Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways.

Abstract

The gene encoding tissue-type plasminogen activator (t-PA) is an immediate response gene, downstream from CREB-1 and other constitutively expressed transcription factors, which is induced in the hippocampus during the late phase of long-term potentiation (L-LTP). Mice in which the t-PA gene has been ablated (t-PA-I-) showed no gross anatomical, electrophysiological, sensory, or motor abnormalities but manifest a selective reduction in L-LTP in hippocampal slices in both the Schaffer collateral-CAl and mossy fiber-CA3 pathways. t-PA-'-mice also exhibit reduced potentiation by cAMP analogs and D1/D5 agonists. By contrast, hippocampal-dependent learning and memory were not affected in these mice, whereas performance was impaired on two-way active avoidance, a striatum-dependent task These results provide genetic evidence that t-PA is a downstream effector gene important for L-LTP and show that modest impairment of L-LTP in CAl and CA3 does not result in hippocampus-dependent behavioral phenotypes.The hippocampus of the mammalian brain contains three major neural pathways that undergo an activity-dependent change in synaptic strength, called long-term potentiation (LTP). In each of these pathways, hippocampal LTP consists of two components, an early, transient, transcriptionally-independent component [earlyphase LTP (E-LTP)] and a later, persistent, long-term component [late-phase LTP (L-LTP)] that requires protein and mRNA synthesis (1-3). Hippocampus-dependent long-term memory (4, 5), unlike short-term memory, also requires protein and mRNA synthesis, which implies that long-term memory requires the expression of specific genes and proteins (6, 7). The gene transcription required for long-term memory is thought to result from a leaming-induced increase in neuronal activity, which ultimately leads to the strengthening of preexisting synapses as well as MATERIALS AND METHODSElectrophysiology. Transverse hippocampal slices (400-500 ,tM) were placed in an interface chamber and perfused continuously with solution containing 124 mM NaCl, 1.3 mM MgSO4, 4 mM KCl, 1.0 mM Na2HPO4, 2.0 mM CaCl2, 26 mM NaHCO3, and 10 mM glucose. The perfusion solution was bubbled with 95% 02 and 5% Co2 at a flow rate of 1.5-2 ml/min. The temperature of -the recording chamber was maintained at either 28°C or 32°C in different experiments. A stainless steel electrode was used for field excitatory postsynaptic potential (EPSP) recording, and a fine tungsten bipolar electrode was used for stimulation. The position of the electrodes for stimulating and recording in CAl and CA3 was the same as described (2,14). Test stimuli were of 0.05-ms pulse duration and 0.016-Hz frequency. LTP was induced by one or four trains of tetanus at the same intensity as test stimuli (100 Hz for 1 s, pulse duration 0.05 ms) in the Schaffer collateralCAl pathway and four trains of tetanus (100 Hz for 1 s) with double-pulse duration (0.1 ms) during tetanus in the mossy fiber-CA3 pathway. The initial slope of the EPSP was measured, and LTP was calculated as per...

Cell-Surface Actin Binds Plasminogen and Modulates Neurotransmitter Release from Catecholaminergic Cells

“…Hao et al, 2006). Hence, these results may suggest an important system and mechanism for the regulation of neurosecretory and catecholaminergic pathways in both central and peripheral nervous systems, with implications, for example, for t-PA/ plasminogen-dependent processes such as long-term potentiation, learning, and memory (Qian et al, 1993;Carmeliet et al, 1994;Frey et al, 1996;Huang et al, 1996;Baranes et al, 1998;Seeds et al, 2003;Pang et al, 2004), and excitotoxin-induced neuronal injury in the CNS (Tsirka et al, , 1997aChenLiu and Strickland, 1997), as well as for the regulation of key systemic cardiovascular and metabolic homeostatic physiological responses governed by sympathoadrenal and sympathoneural activity (Parmer et al, 2000;Jiang et al, 2001;Q. Jiang et al, 2002;X.…”

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).…”

Expression of annexin A2 in GABAergic interneurons in the normal rat brain

“…While still in an early stage, several possibilities based on previously acquired knowledge may direct the future research: First, given ANX2 is a potent co-activator of tPA/ plaminogen (Cesarman et al 1994;Kassam et al 1998), it is of great interest to investigate whether ANX2 is complexed with and required for neuronal tPA/plasminogen activation that has been shown to play an important role in synaptic plasticity and memory formation (Huang et al 1996;Frey et al 1996;Calabresi et al 2000;Baranes et al 1998;Pang et al 2004). Second, global activation of tPA/plasminogen can also be harmful to the brain and has been shown to trigger neuronal death (Gingrich and Traynelis 2000;Tsirka 2002;Siao and Tsirka 2002), which may involve in the activation of glial cells.…”