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
Affiliations
Ahmad H. Alhowail
Department of Pharmacology and Toxicology, Qassim University, Buraydah, Saudi Arabia
Priyanka D. Pinky
Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA
Matthew Eggert
Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA
Jenna Bloemer
Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA; Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY, USA
Lauren N. Woodie
Department of Nutrition, Dietetics and Hospitality Management, College of Human Sciences, Auburn University, Auburn, Alabama, USA; 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
Manal A. Buabeid
College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
Subhrajit Bhattacharya
Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA; Center for Neuroscience Initiative, Auburn University, Auburn, AL, USA
Shanese L. Jasper
Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA
Dwipayan Bhattacharya
Department of Pharmacology, Lake Erie College of Osteopathic Medicine, PA, USA
Muralikrishnan Dhanasekaran
Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA; Center for Neuroscience Initiative, Auburn University, Auburn, AL, USA
Martha Escobar
Department of Psychology, Oakland University, Rochester, MI, USA
Robert D. Arnold
Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA; Center for Neuroscience Initiative, Auburn University, Auburn, AL, USA; Corresponding author.
Vishnu Suppiramaniam
Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA; Center for Neuroscience Initiative, Auburn University, Auburn, AL, USA; Corresponding author.
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.
