ca2+ ions and c-Jun N-terminal protein kinase.

Thapsigargin is a specific inhibitor of the sarco/endoplasmic reticulum Ca(2+) ATPase of the endoplasmic reticulum. Here, we show that stimulation of human HaCaT keratinocytes with nanomolar concentrations of thapsigargin triggers expression of activating transcription factor (ATF) 3, a basic-region leucin zipper transcription factor. ATF3 expression was also up-regulated in thapsigargin-stimulated glioma cells, hepatoma cells, retinal pigment epithelial cells, and airway epithelial cells.

Differential redox regulation of ORAI ion channels: a mechanism to tune cellular calcium signaling.

Reactive oxygen species (ROS) are involved in many physiological and pathophysiological cellular processes. We used lymphocytes, which are exposed to highly oxidizing environments during inflammation, to study the influence of ROS on cellular function. Calcium ion (Ca(2+)) influx through Ca(2+) release-activated Ca(2+) (CRAC) channels composed of proteins of the ORAI family is essential for the activation, proliferation, and differentiation of T lymphocytes, but whether and how ROS affect ORAI channel function have been unclear.

Closed head injury causes hyperexcitability in rat hippocampal CA1 but not in CA3 pyramidal cells.

Traumatic brain injury frequently elicits epileptic seizures hours or days after the impact. The mechanisms on cellular level are poorly understood. Because posttraumatic epilepsy appears in many cases as a temporal-lobe epilepsy which originated the hippocampus, we studied trauma-induced hyperexcitability on the cellular level in this brain area.

Calcium dependence of T cell proliferation following focal stimulation.

Clonal T cell expansion through proliferation is a central process of the adaptive immune response. Apoptosis of activated T cells is required to avoid chronic inflammation. T cell proliferation and apoptosis are often analyzed with stimuli that do not induce formation of a functional immunological synapse.

Paroxysmal extreme pain disorder (previously familial rectal pain syndrome).

Objective: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A.

Methods: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time.

Disruption of the cortical actin cytoskeleton does not affect store operated Ca2+ channels in human T-cells.

Lymphocyte signaling and activation leads to the influx of extracellular Ca(2+) via the activation of Ca(2+) release activated Ca(2+) (CRAC) channels in the plasma membrane. Activation of CRAC channels occurs following emptying of the endoplasmic reticulum intracellular Ca(2+) stores. One model to explain the coupling of store-emptying to CRAC activation is the secretion-like conformational coupling model.

P2X(7) receptor stimulation upregulates Egr-1 biosynthesis involving a cytosolic Ca(2+) rise, transactivation of the EGF receptor and phosphorylation of ERK and Elk-1.

The P2X(7) receptor is an ATP-gated ionotropic receptor that is permeable for small cations including Ca(2+) ions. Using 293 cells expressing P2X(7) receptors, we show that the P2X(7) receptor-specific ligand 2',3'-O-(4-benzoyl-benzoyl)-ATP (BzATP) induces a signaling cascade leading to the biosynthesis of biologically active Egr-1, a zinc finger transcription factor. BzATP-triggered Egr-1 biosynthesis was attenuated by the mitogen-activated protein kinase kinase inhibitor PD98059, by BAPTA-AM, the acetoxymethylester of the cytosolic Ca(2+) chelator BAPTA, and by an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor (AG1478).

TRP channels in lymphocytes.

TRP proteins form ion channels that are activated following receptor stimulation. Several members of the TRP family are likely to be expressed in lymphocytes. However, in many studies, messenger RNA (mRNA) but not protein expression was analyzed and cell lines but not primary human or murine lymphocytes were used.

Calcium-dependent activation of T-lymphocytes.

Activation of T-lymphocytes requires stimulation of T-cell receptors (TCR) and co-stimulatory signals. Among different signalling cascades, TCR engagement induces Ca(2+) entry through plasma membrane Ca(2+) channels, which is an indispensable step for T-cells to expand clonally and to acquire effector functions. The Ca(2+) channels are activated by depletion of Ca(2+) stores and are called Ca(2+) release-activated Ca(2+) (CRAC) channels.

Two-photon analysis of calcium signals in T lymphocytes of intact lamina propria from human intestine.

Lamina propria (LP) T cells of the human intestinal mucosa usually do not develop systemic immune responses despite permanent exposure to foreign antigens. The mechanisms maintaining this hyporeactivity in the normal gut are poorly understood. It is, at present, not clear what role the microenvironment of the mucosa plays for low T cell reactivity and in the pathogenesis of mucosal inflammation.

Observations on the use of vagus nerve stimulation earlier in the course of pharmacoresistant epilepsy: patients with seizures for six years or less.

Background: This study retrospectively compared the effectiveness of vagus nerve stimulation (VNS) therapy among a constant cohort of patients in the patient outcome registry, which systematically monitors outcomes of patients receiving VNS therapy. Patients in the study had pharmacoresistant seizures for 6 years or less (early treatment group) or more than 6 years (late treatment group) before initiation of VNS therapy, and results are provided after both 3 and 12 months.

Review Summary: Of 405 patients, 51 were in the early and 354 in the late treatment groups.