Impaired cognitive function and reduced anxiety-related behavior in a promyelocytic leukemia (PML) tumor suppressor protein-deficient mouse.

The promyelocytic leukemia (PML) protein is a tumor suppressor factor mostly known by its involvement in acute promyelocytic leukemia (APL). Interestingly, recent studies have provided evidence that, in the central nervous system, PML is involved in neurogenesis. However, prospective studies of PML in brain are lacking. To further understand the role of PML in the mammalian brain, we studied plasticity and behavioral changes in PML knockout mice. If PML is involved in neurogenesis, and neurogenesis is an important process for proper brain development as well as learning and memory functions, we hypothesized that PML might have a role in plasticity and cognition. Behavioral studies demonstrated that PML knockout mice present abnormalities in conditioned learning and spatial memory, as determined by fear conditioning and Morris water maze tasks. Experiments to determine normal exploratory behavior interestingly revealed that PML knockout mice present reduced anxiety-related responses as compared to control animals. This was confirmed when PML knockout mice spent more time in the open arms of an elevated plus-maze, which is an indication of decreased anxiety. Additionally, impairments in hippocampus-dependent learning were mirrored by altered long-term plasticity at Schaffer collateral-CA1 synapses. We now provide the first evidence for an important role of PML in the brain, indicating that PML might have a role in synaptic plasticity and associated behavioral processes.