HomeLarge Type Edition
HOME ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
PubMed
Right arrow PubMed Citation
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:B242-B248 (2000)
© 2000 The Gerontological Society of America

Delayed and Blunted Induction of mRNA for Tissue Plasminogen Activator in the Brain of Old Rats Following Pentylenetetrazole-Induced Seizure Activity

Aurel Popa-Wagnera, Barbara Fischerb, Dieter Plattb, Harald Schmolla and Christof Kesslera

a Department of Neurology, Ernst-Moritz-Arndt-Universität, Greifswald, Germany
b Institute of Gerontology, University of Erlangen-Nürnberg, Germany

Aurel Popa-Wagner, Department of Neurology, Ernst-Moritz-Arndt-Universit\|[auml ]\|t, Ellernholzstr. 1-2, 17487 Greifswald, Germany E-mail: wagnerap{at}neurologie.uni-greifswald.de.

Decision Editor: Jay Roberts, PhD


   Abstract
Top
 Abstract
Method
 Results
 Discussion
 References
 
The ability of the rodent brain to support plasticity-related phenomena declines with increasing age. Here we investigated the extent to which old rats retain the capacity to initiate transcription for immediate early genes, particularly as it relates to brain plasticity, in response to a strong stimulus. The intraperitoneal administration of pentylenetetrazole (PTZ) to rats of various ages evoked tonic-clonic seizures. Using an RNA gel-blot and in situ hybridization analysis, we found that 1 hour after the onset of seizure, messenger RNA (mRNA) for tissue plasminogen activator (TPA) was increased ~ 3.7-fold in the hippocampi of 3-month-old rats. The levels of TPA mRNA in the hippocampi and cortices of 3-month-old rats returned to control levels by 3 hours after PTZ administration. The levels of TPA mRNA increased 2.5-fold in the hippocampi of 18-month-old rats and 1.8-fold in the brains of the 28-month-old-rats at 3 hours and returned to basal levels by 15 hours following PTZ treatment. Quantitatively similar increases were calculated for the cortex. At peak induction the transcripts were localized throughout the cortical layers of the 3-moth-old rats, whereas the TPA mRNA expression was restricted to cortical layer V of the older rats. Our results suggest that although the aging brain retains the capacity to respond to chemically induced seizures, the induction of TPA mRNA is temporarily delayed and the levels are diminished with increasing age. Because TPA has been implicated in neuronal plasticity, this finding suggests that immediate early genes are important factors in the limited plasticity of the aging brain.

THE proper functioning of the nervous system is dependent on a certain degree of plasticity, which reflects the capacity of the brain to adapt to a changing environment. Although previous studies have documented anatomical changes in the cytoarchitecture of surviving neurons of aging animals (1)(2), the extent to which old animals retain the capacity to coordinate gene activity is not clear, particularly as it relates to brain plasticity in response to a strong stimulus, such as the seizure-inducing chemical, pentylenetetrazole (PTZ). The capacity to coordinate gene expression may reflect, in a broader sense, the degree of brain plasticity.

Generally, the ability of the aging brain to support plasticity-related phenomena is impaired. This conclusion is supported by recent studies showing that levels of growth-associated transcripts, such as growth-associated protein-43 (GAP-43) and neurofilament-68 (NF-68), are much reduced in hilar and CA3 pyramidal neurons at various time points after deafferentation of the hippocampus in young, middle-aged, and aged rats (3)(4).

A variety of experimental paradigms suggest that seizure activity results in long term, progressive changes in neural networks that eventually provoke spontaneous and recurring seizures. This process of network transformation also serves as an interesting model of central nervous system plasticity (5)(6)(7)(8)(9).

Previous results from our laboratory show that the induction of the immediate early gene (IEG) c-fos messenger RNA (mRNA) is considerably delayed in the hippocampi and cortices of 18- and 28-month-old rats as compared with those of 3-month-old rats (10). Similarly, a blunted and delayed induction of c-fos in the suprachiasmatic nuclei of the middle-aged rats following exposure to light has been reported (11).

We have been interested in whether this phenomenon applies to early genes that have been directly implicated in brain plasticity, such as the tissue plasminogen activator (TPA). Tissue plasminogen activator is a serine protease that has been shown to be induced as an IEG during pharmacologically induced seizures (12)(13). In the nervous system, proteases have been implicated in plasticity and neurite outgrowth (14)(15)(16)(17). It is conceivable that the proteolytic capacity of TPA could be implicated in brain remodeling by facilitating the establishement of new synaptic connections by removal of previous connections.

In the present study, using an RNA gel-blot analysis and nonradioactive in situ hybridization, we characterized hippocampal and cortical responses to PTZ-induced seizure changes in the prevalence of mRNA coding for TPA.

A previous study has shown that an altered expression of TPA and its inhibitors accompanies cellular senescence of fibroblasts cultured in vitro (18).


   Method
Top
 Abstract
 Method
Results
 Discussion
 References
 
Administration of Pentylenetetrazole
Female Sprague-Dawley rats 3, 18, and 28 months of age were maintained on a 12 hour light–dark cycle and allowed free access to food and water. The body weights ranged between 190–260 g for the young rats and 320–400 g for the middle-aged and old rats. Seizures were induced by an intraperitoneal injection of PTZ (50 mg/kg, between 9 and 11 AM). Control rats received intraperitoneal physiological saline.

After the rats were sacrificed by decapitation at 0, 1, 3, and 15 hours postseizure, the brains were removed and bisected midsagitally. One-half of each brain (left and right hemispheres were collected alternately) was fixed in a solution of 4% paraformaldehyde and 50 mM of phosphate buffer (pH 7.2) for 24 hours, cryoprotected in a solution of 20% sucrose and 10 mM of phosphate-buffered saline (PBS; pH 7.2), and stored at -70°C. This hemisphere was used for in situ hybridization experiments; the hippocampus and cortex from the other hemisphere was used for Northern blotting.

Preparation of cRNA Probes
Tissue-plasminogen activator: a rat cDNA coding for tPA (in pGEM-1 vector) was a gift from Dr. Tor Ny (UME University, Stockholm, Sweden). This plasmid allowed the synthesis of both sense and antisense probes by use of [32P]uridine (UTP) or digoxigenin-11-UTP. Finally the RNA probes were purified by gel filtration (push columns, Stratagene, Heidelberg, Germany). The specificity of the rat TPA antisense RNA probes was checked by Northern blot analysis.

Northern Blots
Total RNA was extracted by acid guanidinium thiocyanate phenol chloroform extraction and resolved on formaldehyde agarose gels by using established procedures. After electrophoresis the RNA (5 µg) was capillary blotted to positively charged Nylon-Plus membranes (Schleicher & Schuell, Deisenhofen, Germany) and linked to the membrane by ultraviolet cross-linking. Sizes were determined by comparison with an RNA ladder. RNA quality was evaluated by staining of the 18S and 28S rRNA with 0.04% Methylene Blue dye. The amount of 28S RNA loaded per lane was quantitated by means of computerized videodensitometry, using a Kontron system (Munich, Germany), and used to correct for differences between the lanes. Blots were hybridized with 2 x 106 cpm/ml in a solution of 50% formamide, 1.5x saline-sodium phosphate-EDTA (SSPE), 1% sodium dodecyl sulfate (SDS), 0.5% dry milk, 100 µg/ml yeast total RNA, and 300 µg/ml salmon sperm DNA, at 55°C for 15 hours. After hybridization, filters were washed in 2x saline-sodium citrate (SSC) and 0.2% SDS at room temperature and then at high stringency in 0.1x SSC and 0.2% SDS at 75°C, and they were exposed to preflashed Amersham MP film with intensifying screens at -70°C (Amersham; Les Ulis; France). The optical density of a band was determined by computerized videodensitometry with background substraction. Each value was then normalized with respect to the loaded 28S rRNA.

A statistical analysis was done with the interactive statistical software SPSS (SPSS, Chicago, IL). Statistical significance was assessed by a one-way analysis of variance (ANOVA; Scheffé post hoc test).

Nonradioactive in situ Hybridization
A 400 base pairs digoxigenin-11-UTP-labeled antisense RNA probe was synthesized by using a kit supplied by Boehringer Mannheim (Mannheim, Germany) according to the manufacturer's specifications. The cRNA quality and quantity were evaluated by detection of the digoxigenin-labeled cRNA with anti-digoxigenin alkaline phosphatase, Fab fragment (Boehringer Mannheim) conjugate followed by color development using the nitro-blue tetrazolium (NBT) and 5-bromo-4-chloro-3-indolyl phosphate (BCIP) system. A digoxigenin-labeled NF-68 cRNA probe of known size and concentration was also used as a reference probe. Sections (60 µm) were cut on a freezing microtome and processed for in situ hybridization (ISH) as free-floating material. All steps were undertaken in glass-covered Petri dishes with a diameter of 30 mm. Prehybridization was performed in a buffer containing 50% formamide, 5x SSC, 1% blocking reagent, and 500 µg/ml tRNA. Sections were hybridized in the same buffer containing 50 ng/ml of cRNA probe for 3 hours at 65°C. Prehybridization and hybridization were done in sealed boxes containg 50% formamide and 5x SSC. After hybridization, the sections were washed five times in 2x SSC for 5 minutes at room temperature and ten times at 68°C in 0.1x SSC for 50 minutes.

Following high stringency washings, the sections were postfixed in 4% paraformaldehyde in PBS for 30 minutes at room temperature. After posthybridization washes, slides were incubated for 2 hours at room temperature in a blocking buffer consisting of 0.1 M of maleate (pH 7.5); 150 mM of NaCl; 0.1% Tween 20; 0.2% Triton-X 100, and 1% blocking reagent (Boehringer Mannheim, Mannheim, Germany). Alkaline phosphatase-conjugated sheep anti-digoxigenin Fab fragments, diluted 1:1000 in blocking buffer, were then applied. After 15 hours of incubation at 4°C in a humid chamber, unbound conjugate was removed by three 15-minute washes in blocking buffer, followed by one wash in alkaline phosphatase buffer (100 mM of Tris, pH 9.5; 100 mM of NaCl; 10 mM of MgCl2) for 10 minutes. For the detection of signal, slides were incubated at 37°C in darkness for 3–5 hours in a chromogen solution consisting of 330 µg/ml of NBT, 150 µg/ml of BCIP, and 250 µg/ml of levamisole in alkaline phosphatase buffer. The reaction was stopped with 10 mM of Tris, pH 8.0, plus 1 mM of ethylenediamine tetra-acetic acid (EDTA). Finally the sections were mounted on slides, air dried, and coverslipped by using a xylol-based mounting medium.

Controls
Selected tissue sections were hybridized with a mixture consisting of cold antisense and digoxigenin-labeled antisense at a 100:1 ratio. Selected tissue sections were hybridized with a sense probe. Finally, some sections were also treated with 100 µg/ml of RNAase A in 0.5 m of NaCl, 10 mM of Tris, and 1 mM of EDTA (pH 8.0) at 37°C prior to in situ hybridization with digoxigenin-labeled probes.

Semiquantitative Analysis of Tissue Sections
Integrated optical densities were collected from the hippocampal region of each rat by using the NIH software PC Image (National Institutes of Health, Bethesda, MD). The age differences in TPA mRNA expression in the hippocampus were expressed as percentage decreases of the levels shown by the young animals.

Statistical Analysis
The main effect of age, the main effect of time, and the interaction between the two was evaluated by using a two-way analysis of variance (Age x Time) followed by a Tukey post hoc analysis to detect differences between the means, using the SPSS software.

Light Microscopy
For light microscopy, a Nikon microscope was used. Images (768 x 1024 pixels) were captured electronically with a charge-coupled device camera (Optronics, Munich, Germany). The digital images were arranged and labeled by Adobe Photoshop (Adobe Systems Gmbh, Unterschleissheim, Germany) and printed with a Kodak XLS 8000 digital printer (Kodak, Gmbh, Stuttgart, Germany).


   Results
Top
 Abstract
 Method
 Results
Discussion
 References
 
PTZ evoked a series of myoclonic jerks, which were followed by three to eight tonic–clonic convulsions occurring with various delays. There was, however, no relationship between the age of the animals and seizure onset. With a dose of PTZ at 50 mg/kg, rats had seizures within 3–5 minutes and fully recovered by the time of sacrifice.

Northern Blots
A single PTZ injection caused a robust induction in TPA gene expression (Fig. 1). One hour after the administration of PTZ, the levels of TPA mRNA were greatly increased in the hippocampi and cortices of 3-month-old rats and had begun to decline by 3 hours. The hippocampal and cortical levels of TPA mRNA had returned to control levels by 15 hours following PTZ injection. However, the older animals responded differently to the PTZ-induced seizures. In the hippocampi and cortices of 18-month-old rats, the peak expression of TPA mRNA occurred at 3 hours. In the brains of 28-month-old rats, the increase was moderate and also peaked at 3 hours postseizure in both the hippocampi and cortices. Thus, there was a statistically significant interaction between the age of the animals and the time of maximum induction ( p < .001).



View larger version (89K):
[in this window]
[in a new window]
  		Figure 1. Time course of PTZ-induced seizure TPA mRNA expression in the hippocampi (HC) and cortices (CX) of 3-, 18-, and 28-month-old rats. Northern blot hybridization was of 5 µg total RNA. Sizes were determined by comparison with an RNA ladder. RNA quality was evaluated by staining of the 18S and 28S rRNA with 0.04% Methylene Blue dye. Note the shift in the maximum of TPA mRNA expression from 1 hour in the young rats to 3 hours in the old rats.

 
The amount of rRNA loaded per lane is shown for each age group. A quantitative analysis revealed that the maximum increase in TPA mRNA in the hippocampi of 3-month-old rats was approximately 3.7-fold (Fig. 2) as compared with control levels ( p < .001). When the rats were 18 months of age, the increase was 2.5-fold (Fig. 2, p < .001) and when they were 28 months of age, the increase was 1.8-fold (Fig. 2, p < .001) as compared with saline-treated animals.



View larger version (18K):
[in this window]
[in a new window]
  		Figure 2. Quantitative analysis shows the time course of PTZ-induced TPA mRNA expression in the hippocampi and cortices of 3- (A), 18- (B), and 28-month-old (C) rats. The optical density of a band was determined by computerized videodensitometry with background subtraction. Each value was then normalized with respect to the loaded 28S rRNA. Data are mean ± SD values. The number of animals per age group and time point was as follows: 3-month-old rats; (*p < .05 vs controls by ANOVA; **p < .01 vs controls by ANOVA).

 
When the rats were 18 months of age, there was diminished expression (1.9-fold decrease; p < .05) of TPA mRNA in the hippocampi at 3 hours, relative to levels in young animals (Fig. 2 vs 2B). The age difference between the TPA mRNA levels after seizure activity was also significant at 28 months of age, with the young rats having a 3.5-fold higher TPA expression than the aged rats ( p < .005, Fig. 2 vs 2C).

Quantitatively similar increases were calculated for the cortices (not shown).

In situ Hybridization
The levels and regional distribution of TPA mRNA in the hippocampi and cortices are shown in Fig. 3Fig. 4Fig. 5. Hippocampal TPA mRNA of control rats was low at all ages (Fig. 1 and Fig. 3 and Fig. 3). At 1 hour there was a strong upregulation of TPA transcripts in the hippocampal regions of young animals, including the dentate gyri and the CA3 regions (Fig. 3), as compared with controls (Fig. 3). Although the upregulation of TPA mRNA in the hippocampal regions of aged animals was temporally altered, the increases occurred especially in the dentate gyri of 18-month-old rats and to a lesser extent in the CA3 regions (Fig. 3). Hippocampal TPA mRNA expression in the hippocampi of very old rats varied from rat to rat but was localized essentially in the dentate gyri (Fig. 3). Hybridization with a sense probe hybridized to sections from 3-month-old rats at the 1-hour time point gave almost no signal (Fig. 3). The levels of the TPA mRNA at peak induction were decreased by ~29% in the hippocampi of 18-month-old rats, and by 44% in the hipocampi of 28-month-old rats as compared with the levels expressed by 3-month-old rats (Fig. 4).



View larger version (92K):
[in this window]
[in a new window]
  		Figure 3. In situ hybridization of TPA mRNA on sections taken from the hippocampus following a single PTZ injection. A,D: Note the upregulation of TPA mRNA in the hippocampi of young PTZ rats (D) vs controls (A). C: Hybridization with a sense probe. B,E: TPA mRNA expression in the dentate gyri of 18-month-old control rats (B), and at 3 hours (E) postseizure. F: TPA mRNA expression in the hippocampi of 28-month-old rats at 3 hours postseizure. The scale bar is 300 µm. Abbreviations: DG, dentate gyrus; CA1, CA3, hippocampal regions.

 


View larger version (13K):
[in this window]
[in a new window]
  		Figure 4. Densitometric analysis of the levels of TPA mRNA in the hippocampi of 3- (A), 18- (B), and 28-month-old (C) rats following seizure activity. Integrated optical densities for TPA mRNA were measured for the three age groups. Data are presented as gray value ± SD. The number of animals per age group and time point was as follows: 3-month-old rats,

 


View larger version (141K):
[in this window]
[in a new window]
  		Figure 5. TPA mRNA distribution in the temporal cortex following a single PTZ injection. In young control animals the MAP1B transcripts were well expressed in layer II (A). Following PTZ administration the transcripts were localized all over cortical layers II–VI of the young rats (B) but were restricted to cortical layer V of the 18-month-old rats (D). The TPA mRNA levels in the cortices of the 28-month-old rats were low (C). The scale bar is 60 µm. Abbreviations: Cc, corpus calosum; II and V, cortical layers.

 
In the temporal cortices of young animals, the cells in layer II were labeled at all times, regardless of treatment (Fig. 5 and Fig. 5). Following application of PTZ, an intense labeling of neuronal cells was observed in all cortical layers of the 3-month-old rats (Fig. 5). When the rats were 18 months of age, the neuronal labeling became restricted to layer V (Fig. 5), whereas in the cortex of the 28-month-old rats the labeling was, at this sensitivity and staining time, almost absent (Fig. 5).


   Discussion
Top
 Abstract
 Method
 Results
 Discussion
References
 
The main results of this study are that (i) the induction of the protease encoding tissue plasminogen activator mRNA is diminished in the brains of aged rats as compared with that in young animals, and (ii) the aged rat brains responded more slowly and the expression of TPA mRNA was restricted to certain cortical layers of the older rats.

The time course and the magnitude of transcriptional responses to stimuli seem to depend on the nature and intensity of the stimulus as well as on the pathway implicated in activation. For example, an examination of the induction of a panel of IEGs, which are known to be transcriptionally activated after application of long-term potentiation-inducing stimuli, revealed that a number of IEGs are similarly induced in young adult and aged rats. The levels of c-fos mRNA were even higher in the aged animals, indicating a preservation of specific signaling pathways leading to a transcriptional activation of some IEGs in this particular experimental paradigm (19). However, the time course of induction of late genes, such as those coding for cytoskeletal proteins, after seizure activity is quite different, with the peak of expression shifted to earlier times (20).

Besides deregulations in gene expression, age-related differences in the pharmacokinetics of PTZ may account, in part, for the lower levels of TPA mRNA expression in the brains of old rats. For example, previous work suggests that the rodent brain becomes less sensitive to the epileptogenic effects of PTZ with age (21). Although we did not observe significant differences in the behavior of rats with respect to seizure onset and development, it should be kept in mind that the levels of the stimulus were well above the threshold, which is ~30 mg/kg.

Stimuli that evoke seizures are capable of inducing structural changes (22)(23)(24). Previous studies document the robust induction of TPA mRNA shortly after onset of seizure activity in neuronal plasticity (12)(25). As TPA has been implicated in neurite outgrowth and morphological differentiation (14)(16)(26), induction and release of TPA may induce structural changes in the nervous systems (17). This conclusion is consistent with the finding that TPA makes limited cleavages, via plasmin, in fibronectin (27) and laminin (28). This feature has been used in recent years for the treatment of embolic stroke either by systemic infusion (29) or local overexpression (30). Recently another protease, ubiquitin C-terminal hydrolase, has been also implicated in synaptic plasticity in aplysia (31).

Genetic evidence shows that mice in which the TPA gene has been inactivated showed no gross anatomical, electrophysiological, sensory, or motor abnormalities, but they do manifest a selective reduction in late-phase long-term potentiation in hippocampal slices in both the Schaffer collateral-CA1 and mossy fiber-CA3 pathways, suggesting that TPA is a downstream effector gene important for late-phase long-term potentiation (32). Interestingly, we also found consistent reductions in the levels of TPA mRNA in the CA1 and CA3 regions of the hippocampi of old rats.

The phenomenon of plasticity in the brains of aged rats is well documented. Loss of axospinous connections as a consequence of age-related changes in the brain, such as loss of afferent supply and alterations in transmitters, receptors, and trophic factors, is followed by a compensatory regrowth of neuronal connections by surviving neurons to replace defective or lost ones (33). Thus it seems that the aged rodent brain retains the capacity, albeit at a slower rate, to maintain and repair its own circuitry (34)(35). Even in the absence of overt changes there is brain remodeling, as reflected in the continuous growth and regression of neuronal processes (33).

Restricted expression of the protease TPA to certain cortical and hippocampal layers as well as deregulations and reduced levels of gene expression for both IEGs and late genes (10)(20) point to an impaired ability of the aging brain to support plasticity-related phenomena. This conclusion is supported by a recent study showing that the levels of growth-associated transcripts such as growth-associated protein-43 (GAP-43) and neurofilament-68 (NF-68) are much reduced in hilar and CA3 pyramidal neurons at various time points after deafferentation of the hippocampi in young, middle aged, and aged rats (3)(4). However, it is not clear at the present time if there are specific events downstream of the membrane and/or upstream of the transcription machinery that are most affected by age, and further work is required to identify such events.


   Acknowledgments
 
This research was supported by a grant from Deutsche Forschungsgemeinschaft (Po359/5-1) to APW. We have benefited from many fruitful discussions with Drs. Margaret and Lary Walker.

Received January 27, 1999

Accepted October 12, 1999


   References
Top
 Abstract
 Method
 Results
 Discussion
 References
 

  1. Scheff SW, Bernardo LS, Cotman C, 1978. Decrease in adrenergic axon sprouting in the senescent rat. Science 202:775-778. [Abstract/Free Full Text]
  2. Scheff SW, Bernardo LS, Cotman C, 1980. Decline in reactive fiber growth in the dentate gyrus of aged rats compared to young adult rats following entorhinal cortex removal. Brain Res. 199:21-38. [Medline]
  3. Parhad IM, Scott JN, Cellars LA, Bains JS, Krekowski CA, Clark AW, 1995. Axonal atrophy in aging is associated with a decline in neurofilament gene expression. J Neurosci Res. 41:355-366. [Medline]
  4. Schauwecker PE, Cheng HW, Serquinia RM, Mori N, McNeill TH, 1995. Lesion-induced sprouting of commissural/associational axons and induction of GAP-43 mRNA in hilar and CA3 pyramidal neurons in the hippocampus are diminished in aged rats. J Neurosci. 15:2462-2470. [Abstract]
  5. Golarai G, Cavazos JE, Sutula TP, 1992. Activation of the dentate gyrus by pentylenetetrazole evoked seizures induces mossy fiber synaptic reorganization. Brain Res. 593:257-264. [Medline]
  6. Gall CM, Lauterborn JC, Guthrie KM, Stinis CR, 1997. Seizures and the regulation of neurotrophic factor expression: associations with structural plasticity in epilepsy. Adv Neurol. 72:9-24. [Medline]
  7. Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH, 1997. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci. 17:3727-3738. [Abstract/Free Full Text]
  8. Popa-Wagner A, Fischer B, Schmoll H, Platt D, Kessler C, 1997. Increased expression of microtubule-associated protein 1B in the hippocampus, subiculum, and perforant path of rats treated with a high dose of pentylenetetrazole. Exp Neurol. 148:73-82. [Medline]
  9. Popa-Wagner A, Fischer B, Schmoll H, Platt D, Kessler C, 1999. Altered expression of microtubule-associated protein 1B in cerebral cortical structures of pentylenetetrazole-treated rats. J Neurosci Res. 51:646-657.
  10. Retchkiman I, Fischer B, Platt D, Popa-Wagner A, 1996. Seizure induced c-fos mRNA in the rat brain: comparison between young and aging animals. Neurobiol Aging. 17:41-44. [Medline]
  11. Cai A, Lehman MN, Lloyd JM, Wise PM, 1997. Transplantation of fetal suprachiasmatic nuclei into middle-aged rats restores diurnal Fos expression in host. Am J Physiol. 272:R422-R428. [Abstract/Free Full Text]
  12. Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D, 1993. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature. 361:453-457. [Medline]
  13. Carroll P, Tsirka S, Richards W, Frohman M, Strickland S, 1994. The mouse plasminogen activator gene 5í flanking region directs appropriate expression during development and a seizure-enhanced response in the CNS. Development. 120:3173-3183. [Abstract]
  14. Pittman RN, Ivins JK, Buettner HM, 1989. Neuronal plasminogen activators: cell surface binding sites and involvement in neurite outgrowth. J Neurosci. 9:4269-4286. [Abstract]
  15. Monard D, 1988. Cell-derived proteases and protease inhibitors as regulators of neurite outgrowth. Trends Neurosci. 11:541-544. [Medline]
  16. Zurn AD, Nick H, Monard D, 1988. A glia-derived nexin promotes neurite outgrowth in cultured chick sympathetic neurons. Dev Neurosci. 10:17-24. [Medline]
  17. Seeds N, Williams B, Bickford P, 1995. Tissue plasminogen activator induction in Purkinje neurons after cerebellar motor learning. Science 270:1992-1994. [Abstract/Free Full Text]
  18. West MD, Shay JW, Wright WE, Linskens MH, 1996. Altered expression of plasminogen activator and plasminogen activator inhibitor during cellular senescence. Exp Gerontol. 31:175-193. [Medline]
  19. Lanahan A, Lyford G, Stevenson GS, Worley PF, Barnes CA, 1997. Selective alteration of long-term potentiation-induced transcriptional response in hippocampus of aged, memory-impaired rats. J Neurosci. 17:2876-2885. [Abstract/Free Full Text]
  20. Popa-Wagner A, Fischer B, Schmoll H, Platt D, Kessler C, 1999. Anomalous expression of microtubule-associated protein 1B in the hippocampus and cortex of aged rats treated with pentylenetetrazole. Neuroscience. 94:395-403. [Medline]
  21. Nokubo M, Kitani K, Ohta M, Kanai S, Sato Y, Masuda Y, 1986. Age-dependent increase in the threshold for pentylenetetrazole induced maximal seizure in mice. Life Sci. 38:1999-2007. [Medline]
  22. Sutula T, Xiao-Xian H, Cavazos J, Scott G, 1988. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 239:1147-1150. [Abstract/Free Full Text]
  23. Ben-Ari Y, Represa A, 1990. Brief seizure episodes induce long-term potentiation and mossy fibre sprouting in the hippocampus. Trends Neurosci. 13:312-318. [Medline]
  24. Sloviter RS, 1994. The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy. Ann Neurol. 35:640-654. [Medline]
  25. Gualandris A, Jones TE, Strickland S, Tsirka SE, 1996. Membrane depolarization induces calcium-dependent secretion of tissue plasminogen activator. J Neurosci. 16:2220-2225. [Abstract/Free Full Text]
  26. Valinsky JE, LeDouarin NM, 1985. The production of plasminogen activator by migrating cephalic neural crest cells. EMBO J. 4:1403-1406. [Medline]
  27. Quigley JP, Gold LT, Schwimmer R, Sullivan LM, 1987. Limited cleavage of cellular fibronectin by plasminogen activator purified from transformed cells. Proc Natl Acad Sci. 84:2776-2780. [Abstract/Free Full Text]
  28. Chen Z-L, Strickland S, 1997. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91:917-925. [Medline]
  29. Zhang RL, Zhang ZG, Chopp M, Zivin JA, 1999. Thrombolysis with tissue plasminogen activator alters adhesion molecule expression in the ischemic rat brain. Stroke. 30:624-629. [Abstract/Free Full Text]
  30. Waugh JM, Kattash M, Li J, et al. 1999. Gene therapy to promote thromboresistance: local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. Proc Natl Acad Sci USA. 96:1065-1070. [Abstract/Free Full Text]
  31. Hedge AN, Inokuchi K, Pei W, et al. 1997. Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89:115-126. [Medline]
  32. Huang YY, Bach ME, Lipp HP, et al. 1996. 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. Proc Natl Acad Sci USA 93:8699-8704. [Abstract/Free Full Text]
  33. Coleman PD, Rogers KE, Flood DG, 1990. Neuronal plasticity in normal aging and deficient plasticity in Alzheimer's disease: a proposed intercellular cascade. Prog Brain Res. 86:75-87. [Medline]
  34. Geinisman Y, Toledo-Morrell L, Morrell F, Persina IS, Rossi M, 1992. Structural synaptic plasticity associated with the induction of long-term potentiation is preserved in the dentate gyrus of aged rats. Hippocampus. 2:445-456. [Medline]
  35. Hoff SF, Scheff SW, Cotman CW, 1982. Lesion-induced synaptogenesis in the dentate gyrus of aged rats: I. Loss and reacquisition of normal synaptic density. J Comp Neurol. 205:246-252. [Medline]



This article has been cited by other articles:


Home page
 J. Physiol.Home page
D. T Smith, G. L Hoetzer, J. J Greiner, B. L Stauffer, and C. A DeSouza
Effects of ageing and regular aerobic exercise on endothelial fibrinolytic capacity in humans
J. Physiol., January 1, 2003; 546(1): 289 - 298.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
PubMed
Right arrow PubMed Citation

HOME ARCHIVE SEARCH TABLE OF CONTENTS