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1.
Cell Mol Neurobiol ; 43(7): 3179-3189, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37410316

RESUMO

The application of glial cell line-derive neurotrophic factor (GDNF) to cell cultures and animal models has demonstrated positive effects upon dopaminergic neuronal survival and development, function, restoration, and protection. On this basis, recombinant GDNF protein has been trialled in the treatment of late-stage human Parkinson's disease patients with only limited success that is likely due to a lack of viable receptor targets in an advanced state of neurodegeneration. The latest research points to more refined approaches of modulating GDNF signalling and an optimal quantity and spatial regulation of GDNF can be extrapolated using regulation of dopamine as a proxy measure. The basic research literature on dopaminergic effects of GDNF in animal models is reviewed, concluding that a twofold increase in natively expressing cells increases dopamine turnover and maximises neuroprotective and beneficial motor effects whilst minimising hyperdopaminergia and other side-effects. Methodological considerations for measurement of dopamine levels and neuroanatomical distinctions are made between populations of dopamine neurons and their respective effects upon movement and behaviour that will inform future research into this still-relevant growth factor.


Assuntos
Dopamina , Doença de Parkinson , Animais , Humanos , Dopamina/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Substância Negra/metabolismo , Neuroglia/metabolismo , Doença de Parkinson/metabolismo
2.
Eur J Neurosci ; 53(8): 2469-2482, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33481269

RESUMO

Parvalbumin-positive interneurons (PV+) are a key component of inhibitory networks in the brain and are known to modulate memory and learning by shaping network activity. The mechanisms of PV+ neuron generation and maintenance are not fully understood, yet current evidence suggests that signalling via the glial cell line-derived neurotrophic factor (GDNF) receptor GFRα1 positively modulates the migration and differentiation of PV+ interneurons in the cortex. Whether GDNF also regulates PV+ cells in the hippocampus is currently unknown. In this study, we utilized a Gdnf "hypermorph" mouse model where GDNF is overexpressed from the native gene locus, providing greatly increased spatial and temporal specificity of protein expression over established models of ectopic expression. Gdnfwt/hyper mice demonstrated impairments in long-term memory performance in the Morris water maze test and an increase in inhibitory tone in the hippocampus measured electrophysiologically in acute brain slice preparations. Increased PV+ cell number was confirmed immunohistochemically in the hippocampus and in discrete cortical areas and an increase in epileptic seizure threshold was observed in vivo. The data consolidate prior evidence for the actions of GDNF as a regulator of PV+ cell development in the cortex and demonstrate functional effects upon network excitability via modulation of functional GABAergic signalling and under epileptic challenge.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial , Memória Espacial , Animais , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Camundongos , Parvalbuminas/metabolismo
4.
PLoS Genet ; 11(12): e1005710, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26681446

RESUMO

Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3'UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3'UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial expression of GDNF. Furthermore, our results suggest that 3'UTR targeting may constitute a useful tool in analyzing gene function.


Assuntos
Dopamina/genética , Neurônios Dopaminérgicos/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Doença de Parkinson Secundária/genética , Substância Negra/metabolismo , Acetilcisteína/análogos & derivados , Acetilcisteína/toxicidade , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Humanos , Rim/crescimento & desenvolvimento , Rim/metabolismo , Camundongos , Neostriado/metabolismo , Neostriado/patologia , Fármacos Neuroprotetores/metabolismo , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Substância Negra/patologia
5.
Epilepsia ; 49(5): 926-8, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18325016

RESUMO

In a study using a heated chamber for induction of experimental febrile seizures (eFS) in rat pups, ictal activity was shown to be precipitated by a respiratory alkalosis (Schuchmann et al., 2006). In sharp contrast to this, in a recent review Dubé et al., (2007) suggest that the respiratory alkalosis is model specific, and that no increase in respiratory rate is observed in the widely used "hair dryer model" of eFS. The data in the present work, based on well-established techniques for measuring respiratory rates in rat pups, show a pronounced increase in the "hair dryer model" with values that are slightly higher than those recorded in the heated chamber model. Hence, a temperature-evoked increase in respiration is a common feature of these two models of eFS.


Assuntos
Alcalose Respiratória/fisiopatologia , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Febre/fisiopatologia , Hiperventilação/fisiopatologia , Convulsões Febris/fisiopatologia , Alcalose Respiratória/etiologia , Animais , Animais Recém-Nascidos , Temperatura Corporal/fisiologia , Febre/complicações , Abrigo para Animais , Hiperventilação/etiologia , Ratos , Ratos Wistar , Projetos de Pesquisa/estatística & dados numéricos , Convulsões Febris/etiologia
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