Birds use microsecond differences in the arrival times of the sounds at the two ears to infer the location of a sound source in the horizontal plane. These interaural time differences (ITDs) are ...encoded by binaural neurons which fire more when the ITD matches their "best delay." In the textbook model of sound localization, the best delays of binaural neurons reflect the differences in axonal delays of their monaural inputs, but recent observations have cast doubts on this classical view because best delays were found to depend on preferred frequency. Here, we show that these observations are in fact consistent with the notion that best delays are created by differences in axonal delays, provided ITD tuning is created during development through spike-timing-dependent plasticity: basilar membrane filtering results in correlations between inputs to binaural neurons, which impact the selection of synapses during development, leading to the observed distribution of best delays.
Paramyotonia congenita (PC) is a dominantly inherited skeletal muscle disorder caused by missense mutations in the SCN4A gene
encoding the pore-forming α subunit (hSkM1) of the skeletal muscle Na + ...channel. Muscle stiffness is the predominant clinical symptom. It is usually induced by exposure to cold and is aggravated
by exercise. The most prevalent PC mutations occur at T1313 on DIIIâDIV linker, and at R1448 on DIVâS4 of the α subunit. Only
one substitution has been described at T1313 (T1313M), whereas four distinct amino-acid substitutions were found at R1448
(R1448C/H/P/S). We report herein a novel mutation at position 1313 (T1313A) associated with a typical phenotype of PC. We
stably expressed T1313A or wild-type (hSkM1) channels in HEK293 cells, and performed a detailed study on mutant channel gating
defects using the whole-cell configuration of the patch-clamp technique. T1313A mutation impaired Na + channel fast inactivation: it slowed and reduced the voltage sensitivity of the kinetics, accelerated the recovery, and decreased
the voltage-dependence of the steady state. Slow inactivation was slightly enhanced by the T1313A mutation: the voltage dependence
was shifted toward hyperpolarization and its steepness was reduced compared to wild-type. Deactivation from the open state
assessed by the tail current decay was only slowed at positive potentials. This may be an indirect consequence of disrupted
fast inactivation. Deactivation from the inactivation state was hastened. The T1313A mutation did not modify the temperature
sensitivity of the Na + channel per se . However, gating kinetics of the mutant channels were further slowed with cooling, and reached levels that may represent
the threshold for myotonia. In conclusion, our results confirm the role of T1313 residue in Na + channel fast inactivation, and unveil subtle changes in other gating processes that may influence the clinical phenotype.
The inward rectifier K + channel Kir2.1 carries all Andersen's syndrome mutations identified to date. Patients exhibit symptoms of periodic paralysis,
cardiac dysrhythmia and multiple dysmorphic ...features. Here, we report the clinical manifestations found in three families
with Andersen's syndrome. Molecular genetics analysis identified two novel missense mutations in the KCNJ2 gene leading to amino acid changes C154F and T309I of the Kir2.1 open reading frame. Patch clamp experiments showed that
the two mutations produced a loss of channel function. When co-expressed with Kir2.1 wild-type (WT) channels, both mutations
exerted a dominant-negative effect leading to a loss of the inward rectifying K + current. Confocal microscopy imaging in HEK293 cells is consistent with a co-assembly of the EGFP-fused mutant proteins with
WT channels and proper traffick to the plasma membrane to produce silent channels alone or as hetero-tetramers with WT. Functional
expression in C2C12 muscle cell line of newly as well as previously reported Andersen's syndrome mutations confirmed that
these mutations act through a dominant-negative effect by altering channel gating or trafficking. Finally, in vivo electromyographic evaluation showed a decrease in muscle excitability in Andersen's syndrome patients. We hypothesize that
Andersen's syndrome-associated mutations and hypokalaemic periodic paralysis-associated calcium channel mutations may lead
to muscle membrane hypoexcitability via a common mechanism.
Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated ...regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
Little is known about the neuronal substrates of neuropsychiatric symptoms associated with COVID-19 and their evolution during the course of the disease. We aimed at describing the ...longitudinal brain metabolic pattern in COVID-19-related encephalopathy using 18F-FDG-PET/CT.
Methods
Seven patients with variable clinical presentations of COVID-19-related encephalopathy were explored thrice with brain 18F-FDG-PET/CT, once in the acute phase, 1 month later and 6 months after COVID-19 onset. PET images were analysed with voxel-wise and regions-of-interest approaches in comparison with 32 healthy controls.
Results
Patients’ neurological manifestations during acute encephalopathy were heterogeneous. However, all of them presented with predominant cognitive and behavioural frontal disorders. SARS-CoV-2 RT-PCR in the CSF was negative for all patients. MRI revealed no specific abnormalities for most of the subjects. All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities.
Conclusion
The implication of this widespread network could be the neural substrate of clinical features observed in patients with COVID-19, such as frontal lobe syndrome, emotional disturbances and deregulation of respiratory failure perception. This study suggests that this network remains mildly to severely impaired 6 months after disease onset.
The amyloid precursor protein (APP) is cleaved by β- and γ-secretases to generate the β-amyloid (Aβ) peptides, which are present in large amounts in the amyloid plaques of Alzheimer disease (AD) ...patient brains. Non-amyloidogenic processing of APP by α-secretases leads to proteolytic cleavage within the Aβ peptide sequence and shedding of the soluble APP ectodomain (sAPPα), which has been reported to be endowed with neuroprotective properties. In this work, we have shown that activation of the purinergic receptor P2X7 (P2X7R) stimulates sAPPα release from mouse neuroblastoma cells expressing human APP, from human neuroblastoma cells and from mouse primary astrocytes or neural progenitor cells. sAPPα shedding is inhibited by P2X7R antagonists or knockdown of P2X7R with specific small interfering RNA (siRNA) and is not observed in neural cells from P2X7R-deficient mice. P2X7R-dependent APP-cleavage is independent of extracellular calcium and strongly inhibited by hydroxamate-based metalloprotease inhibitors, TAPI-2 and GM6001. However, knockdown of a disintegrin and metalloproteinase-9 (ADAM9), ADAM10 and ADAM17 by specific siRNA, known to have α-secretase activity, does not block the P2X7R-dependent non-amyloidogenic pathway. Using several specific pharmacological inhibitors, we demonstrate that the mitogen-activated protein kinase modules Erk1/2 and JNK are involved in P2X7R-dependent α-secretase activity. Our study suggests that P2X7R, which is expressed in hippocampal neurons and glial cells, is a potential therapeutic target in AD.
The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers in university hospitals and regional networks of neurologists. The routine use of ...European database for multiple sclerosis (EDMUS) in all those centers has paved the way for the constitution of a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes a prospective, standardized, high-quality, and multimodal collection of data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge database is open to the scientific community and might contribute exploring unresolved issues and unmet needs in MS.
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological ...disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Single neurons function along a spectrum of neuronal operating modes whose properties determine how the output firing activity is generated from synaptic input. The auditory brain stem contains a ...diversity of neurons, from pure coincidence detectors to pure integrators and those with intermediate properties. We investigated how intrinsic spike initiation mechanisms regulate neuronal operating mode in the avian cochlear nucleus. Although the neurons in one division of the avian cochlear nucleus, nucleus magnocellularis, have been studied in depth, the spike threshold dynamics of the tonically firing neurons of a second division of cochlear nucleus, nucleus angularis (NA), remained unexplained. The input-output functions of tonically firing NA neurons were interrogated with directly injected in vivo-like current stimuli during whole cell patch-clamp recordings in vitro. Increasing the amplitude of the noise fluctuations in the current stimulus enhanced the firing rates in one subset of tonically firing neurons ("differentiators") but not another ("integrators"). We found that spike thresholds showed significantly greater adaptation and variability in the differentiator neurons. A leaky integrate-and-fire neuronal model with an adaptive spike initiation process derived from sodium channel dynamics was fit to the firing responses and could recapitulate >80% of the precise temporal firing across a range of fluctuation and mean current levels. Greater threshold adaptation explained the frequency-current curve changes due to a hyperpolarized shift in the effective adaptation voltage range and longer-lasting threshold adaptation in differentiators. The fine-tuning of the intrinsic properties of different NA neurons suggests they may have specialized roles in spectrotemporal processing.
Avian cochlear nucleus angularis (NA) neurons are responsible for encoding sound intensity for sound localization and spectrotemporal processing. An adaptive spike threshold mechanism fine-tunes a subset of repetitive-spiking neurons in NA to confer coincidence detector-like properties. A model based on sodium channel inactivation properties reproduced the activity via a hyperpolarized shift in adaptation conferring fluctuation sensitivity.
Echolocating bats are thought to be able to create an image of their environment by emitting pulses and analyzing the reflected echoes. In this paper, the theory of sparse representations and its ...more recent further development into compressed sensing are applied to this biosonar image formation task. Considering the target image representation as sparse allows formulation of this inverse problem as a convex optimization problem for which well defined and efficient solution methods have been established. The resulting technique, referred to as L1-minimization, is applied to simulated data to analyze its performance relative to delay accuracy and delay resolution experiments. This method performs comparably to the coherent receiver for the delay accuracy experiments, is quite robust to noise, and can reconstruct complex target impulse responses as generated by many closely spaced reflectors with different reflection strengths. This same technique, in addition to reconstructing biosonar target images, can be used to simultaneously localize these complex targets by interpreting location cues induced by the bat's head related transfer function. Finally, a tentative explanation is proposed for specific bat behavioral experiments in terms of the properties of target images as reconstructed by the L1-minimization method.
PDF
