title: Effects of amyloid-β plaque proximity on the axon initial segment of pyramidal cells.
abstract: The output of cortical pyramidal cells reflects the balance between excitatory inputs of cortical and subcortical origin, and inhibitory inputs from distinct populations of cortical GABAergic interneurons, each of which selectively innervate different domains of neuronal pyramidal cells (i.e., dendrites, soma and axon initial segment [AIS]). In Alzheimer's disease (AD), the presence of amyloid-β (Aβ) plaques alters the synaptic input to pyramidal cells in a number of ways. However, the effects of Aβ plaques on the AIS have still not been investigated to date. This neuronal domain is involved in input integration, as well as action potential initiation and propagation, and it exhibits Ca2+- and activity-dependent structural plasticity. The AIS is innervated by GABAergic axon terminals from chandelier cells, which are thought to exert a strong influence on pyramidal cell output. In the AβPP/PS1 transgenic mouse model of AD, we have investigated the effects of Aβ plaques on the morphological and neurochemical features of the AIS, including the cisternal organelle, using immunocytochemistry and confocal microscopy, as well as studying the innervation of the AIS by chandelier cell axon terminals. There is a strong reduction in GABAergic terminals that appose AIS membrane surfaces that are in contact with Aβ plaques, indicating altered inhibitory synapsis at the AIS. Thus, despite a lack of gross structural alterations in the AIS, this decrease in GABAergic innervation may deregulate AIS activity and contribute to the hyperactivity of neurons in contact with Aβ plaques.
authors.affiliation: Laboratorio Cajal de Circuitos Corticales (CTB), Universidad Politécnica de Madrid, Campus Montegancedo S/N, Pozuelo de Alarcón, Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: León-Espinosa
authors.forename: Javier
authors.initials: J
authors.lastname: DeFelipe
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D001369:Axons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000473:pathology*; D004195:Disease Models, Animal; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D010320:Parvalbumins / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D017966:Pyramidal Cells / Q000473:pathology*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C094681:Ank3 protein, mouse; D017487:Ankyrins; D050485:GABA Plasma Membrane Transport Proteins; D008840:Microfilament Proteins; C508853:PSEN1 protein, human; D010320:Parvalbumins; D053764:Presenilin-1; C503968:Synpo protein, mouse; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse