The physiological role of the amyloid-precursor protein (APP) is insufficiently understood.Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from APP -/mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-(A and not by APPsα, and it is neither observed in APP +/+ tissue treated with -or -secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca 2+ -dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with increased A levels. SIGNIFICANCE STATEMENTConsiderable effort has been directed to better understand the pathogenic role of the Amyloid Precursor Protein (APP) and its cleavage products in neurodegeneration -with a major focus on the accumulation and deposition of "synaptotoxic" Aβ peptides, which are produced by sequential cleavage of APP by β-and γ-secretases. Although the amyloidogenic APP processing pathway has recently been targeted in patients with Alzheimer's Diseases, the physiological role of APP/Aβ remains unclear, which limits our understanding how such interventions could influence brain functions in health and disease. Here, we report an essential role of Aβ (and not APPsα) in homeostatic synaptic plasticity, suggesting that this could be a major physiological function of Aβ in the healthy brain.
The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. 29 Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence 30 exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we 31 addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue 32 cultures of APP -/mice. In the absence of APP, dentate granule cells failed to strengthen their 33 excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid- (A and 34 not by APPsα, and it is neither observed in APP +/+ tissue treated with or -secretase 35 inhibitors nor in synaptopodin-deficient cultures lacking the Ca 2+ -dependent molecular 36 machinery of the spine apparatus. Together, these results suggest a role of APP processing via 37 the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of 38 relevance for brain physiology as well as for brain states associated with increased A levels. 39Hebbian plasticity, homeostatic plasticity 41 82 and report an essential role of Aβ in homeostatic plasticity of excitatory neurotransmission, 83 suggesting that this could be one of the major physiological functions of Aβ in the normal 84 brain. 85 5 RESULTSHomeostatic synaptic plasticity is not observed in dentate granule cells of APP-deficient 86 entorhinal-hippocampal tissue cultures 87 Considering the role of the hippocampal formation and specifically the dentate gyrus in 88 memory formation (Aimone et al., 2011; Friedman and Goldman-Rakic, 1988), 3-week-old 89 (18 days in vitro; div) organotypic tissue cultures containing the entorhinal cortex and the 90 hippocampus were prepared from APP +/+ and APP -/mice-including age-and time-matched 91 APP +/+ littermates obtained from APP +/intercrossing ( Figure 1A, B). Tissue cultures were 92 treated with tetrodotoxin (TTX; 2 µM; 2 days) to induce homeostatic synaptic plasticity, and 93 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated 94 miniature excitatory postsynaptic currents (mEPSCs) were recorded from individual dentate 95 granule cells (Figure 1C) to assess compensatory (i.e., homeostatic) synaptic changes. 96 In line with previous work [e.g., (Echegoyen et al., 2007; Kim and Tsien, 2008; Strehl et 97 al., 2018; Turrigiano et al., 1998; Vlachos et al., 2013)], a homeostatic increase in excitatory 98 synaptic strength (i.e., a robust increase in mEPSC amplitudes) was observed in the wild-type 99 tissue cultures (Figure 1D, E). In APP -/preparations, no significant changes in mEPSC 100properties were observed in dentate granule cells ( Figure 1F, G). Specifically, mean mEPSC 101 amplitude was 11.5 ± 0.3 pA in vehicle-only-treated and 11.8 ± 0.4 pA TTX-treated APP -/-102 dentate granule cells (p = 0.4; Mann-Whitney-test). 103In an attempt to rescue the ability of granule cells to express homeostatic synaptic 104 plasticity, APP -/tissue cultures were transfected with a bicistronic adeno-associated ...
The cytokine tumor necrosis factor (TNF) is involved in the regulation of physiological and pathophysiological processes in the central nervous system. In previous work, we showed that mice lacking constitutive levels of TNF exhibit a reduction in spine density and changes in spine head size distribution of dentate granule cells. Here, we investigated which TNF-receptor pathway is responsible for this phenotype and analyzed granule cell spine morphology in TNF-R1-, TNF-R2-, and TNF-R1/R2-deficient mice. Single granule cells were filled with Alexa568 in fixed hippocampal brain slices and immunostained for the actin-modulating protein synaptopodin (SP), a marker for strong and stable spines. An investigator blind to genotype investigated dendritic spines using deconvolved confocal image stacks. Similar to TNF-deficient mice, TNF-R1 and TNF-R2 mutants showed a decrease in the size of small spines (SP−negative) with TNF-R1/R2-KO mice exhibiting an additive effect. TNF-R1 mutants also showed an increase in the size of large spines (SP−positive), mirroring the situation in TNFdeficient mice. Unlike the TNF-deficient mouse, none of the TNF-R mutants exhibited a reduction in their granule cell spine densities. Since TNF tunes the excitability of networks, lack of constitutive TNF reduces network excitation. This may explain why we observed alterations in spine head size distributions in TNF-and TNF-R-deficient granule cells. The changes in spine density observed in the TNF-deficient mouse could not be linked to canonical TNF-R-signaling. Instead, noncanonical pathways or unknown developmental functions of TNF may cause this phenomenon.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.