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Published on: October 23, 2014
APOE4 and doxorubicin impair inhibitory interneuron function and homeostatic regulation in the entorhinal cortex
Nancy Luo1,2, Harshul Pandit2, Shreya Kalra2
1Interdisciplinary Program in Neuroscience, Georgetown University, Washington D.C., United States of America.
Abstract:
APOE4 is a risk factor for several disease states associated with cognitive impairment, including Alzheimer's disease and cancer-chemotherapy induced cognitive impairment. Using mouse knock-in models of human APOE alleles, we examined the effects of APOE genotype and chemotherapy on the ex vivo electrophysiological characteristics of excitatory and inhibitory neurons in the entorhinal cortex (EC). We found that APOE4 is associated with a significantly higher excitatory/inhibitory ratio (0.33 ± 0.04) in the layer 2/3 pyramidal cells of the entorhinal cortex compared to APOE3 (0.19 ± 0.04). We crossed APOE mice to mice with parvalbumin (PV) interneurons tagged with tdTomato, allowing us to measure effects specifically on this inhibitory cell type. For EC pyramidal neurons, the chemotherapeutic agent doxorubicin caused increases in the amplitudes of both spontaneous excitatory and inhibitory post-synaptic currents, with significant responses (***p < 0.001; **p < 0.01 respectively) in APOE3 brains. For EC PV neurons, APOE4 genotype was associated with significantly lower firing rates at injections of high currents (**p < 0.01), but rates were unaffected by doxorubicin. Doxorubicin doubled the percentage of PV cells that showed inactivation block in APOE3 brains (25% to 52%) but had no effect on APOE4 brains (50% to 54%). This ex vivo study suggests that APOE4 impairs homeostatic synaptic transmission in pyramidal cells under control conditions and causes a lack of responsiveness to a stressor (doxorubicin treatment) in PV cells.
Insights
The APOE4 gene variant impairs brain cell communication, affecting cognitive function in diseases like Alzheimer's. This study shows APOE4 disrupts normal brain activity and response to chemotherapy drugs.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- The apolipoprotein E4 (APOE4) allele is a significant risk factor for cognitive impairment, including Alzheimer's disease and chemotherapy-induced cognitive dysfunction.
- Understanding the cellular mechanisms underlying APOE4's impact on neuronal function is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the effects of APOE genotype and chemotherapy on the electrophysiological properties of excitatory and inhibitory neurons in the mouse entorhinal cortex (EC).
- To determine how APOE4 influences synaptic transmission and neuronal excitability in response to chemotherapeutic agents.
Main Methods:
- Utilized mouse knock-in models expressing human APOE3 and APOE4 alleles.
- Performed ex vivo electrophysiological recordings on entorhinal cortex (EC) pyramidal and parvalbumin (PV)-expressing interneurons.
- Administered the chemotherapeutic agent doxorubicin to assess its impact on neuronal function.
Main Results:
- APOE4 genotype was associated with a higher excitatory/inhibitory ratio in EC layer 2/3 pyramidal cells compared to APOE3.
- Doxorubicin increased excitatory and inhibitory postsynaptic currents in APOE3 pyramidal neurons but not significantly in APOE4.
- APOE4 PV neurons exhibited lower firing rates and a lack of response to doxorubicin-induced inactivation block, unlike APOE3 PV neurons.
Conclusions:
- APOE4 impairs homeostatic synaptic transmission in EC pyramidal cells under basal conditions.
- The APOE4 genotype leads to a diminished neuronal response to the stressor of doxorubicin treatment in PV interneurons.
- These findings highlight distinct cellular dysfunctions associated with APOE4 that may contribute to cognitive impairment in disease states.
