Desmin is essential for the structure and function of the sinoatrial node:implications for increased arrhythmogenesis

Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and β-catenin in structures we call “lateral intercalated disks” connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des-/-) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des-/mice. Upregulation of mRNA levels of both T-type Ca2+ current channels, Cav3.1 and Cav3.2, in the Des-/- myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des-/- mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis

Long-Term Effects of Early Life Seizures on Endogenous Local Network Activity of the Mouse Neocortex

Understanding the long term impact of early life seizures (ELS) is of vital importance both for researchers and clinicians. Most experimental studies of how seizures affect the developing brain have drawn their conclusions based on changes detected at the cellular or behavioral level, rather than on intermediate levels of analysis, such as the physiology of neuronal networks. Neurons work as part of networks and network dynamics integrate the function of molecules, cells and synapses in the emergent properties of brain circuits that reflect the balance of excitation and inhibition in the brain. Therefore, studying network dynamics could help bridge the cell-to-behavior gap in our understanding of the neurobiological effects of seizures. To this end we investigated the long-term effects of ELS on local network dynamics in mouse neocortex. By using the pentylenetetrazole (PTZ)-induced animal model of generalized seizures, single or multiple seizures were induced at two different developmental stages (P9–15 or P19–23) in order to examine how seizure severity and brain maturational status interact to affect the brain’s vulnerability to ELS. Cortical physiology was assessed by comparing spontaneous network activity (in the form of recurring Up states) in brain slices of adult (>5 mo) mice. In these experiments we examined two distinct cortical regions, the primary motor (M1) and somatosensory (S1) cortex in order to investigate regional differences in vulnerability to ELS. We find that the effects of ELSs vary depending on (i) the severity of the seizures (e.g., single intermittent ELS at P19–23 had no effect on Up state activity, but multiple seizures induced during the same period caused a significant change in the spectral content of spontaneous Up states), (ii) the cortical area examined, and (iii) the developmental stage at which the seizures are administered. These results reveal that even moderate experiences of ELS can have long lasting age- and region-specific effects in local cortical network dynamics

Experience-dependent plasticity in the developing brain

The extent to which individual experiences can shape our cognitive and emotional behaviour has been an issue of intense debate and study for centuries, and the topic takes on different forms depending on the field of study. Any form of behaviour will depend on the existence of functional connections in the brain, linking inputs and outputs. If these connections are damaged, or in any way silenced or suppressed, the related behaviour will be impaired, or modified accordingly. A large part of ontogenesis is devoted to the formation of such connections within and between different brain structures. Whereas the initial formation of connections is largely determined by chemical guidance factors and thus genetically specified, the ensuing neuronal circuits remain ‘plastic’ or modifiable for a prolonged period and, in some cases, throughout life. In this paper, I define notions of plasticity from a neurobiological perspective. I use the example of experience-dependent plasticity in multisensory convergence and integration in the brain, in order to illustrate the extent and limitations of the role of experience in sculpting neuronal circuits. I then describe briefly the various mechanisms that are thought to underlie experience-dependent changes in brain circuits during early development. D 2002 Elsevier Science B.V. All rights reserved

Sex differences in endogenous cortical network activity: spontaneously recurring Up/Down states

Abstract Background Several molecular and cellular processes in the vertebrate brain exhibit differences between males and females, leading to sexual dimorphism in the formation of neural circuits and brain organization. While studies on large-scale brain networks provide ample evidence for both structural and functional sex differences, smaller-scale local networks have remained largely unexplored. In the current study, we investigate sexual dimorphism in cortical dynamics by means of spontaneous Up/Down states, a type of network activity that is exhibited during slow-wave sleep, quiet wakefulness, and anesthesia and is thought to represent the default activity of the cortex. Methods Up state activity was monitored by local field potential recordings in coronal brain slices of male and female mice across three ages with distinct secretion profiles of sex hormones: (i) pre-puberty (17–21 days old), (ii) 3–9 adult (months old), and (iii) old (19–24 months old). Results Female mice of all ages exhibited longer and more frequent Up states compared to aged-matched male mice. Power spectrum analysis revealed sex differences in the relative power of Up state events, with female mice showing reduced power in the delta range (1–4 Hz) and increased power in the theta range (4–8 Hz) compared to male mice. No sex differences were found in the characteristics of Up state peak voltage and latency. Conclusions The present study revealed for the first time sex differences in intracortical network activity, using an ex vivo paradigm of spontaneously occurring Up/Down states. We report significant sex differences in Up state properties that are already present in pre-puberty animals and are maintained through adulthood and old age

Responses of isolated cat retinal ganglion cells to injected currents during development

This chapter explains the response properties of dissociated ganglion cells to constant current stimulation. The whole-cell patch clamp recording technique offers a powerful tool for assessing the membrane properties of developing neurons. This method to record from acutely dissociated retinal ganglion cells obtained from postnatal and prenatal cats, in order to characterize the development of spiking properties in these neurons. The long-term goal of this work is to relate the functional development of retinal ganglion cells to the structural refinements that are known to occur in these neurons during ontogeny. It has been found recently that somatostatin-containing amacrine cells and ganglion cells, which at maturity are preferentially distributed in the inferior, are widespread in the fetal cat retina. It is conceivable that developing ganglion cells are particularly sensitive to certain transiently expressed neuromodulators, and that this contributes to the correlated discharges that have been noted in the developing retina. © 1993, Academic Press Inc

High-Throughput Analysis of LFP Electrophysiological Signals: A validated workflow/software package

Supplementary Material for the corresponding paper. Software, presentation and sample data