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The role of CRMP2 in the nervous system development.
Žiak, Jakub ; Balaštík, Martin (advisor) ; Jiruška, Přemysl (referee) ; Horák, Martin (referee)
Regulation of axon guidance and pruning of inappropriate synapses is key to development of neural circuits. Secreted semaphorins are integral part of both processes. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating Semaphorin 3A (Sema3A) signaling, however, nothing is known about its role in the synapse pruning. Similarly, it is also not known if CRMP2 mediates signals from other semaphorins. We herein studied CRMP2 protein and revealed its role in growth and pruning of selected axons and dendrites. In newly generated crmp2-/- and crmp2a-/- mice we demonstrate that CRMP2 has a moderate effect on Sema3A-dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and corpus callosum. CRMP2A isoform is specifically involved in development of callosal axons. Surprisingly, we show that crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which are consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). Indeed, we demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2-/- mice display ASD-related social behavior changes in early postnatal period as well...
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The use of stem cells in the treatment of Amyotrophic lateral sclerosis
Řehořová, Monika ; Jendelová, Pavla (advisor) ; Klíma, Jiří (referee) ; Jiruška, Přemysl (referee)
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by degradation of motoneurons (MN). No effective treatment is currently available. Cellular therapy is considered to be a promising experimental treatment that could target the pathology of complex disease through many potential mechanisms. We compared the effect of three types of repeated applications of human mesenchymal stem cells (hMSC): intrathecal administrations, intramuscular administrations and the combination of these applications. Best results were obtained after combined repeated hMSC administrations. We observed the rescue of MN, neuromuscular junctions and decreasing levels of proteins involved in the signaling of necroptosis (Rip1, cl-casp 8), apoptosis (cl-casp 9) and autophagy (beclin 1), decreasing astrogliosis and the level of astrocytic connexin 43. Neural precursors derived from induced pluripotent stem cells (NP-iPS) are considered as other promising candidates for ALS therapy. Intraspinal administration of NP-iPS increased mRNA expression of BDNF and IGF-1, on the other hand decreased expression of proapoptotic casp 3. We also observed their effect on expression of components of perineural nets (PNN). Human embryonic stem cells (hESC) are the other cell candidates for the treatment of neurodegenerative...
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The pathogenesis of autism in relation to maternal antibodies: from molecule to connectome
Rusková, Lívia ; Jiruška, Přemysl (advisor) ; Míková, Hana (referee)
Autism is a neurological disease that affects predominantly boys. It is characterised by anti- social and stereotypical behaviour with a low level of empathy. Most of the studies have been focusing on the genetic aetiology of this disease, however in the past years research has focused on the role of maternal immune system. This thesis is putting together information predominantly about maternal autoimmune antibodies that recognize specific proteins important in neurogenesis. It is focusing on the function of these proteins in neurogenesis and their possible correlation with the pathological brain connectome in autism. Key words: autism, maternal antibodies, connectome, neurodevelopment
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Spatial memory in humans and its disorders: From animal models towards schizophrenia
Fajnerová, Iveta ; Vlček, Kamil (advisor) ; Rokyta, Richard (referee) ; Jiruška, Přemysl (referee)
Spatial memory is often studied using spatial tasks originally developed for animals, such as the Morris water maze and the Carousel maze tasks. Both tasks have an important role in the process of identification of brain areas crucial for spatial memory, and also in pharmacological research of animal models of neuropsychiatric diseases. In recent years considerable attention has been devoted to the research and treatment of cognitive impairment in schizophrenia. Comparative research addressing cognitive abilities of both animals and patients in similar tasks, could therefore lead to verification of the predictive and face validity of animal models of this complex disorder. The aim of this study was to create virtual analogues of these tasks, which would allow this comparative approach. This thesis first describes the experiment testing the performance of an animal model of schizophrenia induced by the application of dizocilpine (MK-801) in reversal version of both mentioned spatial tasks, in order to assess mental flexibility and learning abilities affected in schizophrenia. Other two experiments present the findings of the two virtual analogues tested in the first episode of schizophrenia patients. Our results confirm the presence of deficits in spatial memory and mental flexibility, functions dependent on...
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Otimization of a dose of temozolomide for efficient reduction of adult neurogenesis in the laboratory rat
Pištíková, Adéla ; Stuchlík, Aleš (advisor) ; Jiruška, Přemysl (referee)
The goal of this study is to find an optimal dose of cytostatic Temozolomide (TMZ) for Long-Evans strain of rats. This dose should reduce neurogeneis while having a minimal pernicious health side-effects. Temozolomide is newly used to suppress neurogenesis but similarly to any other cytostatic has an effect on all dividing cells in an organism. This can affect health of an animal. Contrary to the mice, there was no systematic attempt to establish optimal dose. In our experiment rats were divided into four groups - one control group and three treatment groups which received different doses of temozolomide (10, 25, 40 mg/kg of TMZ). To detect level of neurogenesis cells were labeled by bromodeoxyuridine. During the experiment blood element counts were assessed, sensorimotoric tests were conducted, and weight increment was monitored. The results indicate that dose of 10mg/kg is adequate as it reduces neurogenesis by 64% compared to the control group and does not significantly differ from higher doses. In this group weight increment is comparable with the control group, while in the higher doses of TMZ weight increment is significantly lower. Effect of myelosupression is same for all treatment groups.
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Morphological changes of the hippocampus in tetanus toxin model of temporal lobe epilepsy
Demeterová, Ľubica ; Jiruška, Přemysl (advisor) ; Telenský, Petr (referee)
Temporal lobe epilepsy is the most common form of epilepsy and hippocampal sclerosis represents the main underlying structural abnormity. Approximately 20% of TLE cases are non- lesional due to absence of any obvious epileptogenic lesion and tetanus toxin model is traditionally considered as a model of non-lesional temporal lobe epilepsy. The main aim of this study was to evaluate the presence of the cell damage and to determine its spatiotemporal profile. Tetanus toxin was stereotaxically injected into CA3 subregion of dorsal hippocampus in adult male Wistar rats. Brain tissue was extracted 4, 8 and 16 days following the surgery. Postfixed brains were sectioned to 50 µm slices and labeled using Nissl's and FluoroJade B staining (FJB). Hippocampal sclerosis was present only in animals from D16 group, however, it was localized mainly in contralateral CA1 area. Additional finding was decreased Nissl's staining in contralateral hippocampus which corresponded with the presence of FJB positive neurons. In animals from group D8, we have identified presence of FJB positive neurons predominantly in ipsilateral hippocampus. In D4 animals, cellular degeneration was absent. To examine the non- lesional nature of tetanus toxin model, we have performed blind study, when Nissl's staining were reviewed...
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Functional consequences of epileptic seizures and CNS hypoxia-ischemia
Krýsl, David ; Mareš, Jan (advisor) ; Druga, Rastislav (referee) ; Jiruška, Přemysl (referee)
Hypoxic - ischemic CNS lesions and epileptic seizures share many common pathophysiologic features. Basic mechanisms , either detrimental ( excitotoxicity , free radicals, inflammation , changes in permeability of the blood brain barrier , particularly necrotic and apoptotic cell death) , or reparative ( gliosis , neuroplasticity , neurogenesis , vascular proliferation ) occur in Both types of damage , but may be expressed in varying degrees, and may take place in different time term. Hypoxia , but also global and focal ischemia, CNS are in humans and in experimental models under certain conditions accompanied by epileptic seizures. Epileptic seizures vice versa acutely and chronically affect cerebral blood flow (CBF ) . CBF and cerebral metabolism is significantly affected during status epilepticus ( SE). CBF changes can significantly contribute to pathophysiological consequences of seizures and may have links with some of their clinical manifestations (eg Todd's postparoxysmální hemiparesis ( MS Mathews et al. , 2008; Yarnell PR 1975) ) . Focal ischemia, CNS has often consequences in distant , but functionally linked areas ( diaschisis ) . There is a remote influence not only the blood flow and metabolism , but also excitability (Andrews, RJ , 1991 Buchkremer - Ratzmann I. et al. 1996b ) . Also in the...
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Adult neurogenesis in the hippocampus and spatial navigation
Dostálová, Magdalena ; Stuchlík, Aleš (advisor) ; Jiruška, Přemysl (referee)
Hundreds to thousands of new granule neurons are born every day in the hippocampus within the whole life. Inspite of intensive research of the last decades, their function remains unclear. Their participation in spatial memory and the ability of orientation is assumed. Results from behavioral tests like the Morris water maze, the radial maze and many other testing tasks, are often contradictory. Nevertheless, it is highly probable that neurogenesis plays a role in pattern separation and long-term relational memory. Further studies and especially reliable methods of ablation and detection are required for deeper insight into this issue.
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Acute effects of central muscarinic antagonist scopolamine on learning in two cognitive tasks: Comparison of Long-Evans and Wistar outbred rat strains
Entlerová, Marie ; Stuchlík, Aleš (advisor) ; Jiruška, Přemysl (referee)
Spatial navigation is essential for survival not only in mammals. Neural and neuropharmacological changes of learning and memory in humans and rats could be measured through their behavior and responses to stimuli. In focus of experimental models of cognitive deficits, the Morris water maze (MWM) represents a clasiccal test of exact allothetic representation, i.e. the cognitive map. Another important test of spatial navigation is the active place avoidance, or Carousel maze (also AAPA, Active Allothetic Place Avoidance), that can be used to test the ability of cognitive coordination, thus the ability to distinguish relevant stimuli from irrelevant. There are analogous tasks for testing cognitive abilities in humans for both tests (e.g. Blue Velvet Arena for MWM, virtual reality simulations on PC for AAPA, etc.). Aim of the present study is to compare the sensitivity of outbred Long-Evans and Wistar strains of rats from the institutional breeding to the acute administration of scopolamine, the antagonist of central muscarinic acetylcholine receptors, at doses 0.8 mg/kg; 1.5 mg/kg and 3.0 mg/kg. The results show that the Wistar strain is more influenced by cholinergic blockade than Long-Evans strain in both AAPA and the MWM. Furthermore, it appears that the control rat strain Long-Evans have better...
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