Memantine (MEM) is a low affinity N-methyl D-aspartate receptor (NMDA-R) antagonist used in Alzheimer’s disease therapy. NMDA-R antagonism, however, does not satisfactorily explain the cognitive-enhancing effects of this drug. We have used electrophysiological recordings from hippocampal slices prepared from adult rats and mice, in the presence of the NMDA-receptor antagonist, L-689560 (5 μM), to explore non-NMDA-R-mediated actions of MEM. In addition to its well-documented effects on NMDA-R, MEM is reported to inhibit Na+ channels in sensory neurones (Bräu et al 2001). We examined the effects of MEM on Na+ currents (INa) elicited in nucleated macropatches excised from CA1 pyramidal neurones. INa was activated with 10 pulse, 100 Hz trains of 2 ms step depolarizations. MEM (100 μM) inhibited the first current in the train by 66 ± 5 % (n=3). The ratio of the 10th current to the 1st current (P10/P1) was used to address use-dependence. Under control conditions P10/P1 was 0.61 ± 0.03, whereas in the presence of MEM P10/P1 was 0.51 ± 0.01 (n=3); this indicates that whilst MEM produced a substantial inhibition of hippocampal INa, it did so in a relatively non-use-dependent fashion. Reducing INa would be expected to alter action potential (AP) kinetics. In whole-cell current clamp CA1 pyramidal neurones were depolarised (500 ms, +100 pA) to elicit AP firing. Under control conditions the peak and maximum rate of rise of the first AP were 47 ± 1 mV and 641 ± 27 V/s, respectively. AP peak was significantly reduced by both 10 and 100 μM MEM (1.7 ± 0.5 mV reduction, n=8, P<0.01 and 9.0 ± 1.7 mV reduction, n=6, P<0.01, respectively). This was accompanied by a slowing in maximum rate of rise (3 ± 1 %, P<0.01 and 22 ± 2 % P<0.001, respectively). The fast after-depolarisation (ADP) that immediately follows a single AP was enhanced by MEM (10 or 100 μM) (12 ± 5 %, n=8, P<0.05 and 35 ± 8 % n=6, P<0.001, respectively). This ADP is known to drive high frequency (HF) burst firing in these neurones; in line with this we found that MEM resulted in a substantial decrease in the interval between the first two APs elicited by a 500 ms, 100 pA current injection (control 44 ± 9 ms, mematine 13 ± 3 ms; n=4, P<0.05). MEM also increased HF bursting in response to a current stimulus designed to mimic a random synaptic barrage. Finally, in the presence of 100 nM kainate, networks of neurones within hippocampal slices generate γ-oscillations interspersed with HF ripple activity. MEM (10 or 100 μM) did not significantly affect the power of γ-oscillations (P=0.4), but significantly increased the duration of the high frequency ripple activity (control 52 ± 2 ms, MEM 56 ± 1 ms, n=7, P<0.01). These data suggest that MEM may improve cognitive performance by encouraging HF burst firing, thereby promoting the induction of synaptic plasticity.