Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory

Abstract

Induction of long-term depression (LTD) in rat striatal slices revealed that this form of synaptic plasticity is coupled to an increased expression of tissue-plasminogen activator (t-PA) mRNA, as detected by the mRNA differential display technique. To further investigate the involvement of this gene in synaptic remodelling following striatal LTD, we recorded electrical activity 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 striatal neurons recorded from WT mice. Conversely, LTD was absent in a significant proportion of striatal neurons obtained from mice lacking t-PA. Electrophysiological recordings obtained from hippocampal slices in the CA1 area showed that mainly the late phase of long-term potentiation (LTP) was reduced in t-PA-KO mice. Learning and memory-related behavioural abnormalities were also found in these transgenic mice. Disruption of the t-PA gene, in fact, altered both the context conditioning test, a hippocampus-related behavioural 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 habituation and reactivity to spatial change that are consistent with an altered hippocampal function. Nevertheless, decreased rearing and poor initial object exploration were also observed, further suggesting an altered striatal function. These data indicate that t-PA plays a critical role in the formation of various forms of synaptic plasticity and memory.

Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

“…In the brain parenchyma, tPA interactions extend beyond plasminogen to the NMDAR in the control of functions such as learning processes in the hippocampus (LTP and LTD) [24][25][26] and dysfunctions such as neurotoxicity. 7,27 Our present data set emphasize the role of tPA molecular form on its interaction with NMDAR in different structures of the central nervous system (CNS).…”

Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice

“…t-PA is an extracellular serine protease that is expressed after LTP induction and released after local mGluR-dependent synthesis (28,29). Proteolytic activity of t-PA is necessary for experience-dependent synaptic pruning, LTP consolidation, and the formation of perforated synaptic profiles (30). Levels of SERBP1, an mRNA-binding protein mediating cyclic nucleotide destabilization of the mRNA encoding the major endogenous inhibitor of t-PA, PAI-1 (31), were up-regulated.…”

Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats

“…Additionally, early phases of instrumental learning (Hernandez et al 2006;Kelly and Deadwyler 2003) elicit widespread zif/268 and arc induction throughout an extensive corticostriatal network in rats. Furthermore, knockdown of c-fos, zif/268, arc, or tissue plasminogen activator (tPA) that cleaves proBDNF to mature BDNF impairs longterm memory consolidation (Calabresi et al 2000, Guzowski et al 2000Fleischmann et al 2003;Jones et al 2001 and produces deficits in drug-induced conditioned place preference (Valjent et al 2006). …”