Overexpression of urokinase-type plasminogen activator in transgenic mice is correlated with impaired learning.

Abstract

Transgenic mice desi ated aMUPA overproduce in the brain murine urokinase-type plainogen activator (uPA), an extracellular protease implicated in tissue remodeling. We have now lid, by in situ hybridization, extensive signal of uPA mRNA in the aMUPA cortex, hippocampus, and amygdala, sites that were not labeled in counterpart wild-type mice. Furthermore, biochemical measurements reveal a remarkably high level of enzymatic activity of uPA in the cortex and hippocampus of aMUPA compared with wildtype mice. We have used the aMUPA mice to exami whether the abnormal level of uPA in the cortex and the limbic system affects lrning ability. We report that aMUPA mice perform poorly in tasks of spatial, olfactory, and taste-aversion learning, while displaying normal sensory and motor capabiliti. Our results snuest that uPA is involved in neural processes subserving a variety of laing types.

Effects of urokinase-type plasminogen activator in the acquisition, expression and reinstatement of cocaine-induced conditioned-place preference

“…Its localized expression during neuronal development suggests that plasmin-mediated proteolysis facilitates neurite outgrowth and cell migration [59,60]. Plasmin regulates a cascade of extracellular proteolytic activities involved in longterm potentiation and depression [52,[61][62][63] or in learning and memory [63][64][65][66]. Endogenous uPA may also regulate synaptic plasticity through mechanisms independent of plasmin or laminin, such as mediating an interaction between microglia and dopaminergic neurons, in analogy to mechanisms proposed for tPA [67].…”

Enhanced GFAP expression in astrocytes of transgenic mice expressing the human brain‐specific trypsinogen IV

“…In the central nervous system (CNS) and peripheral nervous system (PNS), serine proteases such as plasminogen activators or thrombin, were shown to be involved in restructuring of the synaptic connectivity during development and regeneration, including processes such as synapse elimination during development (Connold and Vrbova, 1994;Hantai et al, 1989;Liu et al, 1994) and synaptic plasticity associated with learning and memory in adults (Meiri et al, 1994;Qian et al, 1993). Identification of the Kunitz-type serine protease inhibitor domain of APP (Kitaguchi et al, 1988;Tanzi et al, 1988) led to the hypothesis that they may also be implicated in the pathogenesis of Alzheimer's disease.…”

Endogenous Serine Protease Inhibitor Modulates Epileptic Activity and Hippocampal Long-Term Potentiation

“…TSP1 is a ligand for the ␣3/␤1 integrin (DeFreitas et al, 1995) and can inhibit plasmin and, like PN-1, uPA (Hogg, 1994). NMDA receptor-mediated neuronal excitability has been shown to be enhanced by plasmin (Inoue et al, 1994), and uPA-overexpressing mice exhibit learning deficits (Meiri et al, 1994). Thus, complex protease-dependent extracellular interactions relevant to neuronal plasticity may be influenced by the level of PN-1 expression.…”

“…PN-1 also can block plasmin, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), and trypsin (Baker et al, 1980;Guenther et al, 1985;Stone et al, 1987;Wagner et al, 1989), suggesting that in the brain PN-1 could modulate the activity of several serine proteases known to process or induce physiologically active macromolecules that control neurite extension (Krystosek and Seeds, 1981;Gurwitz and Cunningham, 1988;Jalink and Moolenaar, 1992;Suidan et al, 1992), neuronal cell viability (Smith-Swintosky et al, 1995;Tsirka et al, 1995;Vaughan et al, 1995), neuronal cell excitability (Yamada and Bilkey, 1993;Tsirka et al, 1995), and synaptic plasticity (Mansuy et al, 1993;Qian et al, 1993;Liu et al, 1994;Meiri et al, 1994;Romanic and Madri, 1994;Seeds et al, 1995;Frey et al, 1996;Huang et al, 1996).…”