Decreased serotonin levels associated with behavioral disinhibition in tissue plasminogen activator deficient (tPA^-/-) mice

Tissue Plasminogen Activator (tPA) is a serine protease expressed in different areas of the mammalian brain. It has been used clinically to dissolve clots and shown to have a role in neurodegeneration. Early studies suggested that tPA plays an important role in the processes of learning and memory, demonstrated at the level of behavior and synaptic plasticity. Herein, we extend the behavioral characterization of these mice to the related dimension of exploratory-related behavior using an extensive battery of behavioral tests as well as the neurotransmitter metabolism associated with the behavioral measures. Our results indicate a behavior tendency in these mice consistent with "impulsivity" or reduced exploratory inhibition. These patterns are accompanied by decreased levels of serotonin in several brain regions important in behavioral regulation in the tPA^-/- mice compared to control animals. Systemic administration of fluoxetine reversed the behavioral disinhibition of tPA^-/- mice, further supporting an important alteration in behavior regulation mediated by serotonin systems as underappreciated but important element of the behavioral phenotype of these animals.