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The effect of variations in GRIN genes on the biogenesis and functional properties of the NMDA receptor
Kuchtiak, Viktor ; Balík, Aleš (advisor) ; Rozbeský, Daniel (referee) ; Ladislav, Marek (referee)
The expression and activity of ionotropic glutamate receptors control signal transduction at the excitatory synapses in the central nervous system. The major class are the calcium-permeable NMDA receptors that are fundamental for the various forms of synaptic plasticity, a key mechanism in the process of learning and memory formation. NMDA receptors are heterotetrameric and are represented by three types of subunits: GluN1, GluN2A-D, and GluN3A-B. Each subunit consists of four domains, with the intracellular C-terminal domain accounting for up to half of the entire NMDA receptor subunit (GluN2A/2B). A body of evidence indicates that the hypofunction of the NMDA receptor plays an important role in the pathogenesis of several neuropsychiatric disorders, including schizophrenia. Schizophrenia is characterised by a high degree of heritability, but its genetic background is not yet fully understood. Previous studies have identified in the human genome several individual loci that contribute to disease susceptibility, including the GRIN genes encoding NMDA receptors. Using a sequencing approach, we identified and annotated genetic variations across all GRIN genes in a cohort of schizophrenia patients and control subjects. The submitted doctoral thesis focuses on the functional analysis of the genetic...
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Significance of neural antibodies in patients with drug refractory epilepsy
Mojžišová, Hana ; Marusič, Petr (advisor) ; Nytrová, Petra (referee) ; Štourač, Pavel (referee)
Significance of neural antibodies in patients with drug refractory epilepsy Abstract One possible etiology of epilepsy is autoimmune, which was included in the classification of epilepsies in its latest revision published in 2017 by the International League Against Epilepsy. The aim of this study was to evaluate the prevalence of neural autoantibodies in patients with epilepsy and to expand the diagnostic possibilities in the Czech Republic. Together with the Dutch authors, we described the prevalence of neural autoantibodies in Dutch and Czech patients with focal epilepsy of unknown etiology and proposed a scoring system to identify patients prioritized for testing for these antibodies. In a Czech cohort of patients, we assessed the presence of antibodies in serum and CSF of patients with drug refractory epilepsy. The results of both these studies showed a lower prevalence of neural autoantibodies than previously described in patients with epilepsy, due to a more rigorous methodology with verification of positive results by a second method. Since neural autoantibodies are primarily associated with autoimmune encephalitis, we also investigated this group, including an assessment of the presence of epileptic seizures in the clinical profile. Together with the Swedish authors, we investigated the proteomics...
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NMDA receptors outside CNS and their subunit composition
Hotovec, Matěj ; Kolcheva, Marharyta (advisor) ; Horáková, Olga (referee)
N-Methyl-D-Aspartate receptors (NMDARs) are a type of ionotropic glutamate receptor that is widely present in the central nervous system and in lesser numbers in other parts of the body, including the gastrointestinal tract. NMDARs play a crucial role in various physiological and pathological processes in the CNS, including synaptic plasticity, learning and memory, and excitotoxic damage. The role of NMDARs outside the CNS is still under investigation. This thesis aims to confirm the presence of NMDARs in the gastrointestinal tract and their subunit composition. Subunit specific NMDAR modulators showed effect on spontaneous phasic activity of ileum, indirectly confirming the presence of GluN1, GluN2A-D and GluN3 subunits. Attempt at direct evidence of protein expression by immunolabeling with monoclonal antibodies against NMDAR subunits was unsuccessful.
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Zebrafish as a model to study the glutamate receptor mediated excitatory neurotrasmission
Chumchal, Lukáš ; Balík, Aleš (advisor) ; Pangrácová, Marie (referee)
Glutamate is the most prominent excitatory neurotransmitter in the vertebrate brain and is used by most synaptic connections in the cortex. Signal transduction on these neurons is mediated by ionotropic glutamate receptors, including the NMDA receptor family. With the development of molecular biological methods and the advent of genomics, genetic changes found in ionotropic glutamate receptors were tested, as well as substances that modulate their activity. Since a large number of genetic changes found, rodents have ceased to be a sufficiently robust system for some, for example, behavioural studies. In these types of studies, the model organism Danio rerio could replace rodents. The use of this model organism could thus expand knowledge about the evolution and physiology of glutamate receptors. This work aims to summarize the current knowledge about the use of Dania rerio in the research of glutamate receptors, especially NMDA type in the central nervous system. This work also focuses on the description of specific behavioural tests available for the analysis of these receptors.
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Intracellular domain of glutamate ion channels and its role in the emergence of pathophysiological states
Sadílková, Lucie ; Balík, Aleš (advisor) ; Kolář, David (referee)
Glutamate mediates most of the excitatory neurotransmissions in the central nervous system of mammals. Its effect depends on the presence of glutamate receptors on postsynaptic neurons. NMDA receptors are class of the ionotropic glutamate receptors and are necessary for normal brain function such as synaptic plasticity, learning, memory and correct development of neu- rons. NMDA receptors are also involved in the pathophysiology of many neurodevelopmental and neuropsychiatric diseases. The aim of this work is to evaluate the current knowledge of the role of the intracellular part of NMDA receptors for their function, particularly with respect to the regulation of their localization at excitatory synapses. In addition, it also provides an over- view of the genetic changes found in this part of the receptor, their effect on the functional properties of the receptor and then also a possible link to specific disease.
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