Voltage-gated potassium (K+) channel sub-family B member 1 (KCNB1, Kv2.1) is known to undergo oxidation-induced oligomerization during aging but whether this process affects brain's physiology was not known. Here, we used 10, 16 and 22 month-old transgenic mice overexpressing a KCNB1 variant that does not oligomerize (Tg-C73A) and as control, mice overexpressing the wild type (Tg-WT) channel and non-transgenic (non-Tg) mice to elucidate the effects of channel's oxidation on cognitive function. Aging mice in which KCNB1 oligomerization is negligible (Tg-C73A), performed significantly better in the Morris Water Maze (MWM) test of working memory compared to non-Tg or Tg-WT mice. KCNB1 and synapsin-1 co-immunoprecipitated and the cognitive impairment in the MWM was associated with moderate loss of synapsin-1 in pre-synaptic structures of the hippocampus, whereas neurodegeneration and neuronal loss were not significantly different in the various genotypes. We conclude that moderate oxidation of the KCNB1 channel during aging can influence neuronal networks by affecting synaptic function. Published by Elsevier Inc.