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

6533b7defe1ef96bd1275e44

RESEARCH PRODUCT

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

David P. Wolfer David P. Wolfer Lutz Slomianka Susann Ludewig Martin Korte Kang Han Dominique Fässler Jakob Von Engelhardt Irmgard Amrein Max Richter Ulrike Müller Michaela K Back Susanne Erdinger Vicky Steubler

subject

Male 10017 Institute of Anatomy Long-Term Potentiation Hippocampal formation Synaptic Transmission Amyloid beta-Protein Precursor 0302 clinical medicine 2400 General Immunology and Microbiology Amyloid precursor protein Molecular Biology of Disease Autism spectrum disorder Mice Knockout Neurons 0303 health sciences biology Behavior Animal General Neuroscience Brain 2800 General Neuroscience Long-term potentiation Articles Phenotype 10076 Center for Integrative Human Physiology Knockout mouse Female learning and memory 610 Medicine & health General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Prosencephalon 1300 General Biochemistry Genetics and Molecular Biology mental disorders 1312 Molecular Biology Animals Learning APLP1 Autistic Disorder Social Behavior Molecular Biology APLP2 CA1 Region Hippocampal 030304 developmental biology synaptic plasticity General Immunology and Microbiology Amyloid precursor protein Synaptic plasticity Forebrain Synapses biology.protein Alzheimer 570 Life sciences; biology Neuroscience 030217 neurology & neurosurgery Neuroscience

description

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.

year	journal	country	edition	language
2021-05-19	The EMBO journal

10.15252/embj.2020107471 https://pubmed.ncbi.nlm.nih.gov/34188229