Abstract
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.
Highlights
The key role of amyloid precursor protein (APP) for Alzheimer pathogenesis is well established
We had shown that APLP1-KO mice, which we used as internal littermate (LM) controls in this study, exhibit a WT-like phenotype with regard to brain anatomy, basal synaptic transmission, and long-term potentiation (LTP), as well as spine density (Schilling et al, 2017)
We report that lack of the entire APP family in excitatory forebrain neurons from E11.5 onwards impairs brain function at multiple levels: (i) NexCre conditional APP/APLP1/APLP2 triple KO (cTKO) mice show deficits in hippocampal lamination and agenesis of the corpus callosum; (ii) electrophysiological recordings in the hippocampus of NexCre cTKO mice revealed impaired basal synaptic transmission and severely reduced LTP, which was associated with impaired neuronal morphology and reduced spine density of hippocampal neurons; (iii) at the behavioral level, NexCre cTKO mice were severely impaired in several tests for learning and memory, and exhibited core autism-like behaviors including stereotypic repetitive behaviors, reduced social communication, and impaired social interaction
Summary
The key role of APP for Alzheimer pathogenesis is well established. 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. Given the importance and prominent expression of all APP family members during development and in particular during synaptogenesis (Wang et al, 2009; Weyer et al, 2014; Schilling et al, 2017), we set out to inactivate the APP gene family already during embryonic development to assess the full extent of APP family functions for brain development, synaptogenesis, and the mature central nervous system To this end, we generated mice lacking APP and APLP2 in excitatory forebrain neurons from E11.5 onwards on a constitutive APLP1-KO background. We generated mice lacking APP and APLP2 in excitatory forebrain neurons from E11.5 onwards on a constitutive APLP1-KO background These NexCre cTKO mice proved fully viable, but showed altered brain morphology with agenesis of the corpus callosum and impaired lamination of the hippocampus. Our study identifies essential functions of the APP family during development, for normal hippocampal function and circuits important for learning and social behavior
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