We examined the electrophysiological properties of neurons cultured from the septum of the trisomy 16 mouse fetus, an animal model for Down's syndrome. The passive membrane properties were not different between trisomic and diploid septal neurons. We distinguished low-firing and high-firing populations of neurons based on differences in the firing rate evoked during current injection. Low-firing neurons fired three or fewer action potentials, high-firing neurons fired four or more. The membrane currents of low-firing trisomic neurons were not different from those of low-firing diploid neurons. However, high-firing trisomic neurons had an increased inward current and conductance, and a greater inward-to-outward conductance ratio. The increased current and conductance were independent of the passive electrical properties. The increased inward current in high-firing trisomic neurons was correlated with action potentials having faster depolarization rates. This greater excitability among this population of trisomic septal neurons, coupled with a reduced excitation in hippocampal neurons, may compromise septohippocampal and memory function.