In other words, DS’ profiles emphasized motives associated with traditional models of dependence (so-called “trough maintenance”; Russell, 1971), whereas ITS’ profiles did not. The motives most important in DS’ profiles reflect dependence processes that lead to greater tobacco consumption, more continuous consumption, and loss of voluntary control see more – core characteristics of dependence. In contrast, ITS endorse motives that facilitate tobacco use even if one is not nicotine dependent in the traditional sense, and not smoking continuously (so called “peak-seeking”; Russell,

1971). Further, the motives most highly endorsed by ITS – Social Goads and Cue Exposure – imply being motivated to smoke in particular circumstances and in response to particular cues, rather than needing to smoking continually, which would be a hallmark of dependent smoking, as conventionally construed. Thus, the analysis of standardized WISDM profiles demonstrates that there are qualitative as well as quantitative differences in DS’ and ITS’ motives for smoking. Our findings validate the proposed distinction (Piasecki et al., 2010a and Piper et al., 2008) between PDM

and SDM: In analyses across all motives, with no preconceived organization of motives into PDM and SDM, DS emphasized motives that were part of the PDM cluster, while ITS emphasized motives associated with SDM. Differences between DS and ITS on scales within the standardized selleck kinase inhibitor profiles (Fig. 1a) map remarkably well onto the assignment of scales to PDM and SDM (Piper et al., 2008), and our analysis of the secondary factor scores confirm the pattern. Our findings are also roughly consistent with the hypothesis put forth by Piper et al. (2008) and Piasecki et al. (2010a) that motives such as Craving, Automaticity, and Loss of Control (which Calpain were relatively more important among DS than ITS) emerge only after smokers progress to smoking heavily and develop other hallmarks

of nicotine dependence (as traditionally defined), whereas other motives develop and increase well before this. We find these “primary” motives to be relatively more important among DS than ITS. However, Piper et al. (2004) also identified Behavioral Choice, Cognitive Enhancement, and Positive and Negative Reinforcement as late-emerging motives, yet we found that ITS give similar or even more weight to these motives relative to others. This may reflect the fact that ITS are not novice smokers, having smoked an average of 42,850 cigarettes (Shiffman et al., 2012c), so may well evince late-emerging motives, consistent with our observation (Shiffman et al., 2012b) that ITS do exhibit signs of dependence.

From these parameters, we estimate that the time required to move the probe is 1.3 ms. Thus, the latency for channel activation is 2.1 ms or less. This latency is longer than the shortest latencies measured for other C. elegans neurons ( O’Hagan et al., 2005 and Kang

et al., 2010), but, because the fastest known second messenger-based sensory transduction pathway has a latency of 20 ms ( Hardie, 2001), we propose that this latency is brief enough to suggest that force acts directly on the MeT channels that carry MRCs in ASH. Sinusoidal oscillations were detected in many of our MRC recordings see more suggesting that channel activation is able to follow the rapid, resonant movements of the probe (Figure 1B). To determine the frequency of MRC oscillations, we fit the total MRC with an alpha function and subtracted this fit from the average current to isolate the sinusoidal variations in current (Figure 1B). In five recordings with high-quality oscillations, the MRC oscillation frequency had an average value of 130 ± 6 Hz (mean ± SEM, n = 5). Thus, channels carrying MRCs in the ASH neurons can follow rapid variations in applied mechanical loads. Mechanoreceptor currents, if mediated by a DEG/ENaC channel complex, should be carried by Na+ ions and blocked by amiloride. Conversely, if MRCs were carried by a TRPV channel complex, they should be permeable to both Na+

and K+ and resistant to amiloride. Wild-type MRCs were reversibly

CHIR-99021 solubility dmso blocked by amiloride (Figures 2A and 2B). The fraction of peak current blocked by 300 μM amiloride was 0.77 ± 0.06 (n = 4) and 0.75 ± 0.10 (n = 3) at −90 and −60 mV, respectively. This same level of MRC block was achieved in the gentle touch receptor neuron PLM that expresses the DEG/ENaC channel subunits MEC-4 and MEC-10 with 200 μM amiloride (O’Hagan et al., 2005). MRCs in ASH may be carried by DEG/ENaC channels that are more resistant to amiloride than MEC-4 and MEC-10 or ASH may express a distinct population of channels that is insensitive to amiloride. Below, we provide evidence that MRCs are carried by two classes of ion channels. The ASH neurons terminate in a single cilium CYTH4 that extends into the external environment through an opening in the amphid (Perkins et al., 1986). If the MeT channels localize to this cilium, then exogenous amiloride should inhibit behavioral responses to nose touch. Consistent with this prediction, animals exposed to amiloride for more than 30 min showed a modest but statistically significant decrease in sensitivity to nose touch (Figure 2C). Such a minor effect on nose touch sensitivity is the expected result for two reasons. First, 300 μM amiloride does not completely block MRCs (Figures 2A and 2B). Second, ASH is not the only mechanoreceptor neuron responsible for sensitivity to nose touch (Kaplan and Horvitz, 1993), but it is the only one exposed to the external environment.

4% in 1% acetic acid) was added to each well and plates were incubated at room temperature for 30 min. The

unbound SRB was quickly removed by washing the wells five times with 1% acetic acid. Plates were air-dried, tris-HCL buffer (100 μl, 0.01 M, pH 10.4) was added to all the wells, and plates were gently stirred for 5 min on a mechanical stirrer. The optical density was recorded on ELISA reader at 540 nm. Suitable blanks and positive controls were also included. Each test was done in triplicate. The value reported here in are mean of two experiments. Non-inbred Swiss albino mice from an in-house colony were used in the present study. The experimental animals were housed in standard size polycarbonate cages providing internationally PD0325901 recommended EPZ-6438 price space for each animal. Animals were fed balanced mice feed supplied by M/s Ashirwad Industries, Chandigarh (India) and autoclaved water was available ad libitum. Animals were housed in controlled conditions of temperature (23 ± 2 °C), humidity (50–60) and 12:12 h of light: dark cycle. The studies were conducted according to the ethical norms and guidelines for animal care and were adhered to as recommended by the Indian National Science Academy, New Delhi (1992). Two different

solid tumor models namely Ehrlich tumor and Sarcoma-180 (S-180) were used.19 Animals of the same sex weighing 20 ± 3 g were injected 1 × 107 cells collected from the peritoneal cavity of non-inbread Swiss mice, bearing 8–10 days old ascitic tumor into the right thigh, intramuscularly on Day. The next day animals were randomized

and divided into test groups (7 animals) and one control group (15 animals). Test materials were administered intraperitonealy to test groups as suspension in 1% gum acacia for nine consecutive days. Doses of test materials administered per animal were contained in 0.2 ml suspension with 1% Gum acacia (solvent evaporated). The control group was similarly administered normal saline (0.2 ml, Isotretinoin i.p). The percent tumor growth inhibition in test groups was measured on Day 13 with respect to tumor weight, 5-Flurouracil (22 mg/kg, i.p) was used as positive control. The doses of the test materials are described under results. Data expressed as mean ± S.D., unless otherwise indicated. Comparisons were made between control and treated groups unpaired Student’s t-test and p values <0.01 was considered significant. In vitro cytotoxicity of all the three extracts (alcoholic, hydro-alcoholic and aqueous) of Cuscuta reflexa against four human cancer cell lines from different tissues namely lung, colon, liver, and breast origin was determined at 10, 30 and 100 μg/ml ( Fig. 1). Growth inhibition in a dose dependent manner was observed in all the cell lines by all the extracts. It was observed that aqueous extract was least effective against all the cell lines. The alcoholic extract and hydro-alcoholic extract were more or less equally active depending upon cell line and concentration.

, 2001). R6/1 mice share most of the R6/2 pathology but at a later age. NIIs appear by 9 weeks (Naver et al., 2003), and R6/1 mice also show minimal gliosis (Yu et al., 2003) and similar dendritic spine atrophy check details by 8 months (Spires et al., 2004). Apoptotic and necrotic cells are rarely seen in the striatum of R6/2 and R6/1 mice, despite significant atrophy and ventricular enlargement; instead, electron micrographs contain so-called dark neurons, displaying condensation of the cytoplasm and nucleus without the chromatin fragmentation and nuclear blebbing characteristic of apoptosis (Yu et al., 2003). In contrast, 3-month-old N171-82Q mice do demonstrate cortical and

striatal apoptotic neurons, with reactive gliosis by 4 months. Note that in old (22–30 week) R6/2 chimeras, gliosis is apparent in regions densely populated in transgenic neurons (Reiner et al., 2007), and particularly old R6/2 animals (17 weeks) show astrocytes with processes enveloping degenerating neurons (Turmaine et al., 2000). Therefore, the signals necessary to develop gliosis in R6/2 mice may be present, but the mice may die before glial recruitment and activation. N171-82Q mice also presented with striatal

degeneration and ventricular enlargement by 17 weeks (Gardian CHIR-99021 supplier et al., 2005) and NIIs in many brain regions (cortex, hippocampus, cerebellum, and striatum among others) by late endstage of 6.5 months. NIIs are not seen until far after symptom onset in full-length transgenic HD lines. YAC128 mice display behavioral symptoms at 12 months, and striatal neuron loss of ∼15% is seen by this time (Slow et al., 2003) along with increased intranuclear HTT staining of

certain brain structures (Van Raamsdonk et al., 2005a). However, NIIs did not show up until 18 months of age and only populated ∼30% of striatal neurons and ∼5% of cortical neurons. NIIs were absent in the YAC128 hippocampus, a site of NII staining in endstage R6/2′s (Morton et al., 2000). In the other distinct full-length transgenic strain, BACHD mice also mafosfamide display atrophy of the cortex and striatum by as much as 30% at 12 months (Gray et al., 2008), with 14% of striatal neurons with the aforementioned dark morphology. Interestingly and as opposed to R6 mice, inclusions (over 90%) were extranuclear and were more common in the cortex than striatum, a feature reminiscent of adult onset HD. R6/2 chimaeras suggest that inclusions themselves may be neither toxic nor markers of cells about to die, and a strain arising with a spontaneous mutation in the YAC128 transgene [termed Shortstop (Ss) for its early termination] provides further evidence to this end (Slow et al., 2005). The mutation truncated the transgene after exon 2, providing a product with 128 glutamines and an expected and observed protein size similar to that encoded by the R6/2 transgene.

We show here

that ITD tuning of these neurons is determined by the timing of their excitatory inputs, that these fast excitatory inputs from both ears sum linearly, and that spike probability depends nonlinearly on the size of synaptic inputs. We used a juxtacellular approach to record from MSO neurons in vivo. In contrast to earlier studies in gerbil (Brand et al., ZD1839 2002; Day and Semple, 2011; Pecka et al., 2008; Spitzer and Semple, 1995), we used a ventral approach, which made it easier to map where the MSO cell layer was located. The use of field potentials (Galambos et al., 1959; Mc Laughlin et al., 2010) was critical for determining the cell layer. Within the somatic layer, all cells were excited by both ears, whereas several previous studies found that many cells were inhibited by one ear (Barrett, 1976; Caird and Klinke, 1983; Goldberg and Brown, 1968, 1969; Hall, 1965; Moushegian et al., 1964). Even

though our sample size was limited, and there may be species differences, this suggests that selleckchem some of the reported heterogeneities in the properties of MSO neurons are caused by differences in response properties between MSO neurons within and outside of the somatic layer (Guinan et al., 1972; Langford, 1984; Tsuchitani, 1977). The recordings from the MSO neurons were characterized by the presence of clear subthreshold responses, even in the absence of sounds, and by the presence of low-amplitude spikes. The observation that the spontaneous events could be picked up even in the juxtacellular recordings is partly due to their low membrane resistance, which is caused by the presence of Ih and low-threshold

K+ channels already open at rest ( Khurana et al., 2011, 2012; Mathews et al., 2010; Scott et al., 2005). In agreement with this, the resistive coupling measured in simultaneous juxtacellular and whole-cell recordings was much larger than in principal neurons of the MNTB, whereas the capacitive coupling was similar ( Lorteije et al., 2009). The small size of the somatic action potential tuclazepam is in agreement with slice recordings ( Scott et al., 2005) and is caused by the restricted backpropagation of the axonal action potential to the soma ( Scott et al., 2007). The high spontaneous event rates of at least 500 events/s were in agreement with average spontaneous firing rates of SBCs of ∼56 sp/s ( Kuenzel et al., 2011) and the estimate of minimally 4–8 SBCs innervating each gerbil MSO neuron ( Couchman et al., 2010). The EPSP kinetics largely matched results obtained with slice recordings. Half-widths of EPSPs in juxtacellular recordings were somewhat smaller than in adult slice recordings (∼0.55 ms; Scott et al.

The first network, synchronizing in the beta-band (Figure 3), consisted of frontal (FEF) and parietal (posterior IPS) regions that have been

implicated in multistable perception (Leopold and Logothetis, 1999, Lumer et al., 1998 and Sterzer et al., 2009) and the control of selective attention (Barcelo et al., 2000, Corbetta and Shulman, 2002, Kastner and Ungerleider, 2000, Moore et al., 2003, Posner and Dehaene, 1994 and Serences and Yantis, 2006). Furthermore, the network included early sensory processing stages selective for the ambiguous feature at hand (here: visual motion, MT+) (Tootell et al., 1995). Thus, fluctuations of beta-synchrony between these stages may reflect fluctuations of visual attention that modulate the perceptual organization Forskolin datasheet of the stimulus, with strong interactions favoring the bounce percept. Our results extend previous CHIR-99021 order findings that have implicated beta-band activity across frontal and parietal regions in visual attention, decision making, and sensorimotor integration (Buschman and Miller, 2007, Donner et al., 2007, Gross et al., 2004, Kopell et al., 2000, Pesaran et al., 2008 and Roelfsema et al., 1997). We propose that beta-band synchronization may serve

as a general mechanism mediating large-scale interactions across a network of frontal, parietal, and extrastriate visual areas. The second network synchronizing in the gamma-band (Figure 4 and Figure 5) included central areas consistent with sensorimotor and premotor regions, as well as temporal

areas. Both regions have been implicated in multisensory processing. Premotor regions are responsive to auditory, visual, and somatosensory stimuli (Fogassi et al., 1996, Graziano et al., 1994, Graziano et al., 1999 and Lemus et al., 2009), and temporal regions are involved in the cross-modal integration of audiovisual stimuli Phosphoprotein phosphatase (Barraclough et al., 2005, Bushara et al., 2003, Dahl et al., 2009, Maier et al., 2008, Noesselt et al., 2007 and Schneider et al., 2008). Consistent with this evidence, fluctuations of synchrony within the gamma network did not only reflect the subjects’ percept of the ambiguous stimulus but also predicted interindividual differences in the cross-modal integration of auditory and visual information. Enhanced synchronization was specifically associated with the cross-modally more integrated bounce percept. These results accord well with recent accounts of cross-modal processing that emphasize the role of recurrent interactions between processing streams traditionally considered as unimodal as well as between early sensory and higher-order multimodal processing stages (Driver and Noesselt, 2008, Driver and Spence, 2000, Ghazanfar and Schroeder, 2006, Kayser et al., 2008, Lakatos et al., 2007, Lewis and Noppeney, 2010, Meredith et al., 2009 and Stein and Meredith, 1993).

Our data also suggest that the continuous intra-NAc delivery of DNMT inhibitors represses the expression of Dnmts at the transcription level in postmitotic neurons. Although DNA methylation is generally thought to be associated with transcriptional repression of the target genes, a recent study suggested that the binding of a complex of MeCP2 and cyclic AMP response element (CRE)-binding protein (CREB) to the methylated CpG site can activate transcription (Chahrour et al.,

2008). Interestingly, the putative CRE site is adjacent to CpG site 2 of the Gdnf gene ( Figure 7A). In addition, we found that MeCP2 and CREB are colocalized in the NAc ( Figure 7B). These facts led us to speculate that the binding of the MeCP2-CREB complex to the Gdnf promoter may be a causal mechanism of the increased Gdnf expression in stressed B6

mice. To test this Roxadustat manufacturer possibility, we assessed the interactions of MeCP2 and CREB in vSTR proteins of B6 and BALB mice. IP-Western blot analysis showed that there is no apparent difference in the formation of MeCP2-CREB complexes between stressed and nonstressed mice in both strains ( Figure 7C). Next, to investigate the binding of MeCP2-CREB complexes at the Gdnf promoter, we performed re-ChIP assays using an antibody for CREB on vSTR samples that had been initially immunoprecipitated with an antibody for MeCP2. Consistent with a previous report ( Chahrour et al., 2008), CREB-MeCP2 complexes on the somatostatin promoter were enriched, whereas they were reduced on the selleck chemicals myocyte enhancer factor 2c promoter (data not shown), validating the specificity of the re-ChIP used. We found that the Gdnf promoter-containing DNA fragments of stressed B6 mice were significantly enriched in the reimmunoprecipitates of samples treated with CREB antibodies compared with those of nonstressed mice. This effect was not seen in stressed BALB mice ( Figure 7D). These results L-NAME HCl suggest that the CUMS-induced binding of MeCP2-CREB complexes to the Gdnf promoter leads to the activation of its transcription. This study used genetically distinct

inbred mouse strains to describe one of the molecular mechanisms underlying susceptibility and adaptation responses to chronic stress. The proposed mechanisms underlying stress susceptibility and adaptation are described in Figure 7E. Our results suggest that CUMS increases DNA methylation at CpG site 2, and this is associated with increased MeCP2 binding. MeCP2 associated with CpG site 2 interacts with HDAC2, which in turn decreases the level of H3 acetylation and concomitantly represses Gdnf transcription, leading to the formation of a more depression-susceptible phenotype in BALB mice. Continuous IMI treatment relieves MeCP2 occupancy and reverses HDAC2 levels, which leads to normal levels of H3 acetylation and subsequent Gdnf transcription, resulting in normal emotional behaviors.

The recent development of imaging-based biomarkers that track the progression of tau pathology in living patients should greatly facilitate the early phase testing of tau immunotherapies and other tau-targeting therapeutics (Maruyama et al., 2013). “
“Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders

that share overlapping pathologies, genetic causes, and a lack of disease-modifying PI3K inhibitor treatments (Ling et al., 2013). Precisely two years ago, adjoining papers in Neuron identified large intronic GGGGCC repeat expansions in a gene of unknown function, C9orf72, as a common genetic cause of both FTD and ALS (C9FTD/ALS) ( Renton et al., 2011 and DeJesus-Hernandez et al., 2011). The discovery sparked great interest selleck chemical in the field, partly because the C9orf72 expansion looked a lot like something scientists had seen before: the CUG and CCUG repeats that cause the common dominantly inherited muscle disease myotonic

dystrophy (DM). Work over the past 20 years has demonstrated that repeat expansions in two genes, a CUG repeat in DMPK (in DM1) and a CCUG repeat in ZF9 (in DM2), elicit dominantly inherited disease through a “toxic RNA” gain-of-function mechanism: as RNA, the expanded repeats bind to splicing factors, inhibiting their normal functions. In DM1, for example, the expanded CUG repeat binds Muscleblind-Like

(MBNL) RNA binding proteins, sequestering them in nuclear foci and causing abnormal splicing of key transcripts in muscle and brain. Sodium butyrate Mice lacking MBNL1 or MBNL2 recapitulate disease features of DM1, and conversely, boosting MBNL protein expression suppresses CUG repeat-associated toxicity in model systems (reviewed in Lee and Cooper, 2009). These findings laid the groundwork for successful preclinical trials using antisense oligonucleotides (ASOs) to eliminate the toxic CUG repeat RNA in mouse models ( Wheeler et al., 2012), with plans for a follow-up clinical trial in DM1 patients soon. By contrast, how the GGGGCC repeat expansion triggers C9FTD/ALS is less clear for at least three reasons. First, the case for RNA toxicity in C9FTD/ALS is incomplete. Although GGGGCC RNA foci are present in disease tissues, it remains uncertain whether proteins are bound by the RNA repeat to a degree that would impair normal functions. Experiments that rescue disease features by overexpressing specific sequestered proteins or recapitulate disease features by knocking down the same sequestered proteins have not been reported. Second, expression of C9orf72 mRNA in C9FTD/ALS patients is reduced by ∼50% (DeJesus-Hernandez et al., 2011 and Gijselinck et al., 2012) and the expanded repeat and neighboring CpG islands are hypermethylated (Xi et al.

We quantified α2 subunit of the GABAA receptor (GABAAα2)

clusters, because this subunit is enriched at axo-axonic synapses in the axon initial segment (AIS) ( Loup et al., 1998 and Nusser et al., 1996). We found that the AIS of hippocampal pyramidal cells contained significantly fewer GABAAα2 clusters in conditional Erbb4 mutants than in controls ( Figures 2F–2I). A similar deficit was observed in the lateral entorhinal cortex ( Figure 2I). The length of candlesticks visualized with the presynaptic marker GABA transporter-1 (GAT-1) in the lateral entorhinal cortex was learn more also reduced in the absence of ErbB4 (data not shown). Altogether, these results demonstrate that ErbB4 is necessary for the development and/or maintenance of axo-axonic synapses in the cortex. We next examined whether ErbB4 function was also required for the formation of somatic inhibitory synapses by PV+ basket cells. We quantified the number of PV+ boutons contacting the soma of NeuN+ pyramidal cells in the CA1 region of control and conditional Erbb4 mutants ( Figure 2J). The number of PV+ terminals surrounding the

soma of hippocampal neurons was similar between control and conditional Erbb4 mutants ( Figures 2K–2M). There were no differences in the density of postsynaptic Gephyrin+ clusters and PV+/ Gephyrin+ clusters in the soma of pyramidal cells of conditional Erbb4 mutants and control mice ( Figures S4A–S4G). Likewise, the size of the somatic PV+ terminals Paclitaxel was also indistinguishable between both genotypes ( Figures 2K–2M), suggesting that ErbB4 function is dispensable for PV+ basket cell synapses. We also analyzed all the organization of the postsynaptic compartment in the basket cell. We quantified the density of clusters

of the α1 subunit of the GABAA receptor (GABAAα1) present in the ring-like PV+ structures that identify the inhibitory perisomatic synapses contacting pyramidal cells (Chattopadhyaya et al., 2007 and Huang et al., 1999). We observed a small but significant decrease in the number of GABAAα1+ clusters found in the soma of pyramidal cells in conditional Erbb4 mutants compared to controls ( Figures 2N–2R). The fraction of PV+ terminals contacting a postsynaptic GABAAα1+ cluster and the number of PV+/GABAAα1+ clusters in the soma of pyramidal cells was also significantly reduced, whereas no differences were observed in the density of somatic GABAAα1+ clusters outside PV+ terminals ( Figures 2N–2R). We next measured synaptic activity with whole-cell recordings from hippocampal CA1 pyramidal neurons in acute slices obtained from P20–P22 control and conditional Erbb4 mutant mice ( Figure S4H). Analysis of miniature inhibitory postsynaptic currents (mIPSCs) showed a significant decrease in the frequency of synaptic events in Erbb4 mutants compared to controls, whereas the amplitude of mIPSCs remained unchanged ( Figures S4I–S4K).

The block was trimmed to include

the area of interest and 10 μm serial sections were cut using a diamond Histo-knife with this website an ultramicrotome. Relevant regions were selected for thin sectioning and remounted on blank epon blocks using a small amount of fresh epon and allowed to polymerize overnight. Thin sections were collected on formvar-coated slot grids and stained with uranyl acetate and lead citrate. Grids were viewed using a JEOL 1200EX electron microscope and photographed using a digital camera. For Coracle labeling prior to electron microscopy, animals were fixed in 2.5% paraformaldehyde/0.5% glutaraldehyde in phosphate buffer, and primary antibody labeling was performed with 1:10 anti-Coracle in 0.1% learn more PBS-TX. We used peroxidase conjugated goat anti-mouse

at 1:200 in 0.1% PBS-TX, followed by detection using 1:20 diaminobenzidine in 0.1% PBS-TX with NiCl2 and 3 μl of a 3% hydrogen peroxide solution. The reaction was terminated by several rinses in PBS. Preparations were then mounted as above and photographed on a Zeiss A1 microscope fitted with a Zeiss digital camera and software prior to sectioning for TEM. We are grateful to Dr. Yuh-Nung Jan for discussion of results prior to publication. We thank Drs. Kendal Broadie, Lynn Cooley, John Fessler and Lisa Fessler, Cynthia Hughes, Mark Krasnow, Maria Martin-Bermudo, Ben Ohlstein, Emma Rushton, the Bloomington Stock Center, and Developmental Studies Adenylyl cyclase Hybridoma Bank for fly stocks and antibodies. We thank members of the Grueber lab for contributing

to analysis of GFP trap lines and Rachel Kim and Payal Jain for work on establishing EM protocols. We thank Drs. Jane Dodd, Oliver Hobert, and members of the Grueber lab for comments on the manuscript, and Dr. Qais Al-Awqati for helpful discussion. This work was supported by NIH NINDS R01 NS061908, the Searle Scholars Program, the Klingenstein Foundation, and the McKnight Endowment Fund (W.B.G.). “
“Neurons are highly polarized cells comprised of specialized membrane domains that function in reception, integration, and propagation of electrical activity. Neurons are broadly divided into somatodendritic and axonal compartments, each of which are further organized into distinct subdomains that differ in their composition of ion channels, adhesion molecules, and cytoskeletal scaffolding proteins (Lai and Jan, 2006). One of the most prominent subdomains is the nodal region comprised of the nodes of Ranvier, the flanking paranodal junctions, and the juxtaparanodes (Salzer et al., 2008 and Susuki and Rasband, 2008). This organization is critical to the function of myelinated axons in saltatory conduction. Disturbances of domain organization and function are increasingly appreciated to contribute to axonal pathology in myelin disorders.