Hippocampal dysfunction and behavioral deficit in the water maze in mice: an unresolved issue?

Dysfunction of the hippocampal formation manifests as impaired relational learning and memory in humans and animals. One of the most frequently applied relational learning paradigms in animals is the Morris water maze (MWM), in which the subject is required to learn complex spatial relationships of visual cues. MWM has been employed as a diagnostic tool to investigate effects of drugs and mutations. However, the validity of this test and its ability to properly detect hippocampal dysfunction have been questioned. In order to corroborate the role of hippocampus in spatial learning, we employed ibotenic acid lesioning and ablated the hippocampus bilaterally or unilaterally in mice, as ascertained by magnetic resonance imaging. We found a significant impairment in response to hippocampal disruption that was more pronounced in mice with bilateral lesion than with unilateral lesion. However, the results also indicated that even the mice with bilateral lesion could improve their performance, which confirms the notion that the MWM has an important non-hippocampal component. It is thus possible that experimental alteration of brain function does not manifest as modified performance in MWM, even when hippocampal function is modified (false-negative finding), or manifest as altered performance without varying hippocampal function (false-positive finding), possibilities that have important implications for studies using genetic and pharmacological manipulation of the brain.