Children with autism exhibit a host of motor disorders including poor coordination, poor tool use and delayed learning of complex motor skills like riding a tricycle. Theory suggests that one of the crucial steps in motor learning is the ability to form internal models: to predict the sensory consequences of motor commands and learn from errors to improve performance on the next attempt. The cerebellum appears to be an important site for acquisition of internal models, and indeed the development of the cerebellum is abnormal in autism. Here, we examined autistic children on a range of tasks that required a change in the motor output in response to a change in the environment. We first considered a prism adaptation task in which the visual map of the environment was shifted. The children were asked to throw balls to visual targets with and without the prism goggles. We next considered a reaching task that required moving the handle of a novel tool (a robotic arm). The tool either imposed forces on the hand or displaced the cursor associated with the handle position. In all tasks, the children with autism adapted their motor output by forming a predictive internal model, as exhibited through after-effects. Surprisingly, the rates of acquisition and washout were indistinguishable from normally developing children. Therefore, the mechanisms of acquisition and adaptation of internal models in self-generated movements appeared normal in autism. Sparing of adaptation suggests that alternative mechanisms contribute to impaired motor skill development in autism. Furthermore, the findings may have therapeutic implications, highlighting a reliable mechanism by which children with autism can most effectively alter their behaviour.
reach adaptation; prism adaptation; motor control; autism
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
comorbidity; depression; epilepsy; hippocampus; serotonin
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioral and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naïve animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioral equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
Comorbidity; depression; epilepsy; hippocampus; serotonin
Children with autism exhibit a host of motor disorders including poor coordination, poor tool use, and delayed learning of complex motor skills like riding a tricycle. Theory suggests that one of the crucial steps in motor learning is the ability to form internal models: to predict the sensory consequences of motor commands and learn from errors to improve performance on the next attempt. The cerebellum appears to be an important site for acquisition of internal models, and indeed the development of the cerebellum is abnormal in autism. Here, we examined autistic children on a range of tasks that required a change in the motor output in response to a change in the environment. We first considered a prism adaptation task in which the visual map of the environment was shifted. The children were asked to throw balls to visual targets with and without the prism goggles. We next considered a reaching task that required moving the handle of a novel tool (a robotic arm). The tool either imposed forces on the hand or displaced the cursor associated with the handle position. In all tasks, the children with autism adapted their motor output by forming a predictive internal model, as exhibited through after-effects. Surprisingly, the rates of acquisition and washout were indistinguishable from normally developing children. Therefore, the mechanisms of acquisition and adaptation of internal models in self-generated movements appeared normal in autism. Sparing of adaptation suggests that alternative mechanisms contribute to impaired motor skill development in autism. Furthermore, the findings may have therapeutic implications, highlighting a reliable mechanism by which children with autism can most effectively alter their behavior.
reach adaptation; prism adaptation; motor control; autism
have recently identified 1,8-naphthyridin-2(1H)-one-3-carboxamide
as a new scaffold very suitable for the development
of new CB2 receptor potent and selective ligands. In this paper we
describe a number of additional derivatives in which the same central
scaffold has been variously functionalized in position 1 or 6. All
new compounds showed high selectivity and affinity in the nanomolar
range for the CB2 receptor. Furthermore, we found that their functional
activity is controlled by the presence of the substituents at position
C-6 of the naphthyridine scaffold. In fact, the introduction of substituents
in this position determined a functionality switch from agonist to
antagonists/inverse agonists. Finally, docking studies showed that
the difference between the pharmacology of these ligands may be in
the ability/inability to block the Toggle Switch W6.48(258) (χ1 g+ → trans) transition.
Background & objectives
Little is known about outcomes after transfer out (TFO) and loss to follow-up (LTF) and how differential outcomes might bias mortality estimates, as analyses generally censor or exclude TFOs/LTF. Using data linked to the National Population Register (NPR), we explored mortality among patients TFO and LTF compared with patients retained and investigated how linkage impacted on mortality estimates.
A cohort analysis of routine data on adults with civil-identification numbers starting ART 2004–2009 in four large South African ART cohorts. The number, proportion, timing and mortality of TFOs and LTF were reported. Mortality was compared using Kaplan-Meier curves, Cox’s proportional hazards and competing risks regression.
Before linkage, 1207 patients (6%) had died, 2624 (13%) were LTF, 1067 (5%) were TFO and 14583 (75%) were retained. Compared with retained, mortality risk was three times higher among TFOs (aHR 3.11, 95% CI 2.42–3.99) and 20 times higher among LTF patients (aHR 22.03, 95% CI 20.05–24.21). Excluding early deaths after TFO or LTF, the risk was comparable among TFOs and retained (aHR 0.75, 95% CI 0.54–1.03) and higher among LTF (aHR 2.85, 95% CI 2.43–3.33). After linkage, corrected mortality was higher than site-reported mortality. Censoring did not however lead to substantial underestimation of mortality among TFOs.
While TFO and LTF predicted mortality, the lower incidence of TFO and subsequent death compared with LTF meant that censoring TFOs did not bias mortality estimates. Future cohort analyses should explicitly consider proportions TFO/LTF and mortality event rates.
antiretroviral therapy; mortality; transfers; lost to follow-up
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific cofactors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells. Using mouse models of Raptor or Rictor gene targeting, we discovered that Rictor ablation inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, whereas the loss of Raptor had only a modest effect on endothelial cells (ECs). Mechanistically, the loss of Rictor reduced the phosphorylation of AKT, protein kinase Cα (PKCα), and NDRG1 without affecting the mTORC1 pathway. In contrast, the loss of Raptor increased the phosphorylation of AKT despite inhibiting the phosphorylation of S6K1, a direct target of mTORC1. Reconstitution of Rictor-null cells with myristoylated AKT (Myr-AKT) rescued vascular assembly in Rictor-deficient endothelial cells, whereas PKCα rescued proliferation defects. Furthermore, tumor neovascularization in vivo was significantly decreased upon EC-specific Rictor deletion in mice. These data indicate that mTORC2 is a critical signaling node required for VEGF-mediated angiogenesis through the regulation of AKT and PKCα in vascular endothelial cells.
Autosomal recessive polycystic kidney disease (ARPKD) results from mutations in the human PKHD1 gene. Both this gene, and its mouse ortholog, Pkhd1, are primarily expressed in renal and biliary ductal structures. The mouse protein product, fibrocystin/polyductin complex (FPC), is a 445-kDa protein encoded by a 67-exon transcript that spans >500 kb of genomic DNA. In the current study, we observed multiple alternatively spliced Pkhd1 transcripts that varied in size and exon composition in embryonic mouse kidney, liver, and placenta samples, as well as among adult mouse pancreas, brain, heart, lung, testes, liver, and kidney. Using reverse transcription PCR and RNASeq, we identified 22 novel Pkhd1 kidney transcripts with unique exon junctions. Various mechanisms of alternative splicing were observed, including exon skipping, use of alternate acceptor/donor splice sites, and inclusion of novel exons. Bioinformatic analyses identified, and exon-trapping minigene experiments validated, consensus binding sites for serine/arginine-rich proteins that modulate alternative splicing. Using site-directed mutagenesis, we examined the functional importance of selected splice enhancers. In addition, we demonstrated that many of the novel transcripts were polysome bound, thus likely translated. Finally, we determined that the human PKHD1 R760H missense variant alters a splice enhancer motif that disrupts exon splicing in vitro and is predicted to truncate the protein. Taken together, these data provide evidence of the complex transcriptional regulation of Pkhd1/PKHD1 and identified motifs that regulate its splicing. Our studies indicate that Pkhd1/PKHD1 transcription is modulated, in part by intragenic factors, suggesting that aberrant PKHD1 splicing represents an unappreciated pathogenic mechanism in ARPKD.
Autosomal recessive polycystic kidney disease; PKHD1; Alternative splicing; Exon splice enhancers
Multiple sclerosis (MS) is a complex multifactorial disease that results from the interplay between environmental factors and a susceptible genetic background. Experimental autoimmune encephalomyelitis (EAE) has been widely used to investigate the mechanisms underlying MS pathogenesis. Chemokines, such as C-C Chemokine Ligand 2 (CCL2), are involved in the development of EAE. We have previously shown that thiamine deficiency (TD) induced CCL2 in neurons. We hypothesized that TD may affect the pathogenesis of EAE. In this study, EAE was induced in C57BL/6J mice by the injection of myelin oligodendroglial glycoprotein (MOG) peptide 35–55 with/without TD. TD aggravated the development of EAE which was indicated by clinical scores and pathological alterations in the spinal cord. TD also accelerated the development of EAE in an adoptive transfer EAE model. TD caused microglial activation and a drastic increase (up 140%) in leukocyte infiltration in the spinal cord of the EAE mice; specifically TD increased Th-1 and Th-17 cells. TD upregulated the expression of CCL2 and its receptor CCR2 in the spinal cord of EAE mice. Cells in peripheral lymph node and spleen isolated from MOG-primed TD mice showed much stronger proliferative responses to MOG. CCL2 stimulated the proliferation and migration of T lymphocytes in vitro. Our results suggested that TD exacerbated the development of EAE through activating CCL2 and inducing pathological inflammation.
TD; EAE; MOG; infiltration of T lymphocyte; inflammation
Recent studies showed loss of CD36 or scavenger receptor-AI/II (SR-A) does not ameliorate atherosclerosis in hyperlipidemic mouse model, suggesting receptors other than CD36 and SR-A may also contribute to atherosclerosis. In this report, we show that apoE-CD16 double knockout mice (apoE-CD16 DKO) have reduced atherosclerotic lesions compared with apoE KO mice. In vivo and in vitro foam cells analyses showed apoE-CD16 DKO macrophages accumulated less neutral lipids. Reduced foam cell formation in apoE-CD16 DKO mice is not due to change in expression of CD36, SR-A and LOX-1. This led to a hypothesis that CD16 may have scavenger receptor activity. We presented evidence that a soluble form of recombinant mouse CD16 (sCD16) bound to malondialdehyde-modified low-density lipoprotein (MDALDL), and this binding is blocked by molar excess of MDA-BSA and anti-MDA mAbs, suggesting CD16 specifically recognizes MDA epitopes. Interestingly, sCD16 inhibited MDALDL binding to macrophage cell line as well as sCD36, sSR-A and sLOX-1, indicating CD16 can cross-block MDALDL binding to other scavenger receptors. Anti-CD16 mAb inhibited IC binding to sCD16, while partially inhibited MDALDL binding to sCD16, suggesting MDALDL binding site may be in close proximity to the IC binding site in CD16. Loss of CD16 expression resulted in reduced levels of MDALDL induced pro-inflammatory cytokine expression. Finally, CD16 deficient macrophages showed reduced MDALDL-induced Syk phosphorylation. Collectively our findings suggest scavenger receptor activity of CD16 may in part contribute to the progression of atherosclerosis.
Interleukin-2 (IL-2), a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents organ damage remains unclear. Using an inducible recombinant adeno-associated virus (rAAV) vector we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Faslpr/lpr (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-rAAV resulted in reduced mononuclear cell infiltration and pathology of various tissues including skin, lungs and kidneys. In parallel, we noted a significant decrease of IL-17-producing CD3+CD4−CD8− double-negative T cells and an increase in CD4+CD25+Foxp3+ immunoregulatory T cells (Treg) in the periphery. We also show that IL-2 can drive DN T cell death through an indirect mechanism. Notably, targeted delivery of IL-2 to CD122+ cytotoxic lymphocytes effectively reduced the number of DN T cells and lymphadenopathy whereas selective expansion of Treg by IL-2 had no effect on DN T cells. Collectively, our data suggest that administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17-producing DN T cells and expanding Treg.
Langerhans cell histiocytosis (LCH) is a rare disease that can infiltrate various organs. LCH presents with solitary organ involvement or as a multi-system disease. We present a patient who has tonsillary infiltration with LCH. A 74 year-old Caucasian male was admitted for swelling of the neck and difficulty swallowing for 3 months. Physical examination showed submandibular lymph node enlargement of approximately 3 cm and tonsil enlargement. A tonsillectomy and excisional biopsy of the lymph node were done. Histiocyte-like cell infiltration was seen in the tonsil biopsy. CD3, CD20, CD15, CD30, CD5, CD138, Lambda, Kappa, Bcl-2, ALK, CD23, CD10, Bcl-6, keratin, EMA, HMB-45, and Cyl D1 were negative. CD68, S-100, CD1a, and fascin were positive, and the Ki-67 proliferation index was 20 % in immunocytochemical staining. The most commonly infiltrated bones are the skull, femur, lower jaw, pelvis, and vertebrae in LCH. Oral or perioral lesions are present in 30 % of cases. Oral lesions most often involve bone loss, unexpected tooth loss, and gum inflammation. We administered oral prednisolone to our patient due to the presence of lytic lesion of the bone, mild anemia and a higher sedimentation rate, which was from a separate, explained cause. Isolated tonsillar involvement in adult LCH was reported in only 2 cases in the literature. There is no standard recommendation for treatment. Our patient responded well to steroid therapy.
Langerhans cell histiocytosis; Tonsillar neoplasms; Prednisolone
Sepsis is a severe condition with possible high mortality outcomes. A multicentre-survey to detect the knowledge of the physicians who are involved in sepsis management in daily work was conducted.
Materials and Methods
The study was held in October 2013. A questionnaire consisting of questions about sepsis bundles was prepared. Eight centers from different regions of the country were invited to join the survey. The questionnaires were introduced to physicians from infectious diseases, internal diseases, emergency (ER) and anaesthesiology departments.
Two-hundred-and-twenty-three physicians from eight different centers were included. Of total 112 (50%) were male, median age was 30 years (24-59 years). Median working duration of participants was 5 years; 153 (69%) were residents, 70 (31%) were consultants. Of total 131 (59%) declared that they have enough knowledge on sepsis management. About the most important approach in sepsis, 151 (68%) voted for fluid replacement while 59 (26%) and 13 (6%) said early antibiotic use and inotropic support are the most important approaches respectively. Physicians from ER (56.5%) and anaesthesiology departments (55.4%) were more aware of the fluid replacement element of the bundle (30ml/kg, 3-hours bundle) in severe sepsis. The ID physicians, who routinely follow sepsis patients, were not aware of the fluid resuscitation (only 20% replied the element correctly) but almost all of them answered the question on early antibiotic use and blood culture sampling correctly. The knowledge of target CVP and MAP in severe sepsis were also below expectant among ID physicians. The overall knowledge of sepsis bundles of internal medicine physicians was poor. Almost all of the ER physicians knew that they have to measure lactate level upon admission but they were not aware of the threshold of the lactate level.
The knowledge of the sepsis bundles of the physicians, who are in charge of sepsis patients in routine work, was suboptimal. Most of the participants were unaware of SSC and new bundles. Training of the physicians of all centers about sepsis bundles is suggested according to these results.
Improvement; Sepsis performance; Septic shock; Severe sepsis; Surviving sepsis campaign
Observers tend to remember seeing a greater expanse of a scene than was shown (boundary extension [BE]). Is undivided visual attention necessary for BE? In Experiment 1, 108 observers viewed photographs with superimposed numerals (2s and 5s). Each appeared for 750 msec, followed by a masked interval and a test picture (same, closer up, or wider angled). Test pictures were rated as the same, closer, or wider angled on a 5-point scale. Visual attention was manipulated with a search task: The observers reported the number of 5s (zero, one, or two). The observers performed search only, picture rating only, or both (giving search priority). Search accuracy was unaffected by condition. BE occurred in both conditions but was greater with divided attention. The results were replicated using incidental BE tests (Experiments 2 and 3). We propose that anticipatory representation of layout occurs automatically during scene perception, with focal attention serving to constrain the boundary error.
CSF constituents are altered in multiple sclerosis, but whether this is a cause or a consequence of axonal degeneration is unclear. Vidaurre et al. identify two lipids that are enriched in the CSF of patients, and show that these induce bioenergetic dysfunction and oxidative damage in rat neuronal cultures.
Axonal damage is a prominent cause of disability and yet its pathogenesis is incompletely understood. Using a xenogeneic system, here we define the bioenergetic changes induced in rat neurons by exposure to cerebrospinal fluid samples from patients with multiple sclerosis compared to control subjects. A first discovery cohort of cerebrospinal fluid from 13 patients with multiple sclerosis and 10 control subjects showed that acute exposure to cerebrospinal fluid from patients with multiple sclerosis induced oxidative stress and decreased expression of neuroprotective genes, while increasing expression of genes involved in lipid signalling and in the response to oxidative stress. Protracted exposure of neurons to stress led to neurotoxicity and bioenergetics failure after cerebrospinal fluid exposure and positively correlated with the levels of neurofilament light chain. These findings were validated using a second independent cohort of cerebrospinal fluid samples (eight patients with multiple sclerosis and eight control subjects), collected at a different centre. The toxic effect of cerebrospinal fluid on neurons was not attributable to differences in IgG content, glucose, lactate or glutamate levels or differences in cytokine levels. A lipidomic profiling approach led to the identification of increased levels of ceramide C16:0 and C24:0 in the cerebrospinal fluid from patients with multiple sclerosis. Exposure of cultured neurons to micelles composed of these ceramide species was sufficient to recapitulate the bioenergetic dysfunction and oxidative damage induced by exposure to cerebrospinal fluid from patients with multiple sclerosis. Therefore, our data suggest that C16:0 and C24:0 ceramides are enriched in the cerebrospinal fluid of patients with multiple sclerosis and are sufficient to induce neuronal mitochondrial dysfunction and axonal damage.
neurodegenerative mechanism; demyelinating disease; axonal degeneration; mitochondria; lipid metabolism
The role of the insula in integrating cognitive, affective, autonomic and somatosensory information to guide behaviour is increasingly well recognized. However, the involvement of the insula in Parkinson's disease is often overlooked. Christopher et al. review studies linking the insula to non-motor symptoms, including cognitive decline, affective and somatosensory disturbances.
Patients with Parkinson’s disease experience a range of non-motor symptoms, including cognitive impairment, behavioural changes, somatosensory and autonomic disturbances. The insula, which was once thought to be primarily a limbic cortical structure, is now known to be highly involved in integrating somatosensory, autonomic and cognitive-affective information to guide behaviour. Thus, it acts as a central hub for processing relevant information related to the state of the body as well as cognitive and mood states. Despite these crucial functions, the insula has been largely overlooked as a potential key region in contributing to non-motor symptoms of Parkinson’s disease. The insula is affected in Parkinson’s disease by alpha-synuclein deposition, disruptions in normal neurotransmitter function, alterations in connectivity as well as metabolic and structural changes. Although research focusing on the role of the insula in Parkinson’s disease is scarce, there is evidence from neuroimaging studies linking the insula to cognitive decline, behavioural abnormalities and somatosensory disturbances. Here, we review imaging studies that provide insight into the potential role of the insula in Parkinson’s disease non-motor symptoms.
Parkinson’s disease; neuroimaging; insula; cognition; behaviour
See Friston (doi:10.1093/brain/awu147) for a scientific commentary on this article.
By modelling seizure dynamics mathematically, Jirsa et al. develop a taxonomy of seizures based on first principles. Using a canonical model (‘Epileptor’) and experimental validation, they demonstrate that seizures with focal onset mostly fall into one particular class that is universal across brain regions and species, from flies to humans.
Seizures can occur spontaneously and in a recurrent manner, which defines epilepsy; or they can be induced in a normal brain under a variety of conditions in most neuronal networks and species from flies to humans. Such universality raises the possibility that invariant properties exist that characterize seizures under different physiological and pathological conditions. Here, we analysed seizure dynamics mathematically and established a taxonomy of seizures based on first principles. For the predominant seizure class we developed a generic model called Epileptor. As an experimental model system, we used ictal-like discharges induced in vitro in mouse hippocampi. We show that only five state variables linked by integral-differential equations are sufficient to describe the onset, time course and offset of ictal-like discharges as well as their recurrence. Two state variables are responsible for generating rapid discharges (fast time scale), two for spike and wave events (intermediate time scale) and one for the control of time course, including the alternation between ‘normal’ and ictal periods (slow time scale). We propose that normal and ictal activities coexist: a separatrix acts as a barrier (or seizure threshold) between these states. Seizure onset is reached upon the collision of normal brain trajectories with the separatrix. We show theoretically and experimentally how a system can be pushed toward seizure under a wide variety of conditions. Within our experimental model, the onset and offset of ictal-like discharges are well-defined mathematical events: a saddle-node and homoclinic bifurcation, respectively. These bifurcations necessitate a baseline shift at onset and a logarithmic scaling of interspike intervals at offset. These predictions were not only confirmed in our in vitro experiments, but also for focal seizures recorded in different syndromes, brain regions and species (humans and zebrafish). Finally, we identified several possible biophysical parameters contributing to the five state variables in our model system. We show that these parameters apply to specific experimental conditions and propose that there exists a wide array of possible biophysical mechanisms for seizure genesis, while preserving central invariant properties. Epileptor and the seizure taxonomy will guide future modeling and translational research by identifying universal rules governing the initiation and termination of seizures and predicting the conditions necessary for those transitions.
epilepsy; bifurcation; non-linear dynamics; modelling; EEG
Using whole-exome sequencing, Bannwarth et al. identify a missense mutation in the mitochondrial gene, CHCHD10, in two families with frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). CHCHD10 helps to maintain the morphology of mitochondrial cristae and the stability of mitochondrial DNA. Other cases of FTD-ALS may be mitochondrial in origin.
Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.
CHCHD10; mitochondrial DNA instability; mitochondrial disorder; FTD-ALS
Increasing evidence suggests that spinal cord astrocytes maintain neuropathic pain sensitization, but precisely how they do this is unclear. Using a mouse model of neuropathic pain, Chen et al. demonstrate that the hemichannel connexin-43 is upregulated in astrocytes after nerve injury, and maintains late-phase neuropathic pain by inducing chemokine release.
Accumulating evidence suggests that spinal cord astrocytes play an important role in neuropathic pain sensitization by releasing astrocytic mediators (e.g. cytokines, chemokines and growth factors). However, it remains unclear how astrocytes control the release of astrocytic mediators and sustain late-phase neuropathic pain. Astrocytic connexin-43 (now known as GJ1) has been implicated in gap junction and hemichannel communication of cytosolic contents through the glial syncytia and to the extracellular space, respectively. Connexin-43 also plays an essential role in facilitating the development of neuropathic pain, yet the mechanism for this contribution remains unknown. In this study, we investigated whether nerve injury could upregulate connexin-43 to sustain late-phase neuropathic pain by releasing chemokine from spinal astrocytes. Chronic constriction injury elicited a persistent upregulation of connexin-43 in spinal astrocytes for >3 weeks. Spinal (intrathecal) injection of carbenoxolone (a non-selective hemichannel blocker) and selective connexin-43 blockers (connexin-43 mimetic peptides 43Gap26 and 37,43Gap27), as well as astroglial toxin but not microglial inhibitors, given 3 weeks after nerve injury, effectively reduced mechanical allodynia, a cardinal feature of late-phase neuropathic pain. In cultured astrocytes, TNF-α elicited marked release of the chemokine CXCL1, and the release was blocked by carbenoxolone, Gap26/Gap27, and connexin-43 small interfering RNA. TNF-α also increased connexin-43 expression and hemichannel activity, but not gap junction communication in astrocyte cultures prepared from cortices and spinal cords. Spinal injection of TNF-α-activated astrocytes was sufficient to induce persistent mechanical allodynia, and this allodynia was suppressed by CXCL1 neutralization, CXCL1 receptor (CXCR2) antagonist, and pretreatment of astrocytes with connexin-43 small interfering RNA. Furthermore, nerve injury persistently increased excitatory synaptic transmission (spontaneous excitatory postsynaptic currents) in spinal lamina IIo nociceptive synapses in the late phase, and this increase was suppressed by carbenoxolone and Gap27, and recapitulated by CXCL1. Together, our findings demonstrate a novel mechanism of astrocytic connexin-43 to enhance spinal cord synaptic transmission and maintain neuropathic pain in the late-phase via releasing chemokines.
carbenoxolone (CBX); CXCL1; CXCR2; hemichannels; neuro-glial interaction
High frequency oscillations have been associated with focal epilepsy, but their role in human cognition is less clear. During intracranial recordings in patients undergoing seizure monitoring, Kucewicz et al. detect high gamma, ripple and fast ripple oscillations that are induced by image processing, and modulated by memory encoding and recall.
High frequency oscillations are associated with normal brain function, but also increasingly recognized as potential biomarkers of the epileptogenic brain. Their role in human cognition has been predominantly studied in classical gamma frequencies (30–100 Hz), which reflect neuronal network coordination involved in attention, learning and memory. Invasive brain recordings in animals and humans demonstrate that physiological oscillations extend beyond the gamma frequency range, but their function in human cognitive processing has not been fully elucidated. Here we investigate high frequency oscillations spanning the high gamma (50–125 Hz), ripple (125–250 Hz) and fast ripple (250–500 Hz) frequency bands using intracranial recordings from 12 patients (five males and seven females, age 21–63 years) during memory encoding and recall of a series of affectively charged images. Presentation of the images induced high frequency oscillations in all three studied bands within the primary visual, limbic and higher order cortical regions in a sequence consistent with the visual processing stream. These induced oscillations were detected on individual electrodes localized in the amygdala, hippocampus and specific neocortical areas, revealing discrete oscillations of characteristic frequency, duration and latency from image presentation. Memory encoding and recall significantly modulated the number of induced high gamma, ripple and fast ripple detections in the studied structures, which was greater in the primary sensory areas during the encoding (Wilcoxon rank sum test, P = 0.002) and in the higher-order cortical association areas during the recall (Wilcoxon rank sum test, P = 0.001) of memorized images. Furthermore, the induced high gamma, ripple and fast ripple responses discriminated the encoded and the affectively charged images. In summary, our results show that high frequency oscillations, spanning a wide range of frequencies, are associated with memory processing and generated along distributed cortical and limbic brain regions. These findings support an important role for fast network synchronization in human cognition and extend our understanding of normal physiological brain activity during memory processing.
high frequency oscillations; cognitive processing; memory; gamma oscillations; neural networks