APP Causes Hyperexcitability in Fragile X Mice

Abstract

Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO/APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO/APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS.

Multifarious Functions of the Fragile X Mental Retardation Protein

“…The metabotropic glutamate receptor (mGluR) theory of FXS hyperexcitability [68,69] is developmentally restricted, with early defects later corrected [22,24]. In mice, FMRP loss causes mGluR type 1 and/or 5 (mGluR1/5) pathway activation.…”

“…Interestingly, phosphodiesterase 4 (PDE4) inhibition in adult Drosophila reportedly restores mGluR-dependent learning/memory defects, independent of correcting brain learning/memory circuitry defects, showing therapies administered after the developmental critical period can still have efficacy [71]. FMRP and mGluR5 also may modulate excitability by acting together with amyloid precursor protein (APP) to alter signaling pathways, including mTor and ERK discussed above [14,68]. Drosophila FMRP binds APP mRNA, and APP translation is elevated in the Drosophila FXS model.…”

“…Increased APP levels are proposed to mediate hyperexcitation via a variety of mechanisms, including mGluR5 redistribution at synapses via Αβ oligomers metabolites of APP. In the mouse FXS model, genetically reducing APP levels prevents hyperexcitability and corrects behavioral, postsynaptic dendritic spine and glutamate signaling defects [14,68]. Dual dysregulation of APP and α-secretase ADAM10 in the mouse FXS model during the critical period activates the MAP kinase pathway to cause synaptogenic and behavioral deficits [72].…”

“…Earlier work in both mouse and Drosophila FXS models showed impaired GABAergic circuit assembly and function. Recent mouse work shows FMRP binds multiple GABA A R mRNAs (although this is debated [73]), resulting in delay of the developmental GABA inhibitory switch in FMR1 knockouts [68]. In FXS mice, underdevelopment and reduction of many components of the GABAergic system occurs at an early age [73].…”

“…On the other hand, FMRP function is maintained at maturity. In both mouse and Drosophila FXS models, genetic and pharmacological interventions in mature animals have proven efficacious in some cases [68,71]. For example, PDE4 inhibitors in Drosophila adults rescue FXS learning/memory deficits, despite persistent malformation of underlying brain circuitry [71].…”