RESUMEN
Genetic or nutritional disturbances in one-carbon metabolism, with associated hyperhomocysteinemia, can result in complex disorders including pregnancy complications and neuropsychiatric diseases. In earlier work, we showed that mice with a complete deficiency of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate and homocysteine metabolism, had cognitive impairment with disturbances in choline metabolism. Maternal demands for folate and choline are increased during pregnancy and deficiencies of these nutrients result in several negative outcomes including increased resorption and delayed development. The goal of this study was to investigate the behavioral and neurobiological impact of a maternal genetic deficiency in MTHFR or maternal nutritional deficiency of folate or choline during pregnancy on 3-week-old Mthfr(+/+) offspring. Mthfr(+/+) and Mthfr(+/-) females were placed on control diets (CD); and Mthfr(+/+) females were placed on folate-deficient diets (FD) or choline-deficient diets (ChDD) throughout pregnancy and lactation until their offspring were 3weeks of age. Short-term memory was assessed in offspring, and hippocampal tissue was evaluated for morphological changes, apoptosis, proliferation and choline metabolism. Maternal MTHFR deficiency resulted in short-term memory impairment in offspring. These dams had elevated levels of plasma homocysteine when compared with wild-type dams. There were no differences in plasma homocysteine in offspring. Increased apoptosis and proliferation was observed in the hippocampus of offspring from Mthfr(+/-) mothers. In the maternal FD and ChDD study, offspring also showed short-term memory impairment with increased apoptosis in the hippocampus; increased neurogenesis was observed in ChDD offspring. Choline acetyltransferase protein was increased in the offspring hippocampus of both dietary groups and betaine was decreased in the hippocampus of FD offspring. Our results reveal short-term memory deficits in the offspring of dams with MTHFR deficiency or dietary deficiencies of critical methyl donors. We suggest that deficiencies in maternal one-carbon metabolism during pregnancy can contribute to hippocampal dysfunction in offspring through apoptosis or altered choline metabolism.
Asunto(s)
Deficiencia de Colina/fisiopatología , Deficiencia de Ácido Fólico/fisiopatología , Hipocampo/crecimiento & desarrollo , Homocistinuria/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos , Memoria a Corto Plazo/fisiología , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Espasticidad Muscular/fisiopatología , Complicaciones del Embarazo/fisiopatología , Animales , Apoptosis/fisiología , Peso Corporal/fisiología , Colina O-Acetiltransferasa/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipocampo/patología , Hipocampo/fisiopatología , Homocisteína/sangre , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Ratones Transgénicos , Neurogénesis/fisiología , Tamaño de los Órganos , Embarazo , Trastornos Psicóticos/fisiopatología , Reconocimiento en Psicología/fisiologíaRESUMEN
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme key regulator in folate metabolism. Deficiencies in MTHFR result in increased levels of homocysteine, which leads to reduced levels of S-adenosylmethionine (SAM). In the brain, SAM donates methyl groups to catechol-O-methyltransferase (COMT), which is involved in neurotransmitter analysis. Using the MTHFR-deficient mouse model the purpose of this study was to investigate levels of monoamine neurotransmitters and amino acid levels in brain tissue. MTHFR deficiency affected levels of both glutamate and γ-aminobutyric acid in within the cerebellum and hippocampus. Mthfr (-/-) mice had reduced levels of glutamate in the amygdala and γ-aminobutyric acid in the thalamus. The excitatory mechanisms of homocysteine through activation of the N-methyl-d-aspartate receptor in brain tissue might alter levels of glutamate and γ-aminobutyric acid.
RESUMEN
Experiential therapies, such as enriched environment (EE), have been shown to influence the neurodegenerative processes that underlie Parkinson's disease. We have previously demonstrated that EE promotes functional improvement in dopamine-depleted rats. Here we compare the influence of exposure to EE prior to versus after dopamine depletion in the 6-hydroxydopamine rat model of Parkinson's disease. Two groups of female rats were placed in an EE while two groups were housed in a standard environment (SE) for 6 weeks prior to receiving a unilateral nigrostriatal bundle infusion of the neurotoxin 6-hydroxydopamine. After the lesion, one group remained in EE, while the second EE group (Pre-Lesion EE) was moved into SE conditions. In addition, a third group of rats was now moved into EE (Post-lesion EE). A fourth group remained in SE throughout the experimental period. Rats were tested in skilled reaching and skilled walking tasks and in non-skilled motor function up to 4 weeks after lesion. The observations demonstrated beneficial effects of both pre- and post-lesion exposure to EE on skilled movement performance by promoting compensatory limb use and partial protection or restoration of skilled movement. Exposure to pre-lesion EE in particular promoted structural plasticity as indicated by increased expression of the main cytoskeletal component microtubule associated protein-2 in the lesion dorsal striatum. Continuous EE showed absence of rotational bias suggesting attenuated dopamine loss. These data indicate that enriched lifestyle before the onset of motor symptoms and rehabilitation programs after diagnosis might be beneficial in patients with Parkinson's disease.
Asunto(s)
Dopamina/deficiencia , Ambiente , Síndromes de Neurotoxicidad , Neurotoxinas/toxicidad , Oxidopamina/toxicidad , Animales , Apomorfina , Corticosterona/sangre , Modelos Animales de Enfermedad , Conducta Exploratoria , Femenino , Lateralidad Funcional , Hipocampo/metabolismo , Hipocampo/patología , Locomoción/fisiología , Proteínas Asociadas a Microtúbulos/metabolismo , Destreza Motora/efectos de los fármacos , Destreza Motora/fisiología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/terapia , Ratas , Ratas Long-Evans , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Previous studies have suggested that experience and environmental conditions can affect the progression and severity of symptoms in Parkinson's disease. Furthermore, earlier reports have indicated that enriched environment promotes the survival of dopaminergic grafts in a rat model of Parkinson's disease. Here we investigated whether environmental enrichment affects normal motor function and the severity of dopamine depletion in a rat model of Parkinson's disease. Adult female Long-Evans rats were pre-trained and tested daily in a skilled reaching task. One group of rats was placed in an enriched environment while one group was housed under standard conditions. During this time period, reaching success of animals exposed to the enriched environment improved as compared with animals living in standard housing. The animals remained in the two housing conditions for six weeks prior to receiving unilateral infusion of the neurotoxin 6-hydroxydopamine into the nigrostriatal bundle. The daily behavioral testing continued up to four weeks after lesion. The observations showed that rats housed in an enriched environment significantly improved in reaching success during the first three weeks after lesion as compared with rats housed in the standard condition. Qualitative movement analysis, drug-induced rotation and histological findings indicate that compensatory processes in particular might have accounted for the behavioral improvements. These data are discussed in relation to possible mechanisms of experience-dependent modulation of the pathology of Parkinson's disease.