The signals that determine whether axons are ensheathed or myelinated by Schwann cells have long been elusive. We now report that threshold levels of neuregulin-1 (NRG1) type III on axons determine their ensheathment fate. Ensheathed axons express low levels whereas myelinated fibers express high levels of NRG1 type III. Sensory neurons from NRG1 type III deficient mice are poorly ensheathed and fail to myelinate; lentiviral-mediated expression of NRG1 type III rescues these defects. Expression also converts the normally unmyelinated axons of sympathetic neurons to myelination. Nerve fibers of mice haploinsufficient for NRG1 type III are disproportionately unmyelinated, aberrantly ensheathed, and hypomyelinated, with reduced conduction velocities. Type III is the sole NRG1 isoform retained at the axon surface and activates PI 3-kinase, which is required for Schwann cell myelination. These results indicate that levels of NRG1 type III, independent of axon diameter, provide a key instructive signal that determines the ensheathment fate of axons.
While most gene transcription yields RNA transcripts that code for proteins, a sizable proportion of the genome generates RNA transcripts that do not code for proteins, but may have important regulatory functions. The brain-derived neurotrophic factor (BDNF ) gene, a key regulator of neuronal activity, is overlapped by a primate-specific, antisense long noncoding RNA (lncRNA) called BDNFOS. We demonstrate reciprocal patterns of BDNF and BDNFOS transcription in highly active regions of human neocortex removed as a treatment for intractable seizures. A genome-wide analysis of activity-dependent coding and noncoding human transcription using a custom lncRNA microarray identified 1288 differentially expressed lncRNAs, of which 26 had expression profiles that matched activity-dependent coding genes and an additional 8 were adjacent to or overlapping with differentially expressed protein-coding genes. The functions of most of these protein-coding partner genes, such as ARC, include long-term potentiation, synaptic activity, and memory. The nuclear lncRNAs NEAT1, MALAT1, and RPPH1, composing an RNAse P-dependent lncRNA-maturation pathway, were also upregulated. As a means to replicate human neuronal activity, repeated depolarization of SY5Y cells resulted in sustained CREB activation and produced an inverse pattern of BDNF-BDNFOS co-expression that was not achieved with a single depolarization. RNAimediated knockdown of BDNFOS in human SY5Y cells increased BDNF expression, suggesting that BDNFOS directly downregulates BDNF. Temporal expression patterns of other lncRNA-messenger RNA pairs validated the effect of chronic neuronal activity on the transcriptome and implied various lncRNA regulatory mechanisms. lncRNAs, some of which are unique to primates, thus appear to have potentially important regulatory roles in activity-dependent human brain plasticity.T HE availability of mammalian genome sequences has made it possible to delineate the boundaries and structures of all genes in a genome and has demonstrated an abundance of non-protein-coding transcriptional units that rivals the numbers of known protein-coding genes (reviewed in Carninci and Hayashizaki 2007). Complex and potentially functional regulatory relationships between protein-coding and noncoding genes, including noncoding RNA genes that are poorly conserved across different species, have recently been delineated (Katayama et al. 2005;Engstrom et al. 2006). These long noncoding RNA (lncRNA) genes can be defined by four fundamental criteria: encoding transcripts that lack any open reading frames (ORFs) .100 amino acids or possessing protein database homologies (Dinger et al. 2008); being within the known range of lengths of mammalian mRNAs; support by transcript-to-genome alignments from complementary DNA (cDNA) data; and absence of matches to any known noncoding-RNA classes. Functionally, lncRNAs can have regulatory effects on coding mRNAs through a number of mechanisms, including those involving endogenous antisense lncRNA transcripts that repress ...
Neurocysticercosis is responsible for increased rates of seizures and epilepsy in endemic regions. The most common form of the disease, chronic calcific neurocysticercosis, is the end result of the host's inflammatory response to the larval cysticercus of Taenia solium. There is increasing evidence indicating that calcific cysticercosis is not clinically inactive but a cause of seizures or focal symptoms in this population. Perilesional edema is at times also present around implicated calcified foci. A better understanding of the natural history, frequency, epidemiology, and pathophysiology of calcific cysticercosis and associated disease manifestations is needed to define its importance, treatment, and prevention.Neurocysticercosis is a major cause of seizures and other neurologic problems in many less developed countries 1 and a significant health concern in developed countries as well, mostly due to migration of infected persons. 2 Over the last two decades the development of MRI and CT imaging, effective and safe cysticidal drugs, and specific and relatively sensitive serologic tests have given rise to a renaissance in our understanding of the disease and efficacy of treatments. Much of our increased understanding has focused on disease associated with viable or degenerating cysts, broadly referred to as "active" cysticercosis, Copyright © 2004 Life cycleHumans harbor the tapeworm that is acquired by eating poorly cooked pork containing cysticerci of Taenia solium. Ova or proglottids containing ova are excreted in the feces and when ingested by free roaming pigs develop into cysts primarily in the muscles and brain. The usual life cycle is fulfilled after humans ingest undercooked pork. Ova, accidentally ingested by humans, also develop into cysts, mostly in the brain, muscle, and subcutaneous tissues, and this condition is referred to as cysticercosis. 5 Course of infectionAlthough incompletely documented, a reasonable view of the natural history can be ascertained from pathologic, radiologic, and parasitologic studies. Cysticercosis and epilepsyWhile many patients present with single or groups of seizures at various stages of this disease, not all patients develop recurrent seizures, or epilepsy. There are three possibly different scenarios concerning the relationship between cysticercosis and epilepsy: 1) causal relationship, namely, cysticercosis as the cause of focal epilepsies; 2) non causal relationship or simple overlap of two independent and unrelated diseases; and 3) dual pathology. At present there is overwhelming evidence supporting neurocysticercosis as a cause of seizures and epilepsy. Because neurocysticercosis, particularly calcific cysticercosis, is so common in endemic regions (see below), it is likely that two pathologies known to incite seizure activity will be present in some individuals 12 and whether there are interactions or dual pathology between two conditions is speculative. 12 Multiple causes of seizures in cysticercosisThere are multiple ways that cysticercosis can ca...
A key component in the response of the nervous system to injury is the proliferation and switch to a "proinflammatory" phenotype by microglia (microgliosis). In situations where the blood-brain barrier is intact, microglial numbers increase via the proliferation and chemotaxis of resident microglia; however, there is limited knowledge regarding the factors mediating this response. After peripheral nerve injury, a dorsal horn microgliosis develops, which directly contributes to the development of neuropathic pain. Neuregulin-1 (NRG-1) is a growth and differentiation factor with a well characterized role in neural and cardiac development. Microglia express the NRG1 receptors erbB2, 3, and 4, and NRG1 signaling via the erbB2 receptor stimulated microglial proliferation, chemotaxis, and survival, as well as interleukin-1 release in vitro. Intrathecal treatment with NRG1 resulted in microglial proliferation within the dorsal horn, and these cells developed an activated morphology. This microglial response was associated with the development of both mechanical and cold pain-related hypersensitivity. Primary afferents express NRG1, and after spinal nerve ligation (SNL) we observed both an increase in NRG1 within the dorsal horn as well as activation of erbB2 specifically within microglia. Blockade of the erbB2 receptor or sequestration of endogenous NRG after SNL reduced the proliferation, the number of microglia with an activated morphology, and the expression of phospho-P38 by microglia. Furthermore, consequent to such changes, the mechanical pain-related hypersensitivity and cold allodynia were reduced. NRG1-erbB signaling therefore represents a novel pathway regulating the injury response of microglia.
Here we put forward a roadmap that summarizes important questions that need to be answered to determine more effective and safer treatments. A key concept in management of neurocysticercosis is the understanding that infection and disease due to neurocysticercosis are variable and thus different clinical approaches and treatments are required. Despite recent advances, treatments remain either suboptimal or based on poorly controlled or anecdotal experience. A better understanding of basic pathophysiologic mechanisms including parasite survival and evolution, nature of the inflammatory response, and the genesis of seizures, epilepsy, and mechanisms of anthelmintic action should lead to improved therapies.
Epilepsy is a disorder of recurrent seizures that affects 1% of the population. To understand why some areas of cerebral cortex produce seizures and others do not, we identified differentially expressed genes in human epileptic neocortex compared to nearby regions that did not produce seizures. The transcriptome that emerged strongly implicates MAP kinase signaling and CREB-dependent transcription, with 74% of differentially expressed genes containing a cyclic AMP response element (CRE) in their proximal promoter, more than half of which are conserved. Despite the absence of recent seizures in these patients, epileptic brain regions prone to seizures showed persistent activation of ERK and CREB. Persistent CREB activation was directly linked to CREB-dependent gene transcription by chromatin immunoprecipitation that showed phosphorylated CREB constitutively associated with the proximal promoters of many of the induced target genes involved in neuronal signaling, excitability and synaptic plasticity. A distinct spatial pattern of ERK activation was seen in superficial axodendritic processes of epileptic neocortex that co-localized with both CREB phosphorylation and CREB target gene induction in well-demarcated populations of layer 2/3 neurons. These same neuronal lamina showed a marked increase in synaptic density. The findings generated in this study generate a robust and spatially-restricted pattern of epileptic biomarkers and associated synaptic changes that could lead to new mechanistic insights and potential therapeutic targets for human epilepsy.
Summary A biomarker is defined as an objectively measured characteristic of a normal or pathological biological process. Identification and proper validation of biomarkers of epileptogenesis, the development of epilepsy, and ictogenesis, the propensity to generate spontaneous seizures, might predict the development of an epilepsy condition; identify the presence and severity of tissue capable of generating spontaneous seizures; measure progression after the condition is established; and determine pharmacoresistance. Such biomarkers could be used to create animal models for more cost-effective screening of potential antiepileptogenic and antiseizure drugs and devices, and to reduce the cost of clinical trials by enriching the trial population, and acting as surrogate markers to shorten trial duration. The objectives of the biomarker subgroup for the London Workshop were to define approaches for identifying possible biomarkers for these purposes. Research to identify reliable biomarkers may also reveal underlying mechanisms that could serve as therapeutic targets for the development of new antiepileptogenic and antiseizure compounds.
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