The aim of the study was focused on problem of electrograms recording from alive tissue. Study of electrograms recording was extended with noise analysis and its elimination. Elimination of noise and disturption was made in program Matlab; lowpass filtration and wavelet transformation was used. Application for electrograms analysis was developed in latter part of this work.

Modification of Hodgkin and Huxley’s experimentally derived set of nonlinear differential equations was implemented to accurately simulate the action potential of the Hirudo Medicinalis’s Retzius cell in MATLAB under analogous conditions to those found in the Retzius cell environment. The voltage-gated sodium and potassium channel responses to changes in membrane potential, as experimentally determined by Hodgkin and Huxley, were manipulated to suit simulation parameters established by electrophysiological Retzius cell recordings. Application of this methodology permitted additional accurate simulation of the Hirudo Medicinalis’s P cell under analogous conditions to those found in the P cell environment. Further refinement of this technique should allow for the voltage-gated behavioral based simulation of action potential waveforms found in variety of neurons under simulation conditions analogous to the nerve cell environment.

The aim of the study was focused on problem of electrograms recording with using voltage sensitive dyes. Study of electrograms recording was extended with thema of optical detectors suitable for measurement and noise analysis. Elimination of noise and disturption was made in program Matlab; lowpass filtration and wavelet transformation was used. Application for electrograms analysis was developed in latter part of this work.

The stochastic behavior of voltage-gated ion channels causes fluctuations of conductances and voltages across neuronal membranes, contributing to the neuronal noise which is ubiquitous in the nervous system. While this phenomenon can be observed also on other parts of the neuron, here we concentrated on the axon and the way the channel noise influences axonal input-output characteristics. This was analysed by working with our newly created computational compartmental model, programmed in Matlab environment, built up using the Hodgkin-Huxley mathematical formalism and channel noise implemented via extended Markov Chain Monte Carlo method. The model was thoroughly verified to simulate plausibly a mammalian axon of CA3 neuron. Based on our simulations, we confirmed quantitatively the findings that the channel noise is the most prominent on membranes with smaller number of Na+ and K+ channels and that it majorly increases the variability of travel times of action potentials (APs) along axons, decreasing thereby the temporal precision of APs. The simulations analysing the effect of axonal demyelination and axonal diameter correlated well with other finding referred in Literature. We further focused on spike pattern and how is its propagation influenced by inter-spike intervals (ISI). We found, that APs fired...

Cardiac accessory β-subunits are part of macromolecular ion channel complexes. They can modulate electrophysiological properties of resulting ion currents and action potentials and are supposed to contribute to cardiac disease e.g. arrhythmias or Brugada syndrome. In my thesis, we characterized the functions of dipeptidyl peptidase-like protein 10 (DPP10), a transmembrane β-subunit of cardiac Na+ and K+ channels. Previous studies revealed that DPP10 is expressed in human heart and acts as regulator of Kv channel kinetics. In electrophysiological experiments, we found that DPP10 modulates Ito through Kv4.3 channel complexes by accelerating current densities and the time course of activation, inactivation and recovery from inactivation. Interestingly, co-expression of DPP10 with Kv4.3 and KChIP2 in CHO cells induced a slowly inactivating fraction of Ito, providing evidence for a contribution of Ito on the sustained outward K+ current in cardiomyoctes. Until then, the sustained fraction of K+ currents was thought to be due to IKur. We further studied the contribution of Kv4-mediated Ito to total K+ currents in human atrial myocytes using 4-Aminopyridine to block IKur in combination with Heteropoda toxin 2 to block Kv4 channels. Using this approach, it was possible to separate an Ito fraction of about 19% contributing to the late current component. These data suggest that the generation of a sustained current component of Ito induced by DPP10 may affect the late repolarization phase of an atrial action potential. To further explore the functions of DPP10, we investigated a potential interaction with Nav channels in cardiomyocytes. It was possible to detect DPP10 in human ventricles, with higher expression levels in patients with heart failure. We demonstrated that DPP10 affects cellular action potentials in isolated rat cardiomyocytes after adenoviral gene transfer indicating a reduction in Na+ current density. Voltage-dependent Na+ channel activation and inactivation curve was shifted to more positive potentials with overexpression of DPP10, resulting in enhanced availability of Na+ channels for activation, along with increasing window Na+ current. Thus, we assumed a role of DPP10 on promotion of arrhythmias via interaction with Nav1.5. The results of this study can help to understand the complex interaction pattern between Nav and Kv channels and the role of their β-subunits, especially DPP10. In conclusion, DPP10 was identified as a new modulator of Kv and Nav currents in the human heart, suggesting that this β-subunit may contributes to cardiac arrhythmias and might be a new therapeutic target.:1 Introduction 1.1 The cardiac action potential 1.2 Cardiac potassium channels 1.2.1 The Kv4.3 channel complex 1.2.2 Accessory β subunits of K+ channel 1.2.3 The Kv1.5 channel 1.2.4 Separation of Ito and IKur in native cardiomyocytes 1.3 Cardiac sodium channels 1.3.1 Molecular construction of Nav1.5 channel 1.3.2 Accessory β subunits of Na+ channel 1.3.3 The role of Nav1.5 in cardiac electrical disorders 1.4 Aim of the thesis and systematic approach 2 The research articles 3 Summary 4 Zusammenfassung 6 References 7 Appendices 7.1 Abbreviations

Short-term synaptic plasticity (STP) is a phenomenon that has been closely associated with how neurons communicate with each other. I study communication between neurons tied to synapses endowed with short-term plasticity (dynamic synapses). This is achieved by using mathematical models of neural phenomena that align with those found in real neurons. In addition to dynamic synapses, a model of static synapses is created, on which control experiments are performed. The response of postsynaptic neurons, to spiking-sequences from presynaptic neurons, is examined in order to infer how information is transmitted across cells. During these computational experiments, it was found that the range of firing rates to which postsynaptic neurons responded, depends heavily on certain parameters of STP-processes. These parameters are the time constants for short-term synaptic depression and facilitation: the two time-dependent processes that define STP. Some results confirm those of the existing literature, while this work places an added emphasis on the sensitivity of the propagation of rate codes to the aforementioned parameters of synapses. This is relevant because it has been found that real synapses display a wide range of time constants in the nervous system. Hence, understanding how this variation carries a significant impact on rate-coding schemes is vital when engaging in further studies of neural rate codes. / Synaptisk plasticitet på kort sikt (STP) är ett fenomen som har blivit nära förknippat med hur nervceller kommunicerar med varandra. Jag studerar kommunikation mellan nervceller som är kopplade till synapser som är försedda med kortsiktig synaptisk plasticitet (dynamiska synapser). Detta har åstadkommits genom matematisk modellering av fenomen i nervsystemet som är konsekventa med de som är funna i verkliga nervceller. Utöver dynamiska synapser, så skapas även en modell av statiska synapser på vilka kontrollexperiment utövas. Gensvaret av postsynaptiska nervceller, på sekvenser av nervimpulser från presynaptiska nervceller, kartläggs för att studera hur information transmitteras mellan celler. I dessa beräkningsmässiga experiment så var det funnet att spannet av frekvenser för vilka postsynaptiska nervceller visade gensvar, var kraftigt beroende på specifika parametrar för STP-processer. Dessa parametrar är tidskonstanterna för synaptisk depression på kort sikt samt synaptisk facilitering på kort sikt: de två tidsberoende processerna som definierar STP. Vissa resultat bekräftade de som återfinns i den befintliga literaturen, samtidigt som detta arbete placerar adderad tyngd på känsligheten som frekvensmässiga koder uppvisar för ovannämnda synaptiska parametrar. Detta är relevant eftersom det är känt att verkliga synapser uppvisar ett brett spann av tidskonstanter i nervsystemet. Följdaktigen är det centralt att förstå hur denna variation innehar signifikant påverkan på frekvenskoder vid fortsatta studier inom frekvensmässiga neurala koder.

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