RESUMEN
Creatine plays a crucial role in developing the brain, so much that its genetic deficiency results in mental dysfunction and cognitive impairments. Moreover, creatine supplementation is currently under investigation as a preventive measure to protect the fetus against oxidative stress during difficult pregnancies. Although creatine use is considered safe, posing minimal risk to clinical health, we found an alteration in morpho-functional maturation of neurons when male rats were exposed to creatine loads during brain development. In particular, increased excitability and enhanced long-term potentiation (LTP) were observed in the hippocampal pyramidal neurons of weaning pups. Since these effects were observed a long time after creatine treatment had been terminated, long-lasting modifications persisting into adulthood were hypothesized. Such modifications were investigated in the present study using morphological, electrophysiological, and calcium imaging techniques applied to hippocampal Cornu Ammonis 1 (CA1) neurons of adult rats born from dams supplemented with creatine. When compared to age-matched controls, the treated adult offspring were found to retain enhanced neuron excitability and an improved LTP, the best-documented neuronal substrate for memory formation. While translating data from rats to humans does have limitations, our findings suggest that prenatal creatine supplementation could have positive effects on adult cognitive abilities.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Creatina/administración & dosificación , Suplementos Dietéticos , Plasticidad Neuronal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Células Piramidales/efectos de los fármacos , Factores de Edad , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Conducta Animal/efectos de los fármacos , Región CA1 Hipocampal/crecimiento & desarrollo , Región CA1 Hipocampal/metabolismo , Señalización del Calcio/efectos de los fármacos , Cognición/efectos de los fármacos , Femenino , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Memoria/efectos de los fármacos , Embarazo , Células Piramidales/metabolismo , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (â¼6 months of age and â¼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a therapeutic intervention, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aß) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Región CA1 Hipocampal/metabolismo , Colina/administración & dosificación , Síndrome de Down/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Células Piramidales/metabolismo , Envejecimiento/metabolismo , Enfermedad de Alzheimer/prevención & control , Animales , Región CA1 Hipocampal/crecimiento & desarrollo , Suplementos Dietéticos , Modelos Animales de Enfermedad , Síndrome de Down/prevención & control , Femenino , Expresión Génica , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Prenatal intake of choline has been reported to lead to enhanced cognitive function in offspring, but little is known about the effects on spatial learning deficits. The present study examined the effects of prenatal choline supplementation on developmental low-protein exposure and its potential mechanisms. Pregnant female rats were fed either a normal or low-protein diet containing sufficient choline (1.1g/kg choline chloride) or supplemented choline (5.0g/kg choline chloride) until delivery. The Barnes maze test was performed at postnatal days 31-37. Choline and its metabolites, the synaptic structural parameters of the CA1 region in the brain of the newborn rat, were measured. The Barnes maze test demonstrated that prenatal low-protein pups had significantly greater error scale values, hole deviation scores, strategy scores and spatial search strategy and had lesser random search strategy values than normal protein pups (all P<.05). These alterations were significantly reversed by choline supplementation. Choline supplementation increased the brain levels of choline, betaine, phosphatidylethanolamine and phosphatidylcholine of newborns by 51.35% (P<.05), 33.33% (P<.001), 28.68% (P<.01) and 23.58% (P<.05), respectively, compared with the LPD group. Prenatal choline supplementation reversed the increased width of the synaptic cleft (P<.05) and decreased the curvature of the synaptic interface (P<.05) induced by a low-protein diet. Prenatal choline supplementation could attenuate the spatial learning deficits caused by prenatal protein malnutrition by increasing brain choline, betaine and phospholipids and by influencing the hippocampus structure.
Asunto(s)
Colina/uso terapéutico , Dieta con Restricción de Proteínas/efectos adversos , Suplementos Dietéticos , Desarrollo Fetal , Discapacidades para el Aprendizaje/prevención & control , Fenómenos Fisiologicos Nutricionales Maternos , Aprendizaje Espacial , Animales , Animales Recién Nacidos , Conducta Animal , Región CA1 Hipocampal/crecimiento & desarrollo , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/patología , Región CA1 Hipocampal/ultraestructura , Femenino , Discapacidades para el Aprendizaje/etiología , Discapacidades para el Aprendizaje/patología , Aprendizaje por Laberinto , Microscopía Electrónica de Transmisión , Neuronas/citología , Neuronas/metabolismo , Neuronas/patología , Neuronas/ultraestructura , Embarazo , Distribución Aleatoria , Ratas Sprague-Dawley , Conducta Espacial , Sinapsis/metabolismo , Sinapsis/patología , Sinapsis/ultraestructuraRESUMEN
NMDA receptors (NMDARs) require the coagonists D-serine or glycine for their activation, but whether the identity of the coagonist could be synapse specific and developmentally regulated remains elusive. We therefore investigated the contribution of D-serine and glycine by recording NMDAR-mediated responses at hippocampal Schaffer collaterals (SC)-CA1 and medial perforant path-dentate gyrus (mPP-DG) synapses in juvenile and adult rats. Selective depletion of endogenous coagonists with enzymatic scavengers as well as pharmacological inhibition of endogenous D-amino acid oxidase activity revealed that D-serine is the preferred coagonist at SC-CA1 mature synapses, whereas, unexpectedly, glycine is mainly involved at mPP-DG synapses. Nevertheless, both coagonist functions are driven by the levels of synaptic activity as inferred by recording long-term potentiation generated at both connections. This regional compartmentalization in the coagonist identity is associated to different GluN1/GluN2A to GluN1/GluN2B subunit composition of synaptic NMDARs. During postnatal development, the replacement of GluN2B- by GluN2A-containing NMDARs at SC-CA1 synapses parallels a change in the identity of the coagonist from glycine to D-serine. In contrast, NMDARs subunit composition at mPP-DG synapses is not altered and glycine remains the main coagonist throughout postnatal development. Altogether, our observations disclose an unprecedented relationship in the identity of the coagonist not only with the GluN2 subunit composition at synaptic NMDARs but also with astrocyte activity in the developing and mature hippocampus that reconciles the complementary functions of D-serine And Glycine In Modulating Nmdars During The Maturation Of Tripartite Glutamatergic Synapses.
Asunto(s)
Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Región CA1 Hipocampal/crecimiento & desarrollo , Región CA1 Hipocampal/metabolismo , Giro Dentado/crecimiento & desarrollo , Giro Dentado/metabolismo , Glicina/metabolismo , Potenciación a Largo Plazo , Masculino , Neuronas/metabolismo , Ratas , Serina/metabolismoRESUMEN
To assess the synaptic vesicle protein synaptophysin as a potential marker for maturation in the human fetal brain, synaptophysin immunoreactivity (sIR) was prospectively studied in postmortem sections of 162 normal human fetal and neonatal brains of both sexes from 6 to 41 weeks' gestational age. There was a consistent temporal and spatial pattern of sIR in the hippocampus and cerebral neocortex. In the rostral hippocampus, sIR was first apparent in the molecular zone of the dentate gyrus at 12 weeks, followed by CA2 at 14 weeks, CA3 and CA4 at 15 to 16 weeks, and CA1 at 19 weeks; it was incomplete until 26 weeks. In frontal neocortex, sIR developed in a laminar pattern above and below the cortical plate as early as 12 weeks, around Cajal-Retzius neurons of the molecular zone at 14 weeks, surrounding pyramidal neurons of Layers 5 and 6 at 16 weeks, and at the surface of neuronal somata in Layers 2 and 4 at 22 weeks. At 33 weeks, Layers 2 and 4 still had less sIR than other layers. Uniform sIR among all cortical layers was evident at 38 weeks. Ascending probable thalamocortical axons were reactive as early as 12 weeks and were best demonstrated by 26 weeks, after which increasing sIR in the neuropil diminished the contrast. The sIR was preserved for more than 96 hours postmortem, even in severely autolytic brains. We conclude that synaptophysin is a reliable marker in human fetal brain and that sIR provides the means for objective assessment of cerebral maturation in normal brains and to enable interpretation of abnormal synaptic patterns in pathological conditions.