Loss of all three APP family members during development impairs synaptic function and plasticity, disrupts learning, and causes an autism-like phenotype.

Autor: Steubler V; Department of Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany., Erdinger S; Department of Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany., Back MK; Institute of Pathophysiology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Ludewig S; Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany.; Helmholtz Centre for Infection Research, Neuroinflammation and Neurodegeneration Group, Braunschweig, Germany., Fässler D; Department of Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany., Richter M; Department of Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany., Han K; Department of Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany., Slomianka L; Institute of Anatomy and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland., Amrein I; Institute of Anatomy and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland., von Engelhardt J; Institute of Pathophysiology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Wolfer DP; Institute of Anatomy and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.; Institute of Human Movement Sciences, ETH Zurich, Zurich, Switzerland., Korte M; Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany.; Helmholtz Centre for Infection Research, Neuroinflammation and Neurodegeneration Group, Braunschweig, Germany., Müller UC; Department of Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2021 Jun 15; Vol. 40 (12), pp. e107471. Date of Electronic Publication: 2021 May 19.
DOI: 10.15252/embj.2020107471
Abstrakt: The key role of APP for Alzheimer pathogenesis is well established. However, perinatal lethality of germline knockout mice lacking the entire APP family has so far precluded the analysis of its physiological functions for the developing and adult brain. Here, we generated conditional APP/APLP1/APLP2 triple KO (cTKO) mice lacking the APP family in excitatory forebrain neurons from embryonic day 11.5 onwards. NexCre cTKO mice showed altered brain morphology with agenesis of the corpus callosum and disrupted hippocampal lamination. Further, NexCre cTKOs revealed reduced basal synaptic transmission and drastically reduced long-term potentiation that was associated with reduced dendritic length and reduced spine density of pyramidal cells. With regard to behavior, lack of the APP family leads not only to severe impairments in a panel of tests for learning and memory, but also to an autism-like phenotype including repetitive rearing and climbing, impaired social communication, and deficits in social interaction. Together, our study identifies essential functions of the APP family during development, for normal hippocampal function and circuits important for learning and social behavior.
(© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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