Previous reports have described increases in the size and number of cholinergic neurons in the basal forebrain in p75 neurotrophin receptor (p75^NTR) knockout mice. In an earlier study, we also found improved spatial memory in these mice, raising the possibility that p75^NTR regulates hippocampal function by its effects on the cholinergic basal forebrain. We therefore investigated hippocampal long‐term potentiation in p75^NTR knockout mice that shared the same genetic background as control 129/Sv mice. We also investigated heterozygous mice, carrying just one functional p75^NTR allele. The p75^NTR knockout mice had enhanced long‐term potentiation in the Schafer collateral fiber synapses of the hippocampus. Heterozygous mice had an intermediate level, greater than controls but less than knockout mice. Hippocampal choline acetyltransferase activity was also markedly elevated in p75^NTR knockout mice, with a smaller increase in heterozygous mice. In the Barnes maze, p75^NTR knockout mice displayed markedly superior learning to controls, and this was evident over the three age brackets tested. At each age, the performance of heterozygous mice was intermediate to the other groups. In the open field test, p75^NTR knockout mice exhibited greater stress‐related behavioral responses, including freezing, than did control animals. There were no differences between the three groups in a test of olfactory function. The dose‐dependent effects of p75^NTR gene copy number on hippocampal plasticity and spatial memory indicate that p75^NTR has profound effects on hippocampal function. Bearing in mind that p75^NTR is very sparsely expressed in the adult hippocampus and has a potent effect on hippocampal choline acetyltransferase activity, the effects of p75^NTR on hippocampal function are likely to be mediated indirectly, by its actions on basal forebrain cholinergic neurons. © 2009 Wiley‐Liss, Inc.