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APP Causes Hyperexcitability in Fragile X Mice
Cara J Westmark1, Shih-Chieh Chuang2, Seth A Hays3
1Department of Neurology, University of Wisconsin-Madison, Madison Madison, WI, USA.
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, Fmr1 mice. Normalization of APP levels in Fmr1 mice (Fmr1 /APP 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 Fmr1 brain slices. Fmr1 /APP 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 Fmr1 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.
Insights
Amyloid-beta precursor protein (APP) levels impact fragile X syndrome (FXS) hyperexcitability. Restoring APP balance in Fmr1 mice rescues disease phenotypes, highlighting APP as a therapeutic target for FXS.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Fragile X syndrome (FXS) is associated with altered Amyloid-beta protein precursor (APP) levels.
- Hyperexcitability is a core neurological phenotype in FXS.
- Normalization of APP levels in Fmr1 mice ameliorates several FXS-related disease characteristics.
Purpose of the Study:
- To investigate the role of APP levels in modulating hyperexcitability within Fmr1 mouse brain slices.
- To explore APP's function as a potential biomarker and therapeutic target for FXS.
Main Methods:
- Electrophysiological recordings from Fmr1 and Fmr1/APP double knockout mouse brain slices.
- Analysis of neocortical UP states and CA3 hippocampal ictal discharge duration.
- Development of a molecular model for APP's role in regulating neural excitability.
Main Results:
- Fmr1/APP slices showed complete rescue of neocortical UP states, a model of hyperexcitability.
- Reduced duration of ictal discharges was observed in the CA3 hippocampal model of epilepsy.
- Both APP over- and under-expression in Fmr1 mice increased seizure propensity, suggesting a critical role for APP homeostasis.
Conclusions:
- APP plays a crucial role in maintaining the excitation-inhibition (E/I) balance in neural circuits.
- A proposed model suggests APP functions as a rheostat, modulating hyperexcitability via mGluR5 and FMRP.
- Restoring APP homeostasis presents a potential therapeutic strategy for FXS by normalizing E/I balance.
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