Huntington’s disease (HD) is an inherited neurodegenerative brain disorder characterised by motor, emotional and cognitive abnormalities. The R6/2 transgenic mouse model of HD (Mangiarini et al. 1996) develops a progressive neurological phenotype with deficits in both motor and cognitive behaviours, including impairments in spatial learning. One possible cellular mechanism underlying learning is long-term potentiation (LTP), a form of synaptic plasticity. Synaptic dysfunction may be a feature of HD because in R6/2 mice neuronal levels of complexin II, a pre-synaptic SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor)-complex-associated protein, are reduced in the hippocampus, a brain region involved in spatial learning. Since knockout mice lacking complexin II (Cplx2 KO mice) also show deficits in spatial learning tasks, we hypothesised that a reduction in complexin II may contribute to abnormal hippocampal mossy fibre LTP, a form of synaptic plasticity dependent on presynaptic mechanisms. Hippocampal slices were prepared from humanely killed wild-type (WT) and transgenic (R6/2, Cplx2 WT and Cplx2 KO) mice aged between 6 and 20 weeks of age. Cplx2 mutant mouse lines were obtained from the Max-Planck-Institute for Experimental Medicine. All experiments were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986 and conformed to local ethical guidelines. Electrically evoked field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA3 subfield of hippocampal slices in the presence of 50 μM picrotoxin. High frequency stimulation (HFS, 3 x 100 Hertz, 1 second duration, 20 second interval) induced N-methyl-D-aspartate (NMDA) receptor-independent mossy fibre LTP that was measured between 30 and 50 minutes post-HFS in control mice (WT 187 ± 17.4%, n = 23; Cplx2 WT 178 ± 8.80%, n = 9). However, mossy fibre LTP was significantly reduced in R6/2 mice (94.9 ± 5.66%, n = 19; p = <0.0001) and in Cplx2 KO mice (93.5 ± 6.47%, n = 10; p = <0.0001). (All data represent mean values ± the standard error of the mean, where ‘n’ represents the number of slices used). Data were subjected to unpaired, two-tailed t-tests to determine statistical significance, with the use of Welch’s correction where unequal variances existed between groups. These findings suggest that complexin II is required for the induction of mossy fibre LTP, and support the idea that loss of complexin II from the R6/2 mouse hippocampus contributes to impairments in mossy fibre glutamatergic synaptic plasticity.