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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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Mechanisms of neurophatic pain states development
Přibáňová, Tereza ; Mrózková, Petra (advisor) ; Kuchtiak, Viktor (referee)
Pain is a natural warning signal that protects organisms from actual or potential damage. Upon the stimulation (burns, cuts, inflammation) of nerve endings - nociceptors, nerve signals are conducted via the peripheral nerve fibres into the spinal cord and brain, where they are then processed as painful, and a reaction occurs. Neuropathic pain, on the other hand, is pain caused by an injury or disease of the somatosensory system itself. Neuropathic pain has a substantial impact on the patient's quality of life and is likely to become more prevalent as the population grows older and the rates of diabetes and chemotherapy treatments rise. However, the treatment of neuropathic pain is often insufficient and comes with a number of undesirable side effects, which constitute a significant clinical problem. Research leading to the understanding of the molecular mechanisms of the development and maintenance of neuropathic pain is necessary in order to enhance the treatment of these states and to make it more effective. There is a myriad of factors responsible for the development of neuropathic pain, namely mechanisms which maintain the balance between inhibitory and excitatory somatosensory signalling, changes in the amount or composition of receptors and channels at the surface of the neuron, and most...
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Iontropic glutamate receptors and their RNA processing in the mammalian suprachaismatic nuclei
Kuchtiak, Viktor ; Balík, Aleš (advisor) ; Sládek, Martin (referee)
Suprachiasmatic nuclei (SCN) are primary center of mammalian circadian rhythms. To maintain a 24 hour period of its rhythms, SCN are synchronized with phase of external environment. Regular changes of light and darkness are known to be the main external synchronizer that determines the period of SCN rhythms. Information about light is being transferred from retina to the ventrolateral region of SCN through excitatory synapses where ionotropic glutamate receptors (iGluRs) play a primary role in the signal transduction. Posttranscriptional modifications of RNA can alter the functional properties of iGluRs, thus this process contributes to synaptic plasticity. The extent of posttranscriptional modifications of iGluRs can be in vitro affected by neuronal activity altered by pharmacological manipulation. The aim of this study was to determine possible changes of posttranscriptional modifications of iGluRs in in vivo rat SCN model and how this process can be regulated. RNA posttranscriptional modifications of GluA2 subunit of AMPA receptor (AMPAR) and GluK2 subunit of kainate receptor were assessed using PCR and subsequent sequencing of amplified DNA. Using quantitative PCR, we also determined mRNA expression of GluA1 and GluA2 subunits of AMPAR and the editing enzyme ADAR2 in SCN. Our results showed...
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Neurobiology of hypoxic-ischemic insult in immature brain
Kuchtiak, Viktor ; Valeš, Karel (advisor) ; Hejnová, Lucie (referee)
Pathology of the hypoxic-ischemic insult is very well described in the adult age, whereas the state of knowledge is largely neglected during the perinatal age. Serious insult in the early postnatal age leads often to the permanent neurological consequences or death. Ischemic insult causes over release of the glutamate in a brain tissue. This process is followed by excitotoxic damage of the tissue. Glutamatergic NMDA receptors play a key role in the excitotoxicity. Over-activated NMDA receptors are one of the possible therapeutic approaches against ischemic damage of the brain. Speaking of contemporary projects focusing on perinatal stroke, it is necessary to take into account developmental differences in the brain tissue and the requirements to minimal toxicity of possible drugs. Pharmacotherapies for hypoxic-ischemic damage implemented in the current perinatology are insufficients.
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Neurobiology of hypoxic-ischemic insult in immature brain
Kuchtiak, Viktor ; Valeš, Karel (advisor) ; Hahnová, Klára (referee)
Pathology of the hypoxic-ischemic insult is very well described in the adult age, whereas the state of knowledge is largely neglected during the perinatal age. Serious insult in the early postnatal age leads often to the permanent neurological consequences or death. Ischemic insult causes over release of the glutamate in a brain tissue. This process is followed by excitotoxic damage of the tissue. Glutamatergic NMDA receptors play a key role in the excitotoxicity. Over-activated NMDA receptors are one of the possible therapeutic approaches against ischemic damage of the brain. Speaking of contemporary projects focusing on perinatal stroke, it is necessary to take into account developmental differences in the brain tissue and the requirements to minimal toxicity of possible drugs. Pharmacotherapies for hypoxic-ischemic damage implemented in the current perinatology are insufficients.
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