Characterizing Entorhinal Cortex Circuit Dysfunction in an APOE Mouse Model of Chemotherapy-Induced Cognitive Impairment

项目摘要

PROJECT ABSTRACT Chemotherapy-induced cognitive impairment (CICI) is a condition commonly reported in cancer patients, where learning, memory, attention, and executive functions are impaired following cancer chemotherapy treatment. To date, the most common genetic risk factor associated with CICI is the APOE4 gene, which is also the strongest genetic risk factor for Alzheimer’s Disease. Little is known about how APOE4 affects excitatory and inhibitory neurons in the entorhinal cortex (a region of the brain critical for information gating between the cerebral cortex and the hippocampus) and how those differences may make APOE4 neurons more susceptible to environmental stress. Using our novel mouse model of CICI that combines the effects of a chemotherapeutic challenge (doxorubicin) and genetic susceptibility (APOE4 genotype), I hypothesize that APOE4-TR mice have a deficit in inhibitory neuron function which prevents them from responding to chemotherapy in a protective manner. I will test two specific hypotheses in this proposal: 1) APOE4-TR mice are vulnerable to the effects of chemotherapy due to an inability to preserve parvalbumin interneuron dendritic complexity in the entorhinal cortex, leading to synaptic excitation-inhibition (E/I) imbalance and 2) apoE isoform levels drive the difference in circuit dysfunction in APOE4-TR mice treated with chemotherapy. The following aims will investigate how APOE genotype and chemotherapy affect entorhinal cortex circuitry: Aim 1: Examine mechanisms underlying entorhinal cortex circuit dysfunction in CICI. I will use a combination of electrophysiology, confocal microscopy, and transgenic mice to measure changes in E/I balance and interrogate underlying causes of E/I dysregulation in the presence and absence of chemotherapy. Aim 2: Test whether increasing apoE levels protects against entorhinal cortex circuit dysfunction in CICI. I will use an AAV construct to introduce astrocytic-apoE3 into APOE3 and APOE4 mice treated with chemotherapy. Changes to E/I balance will be measured to assess if apoE levels minimize vulnerability to CICI. These aims will collectively identify circuit-based mechanisms underlying CICI. Outcomes of this proposal can provide clinical guidance on 1) identifying at-risk patients prior to chemotherapy treatment and 2) reducing the likelihood of CICI by altering apoE levels.