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1. CNTN4 modulates neural elongation through interplay with APP

Author

Rosemary A. Bamford, Amila Zuko, Madeline Eve, Jan J. Sprengers, Harm Post, Renske L. R. E. Taggenbrock, Dominique Fäβler, Annika Mehr, Owen J. R. Jones, Aurimas Kudzinskas, Josan Gandawijaya, Ulrike C. Müller, Martien J. H. Kas, J. Peter H. Burbach, and Asami Oguro-Ando

Subjects
CNTN4, APP, cell, cortex, neuronal, motor, Biology (General), QH301-705.5
Abstract

The neuronal cell adhesion molecule contactin-4 (CNTN4) is genetically associated with autism spectrum disorder (ASD) and other psychiatric disorders. Cntn4-deficient mouse models have previously shown that CNTN4 plays important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex has not yet been investigated. Our study found a reduction in cortical thickness in the motor cortex of Cntn4 −/− mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, confirming an interaction between CNTN4 and amyloid-precursor protein (APP). Knockout human cells for CNTN4 and/or APP revealed a relationship between CNTN4 and APP. This study demonstrates that CNTN4 contributes to cortical development and that binding and interplay with APP controls neural elongation. This is an important finding for understanding the physiological function of APP, a key protein for Alzheimer’s disease. The binding between CNTN4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.

Published
2024
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2. Lack of APP and APLP2 in GABAergic Forebrain Neurons Impairs Synaptic Plasticity and Cognition

Author

Ulrike Herrmann, Jakob von Engelhardt, Annika Mehr, Susann Ludewig, Martin Korte, David P. Wolfer, Meike Hick, Michaela Kerstin Müller, and Ulrike Müller

Subjects
Interneuron, Cognitive Neuroscience, Long-Term Potentiation, Spatial Learning, Hippocampus, Action Potentials, Inhibitory postsynaptic potential, Nesting Behavior, 03 medical and health sciences, Cellular and Molecular Neuroscience, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Cognition, Prosencephalon, Amyloid precursor protein, medicine, Animals, GABAergic Neurons, CA1 Region, Hippocampal, 030304 developmental biology, Spatial Memory, Mice, Knockout, 0303 health sciences, Neuronal Plasticity, biology, Pyramidal Cells, Excitatory Postsynaptic Potentials, Long-term potentiation, medicine.anatomical_structure, nervous system, Inhibitory Postsynaptic Potentials, Synaptic plasticity, Forebrain, Excitatory postsynaptic potential, biology.protein, Neuroscience, 030217 neurology & neurosurgery
Abstract

Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer’s disease, yet its physiological functions remain incompletely understood. Previous studies had indicated important synaptic functions of APP and the closely related homologue APLP2 in excitatory forebrain neurons for spine density, synaptic plasticity, and behavior. Here, we show that APP is also widely expressed in several interneuron subtypes, both in hippocampus and cortex. To address the functional role of APP in inhibitory neurons, we generated mice with a conditional APP/APLP2 double knockout (cDKO) in GABAergic forebrain neurons using DlxCre mice. These DlxCre cDKO mice exhibit cognitive deficits in hippocampus-dependent spatial learning and memory tasks, as well as impairments in species-typic nesting and burrowing behaviors. Deficits at the behavioral level were associated with altered neuronal morphology and synaptic plasticity Long-Term Potentiation (LTP). Impaired basal synaptic transmission at the Schafer collateral/CA1 pathway, which was associated with altered compound excitatory/inhibitory synaptic currents and reduced action potential firing of CA1 pyramidal cells, points to a disrupted excitation/inhibition balance in DlxCre cDKOs. Together, these impairments may lead to hippocampal dysfunction. Collectively, our data reveal a crucial role of APP family proteins in inhibitory interneurons to maintain functional network activity.

Published
2020

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