Suchergebnisse

The entorhinal cortex (EC) is a brain region that has been shown to be essential for memory functions and spatial navigation. However, detailed three-dimensional (3D) synaptic morphology analysis and identification of postsynaptic targets at the ultrastructural level have not been performed before in the human EC. In the present study, we used Focused Ion Beam/Scanning Electron Microscopy to perform a 3D analysis of the synapses in the neuropil of medial EC in layers II and III from human brain autopsies. Specifically, we studied synaptic structural parameters of 3561 synapses, which were fully reconstructed in 3D. We analyzed the synaptic density, 3D spatial distribution, and type (excitatory and inhibitory), as well as the shape and size of each synaptic junction. Moreover, the postsynaptic targets of synapses could be clearly determined. The present work constitutes a detailed description of the synaptic organization of the human EC, which is a necessary step to better understand the functional organization of this region in both health and disease ; Spanish "Ministerio de Ciencia e Innovación" (grant PGC2018-094307-B-I00); the Cajal Blue Brain Project (the Spanish partner of the Blue Brain Project initiative from EPFL, [Switzerland]); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain (CB06/05/0066); the Alzheimer's Association (ZEN-15-321663); the European Union's Horizon 2020 Framework Programme for Research and Innovation (grant agreement No. 945539) to Human Brain Project SGA3; the Spanish "Ministerio de Educación y Formación Profesional" (FPU14/02245 to M.M.-C.); UNED (Plan de Promoción de la Investigación, 2014-040-UNED-POST to L.B.-L.) We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).

Abstract Synaptic dysfunction or loss in early stages of Alzheimer's disease (AD) is thought to be a major structural correlate of cognitive dysfunction. Early loss of episodic memory, which occurs at the early stage of AD, is closely associated with the progressive degeneration of medial temporal lobe (MTL) structures of which the transentorhinal cortex (TEC) is the first affected area. However, no ultrastructural studies have been performed in this region in human brain samples from AD patients. In the present study, we have performed a detailed three-dimensional (3D) ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM) to investigate possible synaptic alterations in the TEC of patients with AD. Surprisingly, the analysis of the density, morphological features and spatial distribution of synapses in the neuropil showed no significant differences between AD and control samples. However, light microscopy studies showed that cortical thickness of the TEC was severely reduced in AD samples, but there were no changes in the volume occupied by neuronal and glial cell bodies, blood vessels, and neuropil. Thus, the present results indicate that there is a dramatic loss of absolute number of synapses, while the morphology of synaptic junctions and synaptic spatial distribution are maintained. How these changes affect cognitive impairment in AD remains to be elucidated. ; This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (SAF 2015–66603-P), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain, CB06/05/0066), the Alzheimer's Association (ZEN-15-321663), and the European Union's Horizon 2020 research and innovation program under grant agreement No. 720270 (Human Brain Project). MM-C was awarded a research fellowship from the Spanish Ministry of Education, Culture and Sport (grant FPU 14/ 02245).