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.