ABSTRACT
Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.
Subject(s)
CA3 Region, Hippocampal/physiopathology , Chromosomes, Human, Pair 21 , Dentate Gyrus/physiopathology , Disease Models, Animal , Down Syndrome/physiopathology , Nerve Net/physiopathology , Animals , CA3 Region, Hippocampal/pathology , Chromosomes, Human, Pair 21/genetics , Dentate Gyrus/pathology , Down Syndrome/genetics , Down Syndrome/pathology , Humans , Male , Maze Learning/physiology , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Nerve Net/pathology , Organ Culture Techniques , Trisomy/geneticsABSTRACT
Alzheimer's disease (AD) is an irreversible neurodegenerative disease that is characterised by the presence of ß-amyloid (Aß) plaques, neurofibrillary tangles (NFTs) and synaptic loss specifically in brain regions involved in learning and memory such as the neocortex and the hippocampus. Aß depositions in the form of neuritic plaques trigger activation of microglia that is believed to be a common neuropathological feature of AD brains. As an integral part of the hippocampus, the dentate gyrus (DG) plays an important role in cognitive function. Although post-mortem studies suggest later involvement of the DG into the AD progression, changes in microglia have not been studied in this subfield of the hippocampus. In the present study the numerical density (Nv, #/mm(3)) of both resting (identified by tomato lectin staining) and activated (identified by Mac-1 immunoreactivity) microglia was analysed in the molecular layer (ML) of the DG in the triple transgenic (3xTg-AD) mouse model of AD at different ages (9, 12 and 18 months). The 3xTg-AD mouse model of AD showed a significant increase in the Nv of resting (by 75%) and activated (by 67%) at 18 months of age compared to non-Tg controls. These results indicate a complex microglial remodelling during AD progression.
Subject(s)
Alzheimer Disease/pathology , CA1 Region, Hippocampal/pathology , Dentate Gyrus/pathology , Microglia/pathology , Plaque, Amyloid/pathology , Age Factors , Alzheimer Disease/genetics , Animals , Cell Count , Macrophage-1 Antigen , Male , Mice , Mice, TransgenicABSTRACT
Oscillations in hippocampal local field potentials (LFP) reflect the coordinated, rhythmic activity of constituent interneuronal and principal cell populations. Quantifying changes in oscillatory patterns and power therefore provides a powerful metric through which to infer mechanisms and functions of hippocampal network activity at the mesoscopic level, bridging single-neuron studies to behavioral assays of hippocampal function. Here, complementary protocols that enable mechanistic analyses of oscillation generation in vitro (in slices and a whole hippocampal preparation) and functional analyses of hippocampal circuits in behaving mice are described. Used together, these protocols provide a comprehensive view of hippocampal phenotypes in mouse models, highlighting oscillatory biomarkers of hippocampal function and dysfunction. Curr. Protoc. Mouse Biol. 2:273-294 © 2012 by John Wiley & Sons, Inc.
ABSTRACT
Amyloid beta (Abeta) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) are thought to be a pivotal toxic species in the pathogenesis of Alzheimer's disease (AD). Furthermore, evidence has been accumulating that components of APP processing pathway are involved in non-pathological normal function of the CNS. In this review we aim to cover the extensive body of research aimed at understanding how components of this pathway contribute to neurophysiological function of the CNS in health and disease. We briefly outline changes to clinical neurophysiology seen in AD patients before discussing functional changes in mouse models of AD which range from changes to basal synaptic transmission and synaptic plasticity through to abnormal synchronous network activity. We then describe the various neurophysiological actions that are produced by application of exogenous Abeta in various forms, and finally discuss a number or other neurophysiological aspects of the APP pathway, including functional activities of components of secretase complexes other than Abeta production.
Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/physiology , Signal Transduction/physiology , Alzheimer Disease/diagnosis , Amyloid beta-Protein Precursor/metabolism , Animals , Humans , Neural Pathways/metabolism , Neural Pathways/pathology , Neuronal Plasticity/physiology , Synapses/metabolism , Synapses/pathologyABSTRACT
The formation of cerebral senile plaques composed of amyloid ß peptide (Aß) is a fundamental feature of Alzheimer's disease (AD). Glial cells and more specifically microglia become reactive in the presence of Aß. In a triple transgenic model of AD (3 × Tg-AD), we found a significant increase in activated microglia at 12 (by 111%) and 18 (by 88%) months of age when compared with non-transgenic (non-Tg) controls. This microglial activation correlated with Aß plaque formation, and the activation in microglia was closely associated with Aß plaques and smaller Aß deposits. We also found a significant increase in the area density of resting microglia in 3 × Tg-AD animals both at plaque-free stage (at 9 months by 105%) and after the development of A plaques (at 12 months by 54% and at 18 months by 131%). Our results show for the first time that the increase in the density of resting microglia precedes both plaque formation and activation of microglia by extracellular Aß accumulation. We suggest that AD pathology triggers a complex microglial reaction: at the initial stages of the disease the number of resting microglia increases, as if in preparation for the ensuing activation in an attempt to fight the extracellular Aß load that is characteristic of the terminal stages of the disease.
Subject(s)
Alzheimer Disease/pathology , Microglia/pathology , Plaque, Amyloid/pathology , Amyloid beta-Peptides/metabolism , Animals , Disease Models, Animal , Mice , Mice, Transgenic , Microglia/physiology , Time FactorsABSTRACT
INTRODUCCIÓN: Sigue suscitando controversia el hecho de si el Cannabis actúa como un factor de riesgo causal para la esquizofrenia u otras psicosis funcionales. OBJETIVOS: Examinar críticamente la evidencia de que el Cannabis causa psicosis utilizando criterios establecidos de causalidad. MÉTODO: Identificamos 5 estudios que incluían una muestra bien definida extraída de registros de poblaciones o cohortes y que utilizaban medidas prospectivas de uso de Cannabis y psicosis adulta. RESULTADOS: Individualmente, el uso de Cannabis confiere un doble incremento global del riesgo relativo de sufrir esquizofrenia posteriormente. En la población general, la eliminación del uso de Cannabis podría reducir la incidencia de esquizofrenia en aproximadamente un 8 por ciento, asumiendo una relación causal. El consumo de Cannabis no parece ser una causa necesaria ni suficiente de psicosis. Es una causa componente, parte de una compleja constelación de factores que conducen a esta enfermedad. CONCLUSIONES: Podrían prevenirse casos de trastorno psicótico mediante la disuasión del uso de Cannabis entre la juventud vulnerable. Se requieren más investigaciones para comprender los mecanismos por los que el Cannabis causa psicosis (AU)
