Oxidative Stress Mediated Glutamate Release and NMDA Receptor-Dependent Synaptic Remodeling in Radiation-Induced Cognitive Dysfunction

Thanh Thai Lam (Advisor: David R. Grosshans, MD, PhD)

         In children younger than 14 years old, the brain and other parts of the central nervous system are the most common sites for solid tumors. Radiotherapy is an effective treatment for central nervous system (CNS) tumors. However, it often causes a progressive decline in cognitive functions, which is especially devastating for pediatric patients. Although post-mitotic neurons are generally considered resistant to radiation-induced immediate cell death, ionizing radiation causes complex neurochemical and structural changes that damage synaptic integrity. In this study, we examined the molecular cascades following a 10 Gy radiation dose applied to mouse cortical neurons. We found that radiation-induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) could trigger excessive extracellular glutamate release. This glutamate surge could initially be mediated by activation of N-methyl-D-aspartate receptors (NMDARs), followed by activation of AMPA receptors. Additionally, in vivo results show a significant memory decline in juvenile mice that received radiation treatment; pharmacological blockade of NMDARs by using memantine or ifenprodil pre-treatment could effectively prevent the radiation-induced memory deficit and preserve cognitive function.

Advisory Committee:

• David R. Grosshans, MD, PhD, Chair
• Michael Beierlein, PhD
• Jospeh G. Duman, PhD
• Steven H. Lin, MD, PhD
• Gabriel O. Sawakuchi, PhD

Join via Zoom (Please contact Mr. Lam for his Zoom meeting info.)