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Posta a punto, validación e manipulación farmacolóxica da potenciación a longo prazo (temprá e tardía) en rodelas de hipocampo de ratos transxénicos e salvaxes

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Posta a punto, validación e manipulación farmacolóxica da potenciación a longo prazo (temprá e tardía) en rodelas de hipocampo de ratos transxénicos e salvaxes

Fernandez Fernandez, Diego
 
DATE : 2015-10-28
UNIVERSAL IDENTIFIER : http://hdl.handle.net/11093/525
UNESCO SUBJECT : 2411.11 Neurofisiología ; 6101.04 Psicopatología ; 3208.08 Mecanismos de Acción de Los Medicamentos
DOCUMENT TYPE : doctoralThesis

ABSTRACT :

Alzheimer's disease (AD) is the most common cause of dementia worldwide, characterized by a profound loss of memory and neuronal death which ultimately leads to the death of the individual. Moreover, the incidence of AD is expected to increase dramatically during this century as a direct consequence of increases in the proportion of the population over the age of risk. Considering this, the development of new drug strategies with the potential to fight this disease is today fundamental. The hippocampus is one of the first brain regions affected in AD patients. Its damage causes deterioration in information processing and memory consolidation, that is, a failure in the mechanisms surrounding learning and memory. Thus, improvement of hippocampal learning and memory is an attractive approach to influence cognitive symptoms of the disease. The research of learning and memory requires experimental model systems that can be utilized both to characterize the underlying mechanisms associated with these phenomena and to explore drug candidates for the treatment of cognitive deficits. ... [+]
Alzheimer's disease (AD) is the most common cause of dementia worldwide, characterized by a profound loss of memory and neuronal death which ultimately leads to the death of the individual. Moreover, the incidence of AD is expected to increase dramatically during this century as a direct consequence of increases in the proportion of the population over the age of risk. Considering this, the development of new drug strategies with the potential to fight this disease is today fundamental. The hippocampus is one of the first brain regions affected in AD patients. Its damage causes deterioration in information processing and memory consolidation, that is, a failure in the mechanisms surrounding learning and memory. Thus, improvement of hippocampal learning and memory is an attractive approach to influence cognitive symptoms of the disease. The research of learning and memory requires experimental model systems that can be utilized both to characterize the underlying mechanisms associated with these phenomena and to explore drug candidates for the treatment of cognitive deficits. Learning and memory are associated with synaptic plasticity, being short-term (paired-pulse facilitation, PPF) and long-term (long-term potentiation, LTP; and long-term depression, LTD) plasticity used as experimental model systems to deepen into their regulating mechanisms. Here, the obtained results demonstrate the successful establishment and validation of PPF, LTP and LTD recordings in both mouse and rat hippocampal slices. The validation of PPF recordings made possible the demonstration, for the first time, of the functional location of phosphodiesterase 2 (a promising drug target for AD therapy) in the presynaptic terminal of CA1 neurons in the hippocampus. Furthermore, the validation of LTP recordings set the stage for the study of how the different phases of LTP, early and late, are affected during aging in a mouse model of AD, the Tg2576. Tg2576 mice overexpress the protein ß amyloid, considered the principal toxic agent during AD and in this regard, a progressive impairment of LTP was found in the Tg2576 mouse. This deterioration of synaptic plasticity starts affecting early LTP, and ultimately leads to the abolishment of both forms of LTP in 15 month old animals. Finally, for the first time, LTP has been studied in a group of rats overexpressing the PKC isoform PKMzeta, proposed to be the molecule underlying memory maintenance. An enhancement of LTP was found in these rats, compared to the negative controls, providing further evidence supporting this molecule as a potential drug target for the treatment of AD. All together, these results configure a comprehensive work of investigation elucidating the different roles that distinct pharmacological and genetic manipulations may exert on AD progression. [-]

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