Animal Models of Hippocampal Deficits in Disorders: Does Size Matter?

Many neuropsychiatric disorders, such as Alzheimer\u27s disease, schizophrenia, and depression, are marked by memory impairment. Some researchers believe that these memory deficits may be due to disorder-related alterations in the size or shape of the hippocampus, a brain region important in learning and memory. Studies of experimentally-induced hippocampal alterations in laboratory animals may provide a means to develop better treatments for the memory deficits associated with neuropsychiatric disorders. To this end, we have characterized behavioral changes in rats with small and moderate hippocampal lesions. Adult male rats received intrahippocampal infusions of either a low or high dose of NMDA, a substance which produces neuronal loss in the hippocampus (i.e. a lesion). Beginning at two weeks post-lesion, all rats along with a control group were tested in several behavioral paradigms. The NMDA infusions produced modest and qualitatively dose-dependent neuronal loss in the hippocampus on a scale consistent with the hippocampal volume loss reported in many neuropsychiatric disorders. The results show that rats with large lesions produced by the high NMDA dose were hyperactive and displayed a clear spatial memory deficit. Additional studies have found that the novel antipsychotic drug, clozapine, can improve memory in rats with large hippocampal lesions. Our work demonstrates that some symptoms of memory loss found in people with neuropsychiatric disorders can be emulated in rats with hippocampal damage. More importantly, we are starting to identify drugs which may improve memory disturbances in neuropsychiatric disorders that may be a consequence of hippocampal dysfunction