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

Abstract

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.

Figure 1

A, The locomotor rates of the tPA^−/− (n = 7) and control wt (n = 8) mice were measured and B, the entry to the central (more anxiogenic) area of a large open field arena were also compared. C, Latency and the numbers of approaches D to a novel object in the open field on the third day were recorded for tPA^−/− mice and control wt mice, For all figures, * p < 0.05 versus control mice, ** p < 0.01 versus control mice, and mean +/− s.e.m. shown.

Figure 2

A, the latency of the first entries in the open areas of an elevated “zero” maze were measured for the tPA^−/− (n = 7) and wt (n = 8) mice, B, the number of entries to the exposed areas during the second day of testing was also quantified, and C, the number of head dips below the maze level on both days of testing. D, In the plus maze, the entry of tPA^−/− mice (n = 12) into the open arms on the second day of testing were measured and compared to control mice (n = 14).

Figure 3

A, the number of errors during the acquisition phase of the task was compared between the tPA^−/− mice (n = 8) and the wt control mice (n = 9). B, Moreover, the time spent in each arm visit while learning the radial arm maze was measured.

Figure 4

The levels of 5-HT were measured in different regions of the tPA^−/− and control mice.

Figure 5

Effects of fluoxetine on exploratory behaviors and reactivity to novel objects. A, Fluoxetine was delivered systemically in tPA^−/− mice and the latencies to approach a novel object in a large open field arena were measured and compared to tPA^−/− mice treated with saline and control mice (n = 9–11 per group). B, The number of approaches towards the novel object were also quantified.