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Presenilin attenuates receptor-mediated signaling and synaptic function
Angèle T Parent1, Natalie Y Barnes, Yoshihito Taniguchi
1Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, USA. aparent@uchicago.edu
Summary
Presenilin (PS) gamma-secretase activity normally limits neurite outgrowth and synaptic connectivity. Inhibiting this process enhances neuronal connections and signaling, impacting glutamatergic transmission and memory.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Presenilin (PS) is crucial for gamma-secretase activity, processing proteins like amyloid precursor protein (APP).
- Dysregulation of PS and gamma-secretase is implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate the role of PS-mediated gamma-secretase activity in regulating neuronal structure and function.
- To explore the impact of altered gamma-secretase activity on intracellular signaling pathways.
Main Methods:
- Utilized transfected neuroblastoma cells and primary cortical neurons from PS1 knockout (PS1(-/-)) and wild-type embryos.
- Administered gamma-secretase inhibitors to wild-type neurons.
- Assessed neurite outgrowth, axodendritic connectivity, spine density, and cAMP signaling.
- Measured short- and long-term glutamatergic synaptic transmission.
Main Results:
- Selective accumulation of a deleted in colorectal cancer (DCC) derivative (DCC-alpha) correlated with increased neurite outgrowth and connectivity.
- PS deficiency or gamma-secretase inhibition led to enhanced spine density and increased cAMP-dependent signaling.
- PS-deficient neurons exhibited enhanced glutamatergic synaptic transmission.
Conclusions:
- PS-mediated gamma-secretase activity attenuates intracellular signaling pathways.
- These pathways are critical for regulating glutamatergic synaptic transmission and memory processes.
- Findings reveal a novel role for PS in synaptic plasticity and neuronal communication.