Doxorubicin induces dysregulation of AMPA receptor and impairs hippocampal synaptic plasticity leading to learning and memory deficits

Ahmad H Alhowail; Priyanka D Pinky; Matthew Eggert; Jenna Bloemer; Lauren N Woodie; Manal A Buabeid; Subhrajit Bhattacharya; Shanese L Jasper; Dwipayan Bhattacharya; Muralikrishnan Dhanasekaran; Martha Escobar; Robert D Arnold; Vishnu Suppiramaniam

doi:10.1016/j.heliyon.2021.e07456

Doxorubicin induces dysregulation of AMPA receptor and impairs hippocampal synaptic plasticity leading to learning and memory deficits

Heliyon. 2021 Jul 1;7(7):e07456. doi: 10.1016/j.heliyon.2021.e07456. eCollection 2021 Jul.

Authors

Ahmad H Alhowail¹, Priyanka D Pinky², Matthew Eggert², Jenna Bloemer^{2

3}, Lauren N Woodie^{4

5}, Manal A Buabeid⁶, Subhrajit Bhattacharya^{2

7}, Shanese L Jasper², Dwipayan Bhattacharya⁸, Muralikrishnan Dhanasekaran^{2

7}, Martha Escobar⁹, Robert D Arnold^{2

7}, Vishnu Suppiramaniam^{2

7}

Affiliations

¹ Department of Pharmacology and Toxicology, Qassim University, Buraydah, Saudi Arabia.
² Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA.
³ Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY, USA.
⁴ Department of Nutrition, Dietetics and Hospitality Management, College of Human Sciences, Auburn University, Auburn, Alabama, USA.
⁵ Institute for Diabetes, Obesity and Metabolism, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶ College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates.
⁷ Center for Neuroscience Initiative, Auburn University, Auburn, AL, USA.
⁸ Department of Pharmacology, Lake Erie College of Osteopathic Medicine, PA, USA.
⁹ Department of Psychology, Oakland University, Rochester, MI, USA.

Abstract

Doxorubicin (Dox) is a chemotherapeutic agent used widely to treat a variety of malignant cancers. However, Dox chemotherapy is associated with several adverse effects, including "chemobrain," the observation that cancer patients exhibit through learning and memory difficulties extending even beyond treatment. This study investigated the effect of Dox treatment on learning and memory as well as hippocampal synaptic plasticity. Dox-treated mice (5 mg/kg weekly x 5) demonstrated impaired performance in the Y-maze spatial memory task and a significant reduction in hippocampal long-term potentiation. The deficit in synaptic plasticity was mirrored by deficits in the functionality of synaptic `α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) channels, including reduced probability of opening, decreased dwell open time, and increased closed times. Furthermore, a reduction in the AMPAR subunit GluA1 level, its downstream signaling molecule Ca²+/calmodulin-dependent protein kinase (CaMKII), and brain-derived neurotrophic factor (BDNF) were observed. This was also accompanied by an increase in extracellular signal regulated kinase (ERK) and protein kinase B (AKT) activation. Together these data suggest that Dox-induced cognitive impairments are at least partially due to alterations in the expression and functionality of the glutamatergic AMPAR system.

Keywords: AMPA; Chemobrain; Cognitive deficits; Doxorubicin; Long-term potentiation; Synaptic plasticity.