Michaela K. Back, Germany
Institut für Pathophysiologie, Universitätsmedizin Mainz Physiologie und Pathophysiologie synaptischer KommunikationAuthor Of 1 Presentation
TRIPLE KNOCKOUT OF APP-FAMILY IMPAIRS LTP AND CORTICAL NETWORK ACTIVITY LEADING TO DEFICITS IN COGNITIVE TESTS AND ASD-LIKE BEHAVIOR
Abstract
Aims
Despite the assumed key role of Aβ for Alzheimer´s pathogenesis, clinical trials directed at reducing Aβ failed to substantially modify the course of the disease. Thus, it now appears crucial to understand AD pathogenesis in the context of APP physiological functions. However, the early postnatal lethality of germline triple knockout mice has so far precluded the analysis of APP family physiological functions in the developing and adult brain.
Methods
Here, we generated conditional APP/APLP1/APLP2 triple KO (cTKO) mice lacking the APP family in excitatory forebrain neurons from E12 onwards using NexCre mice.
Results
Conditional cTKO mice showed altered brain morphology with agenesis of the corpus callosum and impaired lamination of the hippocampus. In addition, electrophysiological recordings in the hippocampus of cTKO mice revealed impaired basal synaptic transmission and severely reduced long-term potentiation that was associated with reduced spine density of hippocampal neurons. At the behavioral level cTKO mice were not only severely impaired in several tests for learning and memory, but also exhibited autism-like behaviors including stereotypic repetitive behaviors, reduced social communication and impaired social interaction. Further, in vivo two-photon imaging of spontaneous Ca2+ transients revealed that behavioral impairments were associated with impaired network activity in the cortex.
Conclusions
Together, our study identifies essential functions of the APP family during brain development and for hippocampal and cortical networks in the adult brain, important to consider for future therapeutic strategies.