Background: Doxorubicin (Dox) is a chemotherapeutic drug used extensively to treat several forms of malignant cancers.  However, Dox chemotherapy is associated with multiple adverse effects, including “chemobrain,” the syndrome where cancer patients’ exhibit learning and memory difficulties extending even beyond treatment.  

Aim: The present study investigated the effect of Dox treatment on learning and memory and hippocampal synaptic plasticity.  

Results and Discussion: Dox-treated mice (5 mg/kg weekly x 5) demonstrated impaired performance in the Y-maze spatial memory task and significantly reduced hippocampal long-term potentiation (LTP), a cellular model of memory. The deficit in LTP 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 open time, and increased closed times. Furthermore, a reduction in the levels of the AMPAR subunit GluA1, its downstream signaling molecule Ca2+/calmodulin-dependent protein kinase (CaMKII), and brain derived neurotrophic factor (BDNF) were observed. This was also accompanied with 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 : Chemotherapy, Glutamate receptor, Chemobrain