Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory

Induction of long-term depression (LTD) in rat striatal slices revealed tha t this form of synaptic plasticity is coupled to an increased expression of tissue-plasminogen activator (t-PA) mRNA, as detected by the mRNA differen tial display technique. To further investigate the involvement of this gene in synaptic remodelling following striatal LTD, we recorded electrical act ivity from mice lacking the gene encoding t-PA (t-PA-KO) and from wild-type (WT) mice. Tetanic stimulation induced LTD in the large majority of striat al neurons recorded from WT mice. Conversely, LTD was absent in a significa nt proportion of striatal neurons obtained from mice lacking t-PA. Electrop hysiological recordings obtained from hippocampal slices in the CA1 area sh owed that mainly the late phase of long-term potentiation (LTP) was reduced in t-PA-KO mice. Learning and memory-related behavioural abnormalities wer e also found in these transgenic mice. Disruption of the t-PA gene, in fact , altered both the context conditioning test, a hippocampus-related behavio ural task, and the two-way active avoidance, a striatum-dependent task. In an open field object exploration task, t-PA-KO mice expressed deficits in h abituation and reactivity to spatial change that are consistent with an alt ered hippocampal function. Nevertheless, decreased rearing and poor initial object exploration were also observed, further suggesting an altered stria tal function. These data indicate that t-PA plays a critical role in the fo rmation of various forms of synaptic plasticity and memory.