Abstract: Radiation therapy (RT) is a standard treatment for head and neck tumors. However, radiation-induced cognitive impairment remains a serious issue due to lack of satisfying prevention and effective treatment. Previous studies have revealed that dysfunction of the hippocampus played a key role in radiation-induced cognitive impairment resulted from hippocampal neurogenesis deficit or neuroinflammation. However, the long-term effect of radiation on electrophysiological adaptation of hippocampal neurons remains poorly recognized. This investigation focused on the impact of 30 Gy radiation-induced functional alternation in the hippocampal neurons by systematically assessing intrinsic physiology, synaptic plasticity and molecular markers in the mice at three months post irradiation. Our results demonstrated that radiation diminished the spike firing of hippocampal CA1 pyramidal neurons. In addition, radiation also reduced excitatory synaptic input and enhanced inhibitory inputs on CA1 pyramidal neurons, in accordance with decreased VGLUT1 and increased VGAT expression in the hippocampus, indicating radiation may have a direct impact on the excitatory/inhibitory balance of synaptic input in the hippocampus. Furthermore, we demonstrated the impaired hippocampal long-term potentiation (LTP) with marked alteration of the GluR1 expression levels at three months post irradiation. Since the radiation-induced hippocampal dysfunction is associated with spatial memory impairment, our findings provide new insights into the pathogenic mechanism underlying radiation-induced cognitive deficits.

Key words: radiation-induced cognitive impairment, whole-cell patch clamp recording, intrinsic excitability, spontaneous excitatory postsynaptic currents, spontaneous inhibitory postsynaptic currents, synaptic plasticity, long-term potentiation, GABA-mediated hyperfunction, type I vesicular glutamate transporter, vesicular GABA transporter, GluR1