RESUMEN
Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies. NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology.
Asunto(s)
Ritmo Delta , Epilepsia/fisiopatología , Potenciales Postsinápticos Excitadores , Neocórtex/fisiopatología , Inhibición Neural , Animales , Niño , Neuronas GABAérgicas/fisiología , Humanos , Masculino , Persona de Mediana Edad , Neocórtex/citología , Ratas , Ratas WistarRESUMEN
Alpha rhythms (9-11 Hz) are a dominant feature of EEG recordings, particularly over occipital cortex on cessation of a visual stimulation. Little is known about underlying neocortical mechanisms so here we constructed alpha rhythm models that follow cessation of cortical stimulation. The rhythm manifests following a period of gamma frequency activity in local V1 networks in layer 4. It associates with network level bias of excitatory synaptic activity in favour of NMDA- rather than AMPA-mediated signalling and reorganisation of synaptic inhibition in favour of fast GABAA receptor-mediated events. At the cellular level the alpha rhythm depended upon the generation of layer 4 pyramidal neuron dendritic bursting mediated primarily by PPDA-sensitive NR2C/D-containing NMDA receptors, which lack the magnesium-dependent open channel block. Subthreshold potassium conductances are also critical. The rhythm dynamically filters outputs from sensory relay neurons (stellate neurons in layer 4) such that they become temporally uncoupled from downstream population activity.
Asunto(s)
Ritmo alfa/fisiología , Dendritas/fisiología , Células Piramidales/fisiología , Ratas/fisiología , Corteza Visual/fisiología , Animales , Masculino , Ratas Wistar , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Infantile spasms (IS) and seizures with focal onset have different clinical expressions, even when electroencephalography (EEG) associated with IS has some degree of focality. Oddly, identical pathology (with, however, age-dependent expression) can lead to IS in one patient vs. focal seizures in another or even in the same, albeit older, patient. We therefore investigated whether the cellular mechanisms underlying seizure initiation are similar in the two instances: spasms vs. focal. We noted that in-common EEG features can include (i) a background of waves at alpha to delta frequencies; (ii) a period of flattening, lasting about a second or more - the electrodecrement (ED); and (iii) often an interval of very fast oscillations (VFO; ~70 Hz or faster) preceding, or at the beginning of, the ED. With IS, VFO temporally coincides with the motor spasm. What is different between the two conditions is this: with IS, the ED reverts to recurring slow waves, as occurring before the ED, whereas with focal seizures the ED instead evolves into an electrographic seizure, containing high-amplitude synchronized bursts, having superimposed VFO. We used in vitro data to help understand these patterns, as such data suggest cellular mechanisms for delta waves, for VFO, for seizure-related burst complexes containing VFO, and, more recently, for the ED. We propose a unifying mechanistic hypothesis - emphasizing the importance of brain pH - to explain the commonalities and differences of EEG signals in IS versus focal seizures.
Asunto(s)
Encéfalo/fisiopatología , Convulsiones/fisiopatología , Espasmo/fisiopatología , Espasmos Infantiles/fisiopatología , Electroencefalografía/métodos , Humanos , LactanteRESUMEN
We studied a new amyloid-beta precursor protein (App) knock-in mouse model of Alzheimer's disease (AppNL-G-F ), containing the Swedish KM670/671NL mutation, the Iberian I716F mutation and the Artic E693G mutation, which generates elevated levels of amyloid beta (Aß)40 and Aß42 without the confounds associated with APP overexpression. This enabled us to assess changes in anxiety-related and social behaviours, and neural alterations potentially underlying such changes, driven specifically by Aß accumulation. AppNL-G-F knock-in mice exhibited subtle deficits in tasks assessing social olfaction, but not in social motivation tasks. In anxiety-assessing tasks, AppNL-G-F knock-in mice exhibited: (1) increased thigmotaxis in the open field (OF), yet; (2) reduced closed-arm, and increased open-arm, time in the elevated plus maze (EPM). Their ostensibly anxiogenic OF profile, yet ostensibly anxiolytic EPM profile, could hint at altered cortical mechanisms affecting decision-making (e.g. 'disinhibition'), rather than simple core deficits in emotional motivation. Consistent with this possibility, alterations in microstructure, glutamatergic-dependent gamma oscillations and glutamatergic gene expression were all observed in the prefrontal cortex, but not the amygdala, of AppNL-G-F knock-in mice. Thus, insoluble Aß overexpression drives prefrontal cortical alterations, potentially underlying changes in social and anxiety-related behavioural tasks.This article has an associated First Person interview with the first author of the paper.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ansiedad/fisiopatología , Conducta Animal , Ritmo Gamma , Técnicas de Sustitución del Gen , Corteza Prefrontal/fisiopatología , Animales , Anisotropía , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , N-Metilaspartato/metabolismo , Corteza Prefrontal/patología , Receptores de N-Metil-D-Aspartato/metabolismo , Conducta Social , Solubilidad , Análisis y Desempeño de TareasRESUMEN
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder with variable genetic etiologies. Here we focused on understanding the precise molecular pathology of a single clinical variant in DSP, the gene encoding desmoplakin. We initially identified a novel missense desmoplakin variant (p.R451G) in a patient diagnosed with biventricular ACM. An extensive single-family ACM cohort was assembled, revealing a pattern of coinheritance for R451G desmoplakin and the ACM phenotype. An in vitro model system using patient-derived induced pluripotent stem cell lines showed depressed levels of desmoplakin in the absence of abnormal electrical propagation. Molecular dynamics simulations of desmoplakin R451G revealed no overt structural changes, but a significant loss of intramolecular interactions surrounding a putative calpain target site was observed. Protein degradation assays of recombinant desmoplakin R451G confirmed increased calpain vulnerability. In silico screening identified a subset of 3 additional ACM-linked desmoplakin missense mutations with apparent enhanced calpain susceptibility, predictions that were confirmed experimentally. Like R451G, these mutations are found in families with biventricular ACM. We conclude that augmented calpain-mediated degradation of desmoplakin represents a shared pathological mechanism for select ACM-linked missense variants. This approach for identifying variants with shared molecular pathologies may represent a powerful new strategy for understanding and treating inherited cardiomyopathies.
Asunto(s)
Arritmias Cardíacas/genética , Calpaína/metabolismo , Cardiomiopatías/genética , Desmoplaquinas/metabolismo , Predisposición Genética a la Enfermedad/genética , Mutación , Adulto , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Calpaína/farmacología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Desmoplaquinas/antagonistas & inhibidores , Desmoplaquinas/química , Femenino , Glicina , Corazón , Insuficiencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Mutación Missense , Linaje , Fenotipo , Proteínas Recombinantes , Células MadreRESUMEN
Rhythmic motor patterns in invertebrates are often driven by specialized "central pattern generators" (CPGs), containing small numbers of neurons, which are likely to be "identifiable" in one individual compared with another. The dynamics of any particular CPG lies under the control of modulatory substances, amines, or peptides, entering the CPG from outside it, or released by internal constituent neurons; consequently, a particular CPG can generate a given rhythm at different frequencies and amplitudes, and perhaps even generate a repertoire of distinctive patterns. The mechanisms exploited by neuromodulators in this respect are manifold: Intrinsic conductances (e.g., calcium, potassium channels), conductance state of postsynaptic receptors, degree of plasticity, and magnitude and kinetics of transmitter release can all be affected. The CPG concept has been generalized to vertebrate motor pattern generating circuits (e.g., for locomotion), which may contain large numbers of neurons - a construct that is sensible, if there is enough redundancy: that is, the large number of neurons consists of only a small number of classes, and the cells within any one class act stereotypically. Here we suggest that CPG and modulator ideas may also help to understand cortical oscillations, normal ones, and particularly transition to epileptiform pathology. Furthermore, in the case illustrated, the mechanism of the transition appears to be an exaggerated form of a normal modulatory action used to influence sensory processing.