Aims: Nuclear pore complex proteins (Nups) play critical roles in cell type-specific gene regulation by orchestrating lineage specification and maintenance of cellular state. However, their roles in adult brain remain largely elusive, especially in post-mitotic functional neurons. Accurate spatio-temporal regulation of neuronal gene programs is vital for neuronal plasticity and ultimately for learning and memory. We hypothesize that Nups play critical roles in neuronal plasticity and cognition through gene regulation. Methods: To address the importance of Nups for cognition and memory, we conducted behaviour tests on Nup153 heterozygous mice (Nup153-het), one of key Nups in gene regulation. In addition, changes in neuronal responsiveness in the hippocampus of Nup153-het mice were measured by cytological, histological and electrophysiological methods. Results: Mid-age Nup153-het mice showed impaired novelty recognition in the Novel Object Recognition test, while young Nup153-het mice did not show cognitive impairment. Hippocampal slice recording by a multi electrode array exhibited circuit hyperexcitability in young Nup153-het mice and hypoexcitability in mid-age Nup153-het mice. Conclusions: Our results suggest age-dependent hippocampal dysfunction in Nup153-het mice, where Nup153 safeguards neuronal response specificity. To understand underlying mechanisms of neuronal activity imbalance, we are analyzing the roles of Nup153 in gene regulation in the adult brain.