Phosphorylation of myelin basic protein in intact oligodendrocytes: inhibition by galactosylsphingosine and cyclic AMP

We have previously shown that cyclic AMP (cAMP) inhibits the protein kinase C (PKC)-mediated phosphorylation of myelin basic protein (MBP) in cultured oligodendrocytes (OLGs). Recently, it has been demonstrated that the long chain base sphingosine inhibits PKC by competing PKC effectors (diacylglycerol and phorbol esters) for a binding site on the kinase (Hannun and Bell: Science 235: 670-674, 1987). In this report we define further the mechanism by which cAMP inhibits MBP phosphorylation by comparing the effects of cAMP with that of galactosylsphingosine (psychosine), a potential catabolite of galactocerebroside, the major OLG glycosphingolipid. We identify the consequences of psychosine treatment and PKC down-regulation on OLG morphology and electrophysiology and discuss their relevance. Our results in intact ovine oligodendrocytes are consistent with a mechanism in which cAMP inhibits MBP phosphorylation by interfering with the release of diacylglycerol (DAG) from phosphatidylinositol. First, the effects of cAMP on MBP phosphorylation are reversed with exogenous TPA; and second, cAMP inhibits the incorporation of 1-[14C]arachidonate into DAG and specifically inhibits the turnover (as judged by 32PO4 3-incorporation) of phosphatidylinositol. Psychosine inhibits MBP phosphorylation, and its action can be reversed by TPA suggesting a mechanism of inhibition similar to that described for other systems. In addition, psychosine has profound effects on OLG morphology; it disintegrates OLG processes while leaving the cell soma intact. Stable hyperpolarized resting potentials were obtained following psychosine treatment, but there was a 66% decrease in membrane capacitance indicating a significant decrement in membrane surface area. The morphological changes induced by psychosine are reversible and can be eliminated by removing the drug but not by the addition of TPA. Whether inhibition of PKC by psychosine plays any role in process dissolution remains an unanswered question. However, current evidence suggests that a PKC-independent mechanism may be at play. This investigation in conjunction with our previous work emphasizes a role for the interregulation of protein kinase A (PKA) and PKC in the control of OLG somal vs. myelin components. This may have significant implications for central nervous system myelin assembly.     

Blockade of BDNF signaling turns chemically‐induced long‐term potentiation into long‐term depression

Long‐term potentiation (LTP) is accompanied by increased spine density and dimensions triggered by signaling cascades involving activation of the neurotrophin brain‐derived neurotrophic factor (BDNF) and cytoskeleton remodeling. Chemically‐induced long‐term potentiation (c‐LTP) is a widely used cellular model of plasticity, whose effects on spines have been poorly investigated. We induced c‐LTP by bath‐application of the N‐methyl‐d ‐aspartate receptor (NMDAR) coagonist glycine or by the K⁺ channel blocker tetraethylammonium (TEA) chloride in cultured hippocampal neurons and compared the changes in dendritic spines induced by the two models of c‐LTP and determined if they depend on BDNF/TrkB signaling. We found that both TEA and glycine induced a significant increase in stubby spine density in primary and secondary apical dendrites, whereas a specific increase in mushroom spine density was observed upon TEA application only in primary dendrites. Both TEA and glycine increased BDNF levels and the blockade of tropomyosin‐receptor‐kinase receptors (TrkRs) by the nonselective tyrosine kinase inhibitor K‐252a or the selective allosteric TrkB receptor (TrkBR) inhibitor ANA‐12, abolished the c‐LTP‐induced increase in spine density. Surprisingly, a blockade of TrkBRs did not change basal spontaneous glutamatergic transmission but completely changed the synaptic plasticity induced by c‐LTP, provoking a shift from a long‐term increase to a long‐term depression (LTD) in miniature excitatory postsynaptic current (mEPSC) frequency. In conclusion, these results suggest that BDNF/TrkB signaling is necessary for c‐LTP‐induced plasticity in hippocampal neurons and its blockade leads to a switch of c‐LTP into chemical‐LTD (c‐LTD). © 2013 Wiley Periodicals, Inc.     

Regulation of cyclic AMP level by progesterone in ovariectomized rat neocortex

Exposure of neocortical slices to progesterone, without prior treatment with estrogen, augmented forskolin-induced cyclic AMP within 15 min. 30 nM progesterone produced approximately 1/2 the maximal effect but as little as 10 nM progesterone produced a detectable increase in cyclic AMP. When forskolin was replaced by dideoxyforskolin, an analog that does not directly stimulate adenylyl cyclase but shares many of its other actions, progesterone did not augment cyclic AMP. Progesterone also failed to affect increased cyclic AMP that followed exposure to norepinephrine or isoproterenol. The effect of progesterone upon cyclic AMP was also evident when tetrodotoxin was added to block voltage-dependent sodium channels, suggesting that intercellular communication that is dependent upon action potentials was not necessary. The effect of progesterone was at least partially blocked by antagonists of GABAA receptor action, suggesting the involvement of GABAA or GABAA-like receptors. The effect of progesterone was also not homogeneous over the neo cortex. While forskolin-stimulated cyclic AMP was augmented by progesterone in the parietal and occipital regions, it was suppressed in the frontal region. These results are envisioned as a progesterone action upon a small and perhaps compartmentalized component of the cellular cyclic AMP system, an effect that is made detectable in our whole-tissue assay by the well known ability of forskolin to potentiate many hormonal effects upon cyclic AMP.     

Adenosine modulation of dynorphin B release by hippocampal synaptosomes

A rat hippocampal preparation enriched in mossy fiber synaptosomes was employed in an attempt to expose any relationship between endogenous adenosine and the release of dynorphin B-like immunoreactivity (DynB-LI). Presumptive blockade of purinergic receptors increased the spontaneous release of DynB-LI, and reducing synaptic adenosine by exogenous adenosine deaminase increased the K(+)-evoked release. Evoked release of DynB-LI was reduced by inhibitors of adenosine uptake and 5'-nucleotidase. Taken together, these data suggest that adenosine endogenous to hippocampal mossy fiber synaptosomes serves to inhibit the release of one of the peptide neuromodulators of this preparation, and provide support for the concept of autoregulation of release.     

Dentate gyrus granule cell firing patterns can induce mossy fiber long‐term potentiation in vitro

Hippocampal granule cells transmit information about behaviorally‐relevant stimuli to CA3 pyramidal cells via mossy fiber synapses. These synapses express a form of long‐term potentiation (mfLTP) that is non‐Hebbian and does not require NMDA receptors. mfLTP is thought to be induced and expressed presynaptically, hence, the major determinant of whether mfLTP occurs is activity in the granule cells. However, it remains unclear whether mfLTP can be induced by activity patterns that granule cells exhibit in vivo, and—if so—what context generates these patterns. To address these issues, we examined granule cell activity from in vivo recordings from rats during performance of a delayed nonmatch‐to‐sample (DNMS) task and found that granule cells exhibit a wide range of spike patterns. In vitro slice experiments in mice demonstrated that some, but not all, of these patterns of activity could induce mfLTP. By further defining the activity thresholds for mfLTP in hippocampal slices, we found that mfLTP can only be induced by spike patterns that fire in high frequency bursts with a low average firing frequency. Using this information, we then screened for suprathreshold bursts of activity during the DNMS task. In a subset of cells, suprathreshold bursts occurred preferentially during the sampling phase of the task. If suprathreshold bursting took place later, during the delay phase, task performance was disrupted. We conclude that mfLTP can be induced by granule cell spike patterns during a memory task, and that the timing of mfLTP induction can predict task performance. © 2010 Wiley Periodicals, Inc.     

Persistent inhibition of hippocampal long‐term potentiation in vivo by learned helplessness stress

The persistent cognitive disruptive effects of stress have been strongly implicated in the pathophysiology of depression and post‐traumatic stress disorder. Here we examined factors influencing the time course of recovery from the inhibitory effect of acute inescapable stressors on the ability to induce long‐term potentiation (LTP) in the dorsal hippocampus in vivo. We tested different forms of LTP, different stressors and different inbred strains of rats. Acute elevated platform stress completely, but transiently (<3 h), inhibited induction of both NMDA receptor‐dependent LTP induced by a standard high frequency (200 Hz) conditioning stimulus and an additional LTP that required voltage‐dependent Ca²⁺ channel activation triggered by strong (400 Hz) conditioning stimulation. In contrast, acute inescapable footshock stress, used to study learned helplessness, inhibited LTP for at least 4 weeks. Contrary to expectations, there was no clear relationship between the ability of the footshock to trigger helpless behavior, a model of stress‐induced depression, and the magnitude of LTP inhibition. Moreover, LTP did not appear to be affected by genetic susceptibility to learned helplessness, a model of genetic vulnerability to depression. This long‐lasting synaptic plasticity disruption may underlie persistent impairment of hippocampus‐dependent cognition by excessive acute inescapable stress. © 2009 Wiley‐Liss, Inc.     

Tyrosine kinase effects on adrenoceptor-stimulated cyclic AMP accumulation in preoptic area and hypothalamus of female rats: modulation by estradiol

These studies examined the functional interactions between adrenergic G-protein coupled receptors and protein tyrosine kinases in the preoptic area and hypothalamus, brain regions that regulate reproductive function in female rats, and evaluated whether in vivo treatment with estradiol for 2 days modulates the cross-talk between these two signaling pathways. In hypothalamic slices genistein, a general tyrosine kinase inhibitor, enhances norepinephrine-stimulated cAMP synthesis independent of estradiol treatment. Genistein appears to act by increasing beta-adrenoceptor signaling. At high norepinephrine concentrations, estradiol potentiates genistein enhancement of the cAMP response in hypothalamic slices. This interaction between estradiol and genistein appears to involve modification of alpha(2)-adrenoceptor signaling mechanisms. In preoptic area slices, genistein enhancement of norepinephrine-stimulated cAMP synthesis is only observed in estradiol-treated rats. In this brain region, genistein enhances cAMP accumulation by modifying alpha(1)- and/or alpha(2)-adrenoceptor rather than beta-adrenoceptor signaling. Genistein amplification of norepinephrine-stimulated cAMP synthesis is not mediated by interactions with estrogen receptors, or by regulation of adenylyl cyclase or phosphodiesterase activities. At the concentration used, genistein inhibits tyrosine phosphorylation in slices from both brain regions. Daidzein, an inactive analogue of genistein, fails to enhance the norepinephrine-stimulated cAMP response in either brain region independent of hormone treatment. These results suggest that protein tyrosine kinases regulate adrenergic responses in the hypothalamus and preoptic area. Moreover, the functional interaction between adrenergic G-protein coupled receptor signaling and protein tyrosine kinases is modified in a brain region and receptor subtype specific manner by estradiol.     

Age‐related synaptic dysfunction in Tg2576 mice starts as a failure in early long‐term potentiation which develops into a full abolishment of late long‐term potentiation

Tg2576 mice are widely used to study amyloid‐dependent synaptic dysfunction related to Alzheimer's disease. However, conflicting data have been reported for these mice with regard to basal transmission as well as the in vitro correlate of memory, long‐term potentiation (LTP). Some studies show clear impairments, whereas others report no deficiency. The present study uses hippocampal slices from 3‐, 10‐, and 15‐month‐old wild‐type (WT) and Tg2576 mice to evaluate synaptic function in each group, including experiments to investigate basal synaptic transmission, short‐ and long‐term plasticity by inducing paired‐pulse facilitation, and both early and late LTP. We show that synaptic function remains intact in hippocampal slices from Tg2576 mice at 3 months of age. However, both early and late LTP decline progressively during aging in these mice. This deterioration of synaptic plasticity starts affecting early LTP, ultimately leading to the abolishment of both forms of LTP in 15‐month‐old animals. In comparison, WT littermates display normal synaptic parameters during aging. Additional pharmacological investigation into the involvement of NMDA receptors and L‐type voltage‐gated calcium channels in LTP suggests a distinct mechanism of induction among age groups, demonstrating that both early and late LTP are differentially affected by these channels in Tg2576 mice during aging. © 2015 Wiley Periodicals, Inc.     

Prenatal ethanol exposure has sex‐specific effects on hippocampal long‐term potentiation

Alcohol consumption during pregnancy is deleterious to the developing brain of the fetus and leads to persistent deficits in adulthood. Long‐term potentiation (LTP) is a biological model for learning and memory processes and previous evidence has shown that prenatal ethanol exposure (PNEE) affects LTP in a sex specific manner during adolescence. The objective of this study was to determine if there are sex specific differences in adult animals and to elucidate the underlying molecular mechanisms that contribute to these differences. Pregnant Sprague–Dawley dams were assigned to either; liquid ethanol, pair‐fed or standard chow diet. In vivo electrophysiology was performed in the hippocampal dentate gyrus (DG) of adult offspring. LTP was induced by administering 400 Hz stimuli. Western blot analysis for glutamine synthetase (GS) and glutamate decarboxylase from tissue of the DG indicated that GS expression was increased following PNEE. Surprisingly, adult females did not show any deficit in N‐methyl‐d ‐aspartate (NMDA)‐dependent LTP after PNEE. In contrast, males showed a 40% reduction in LTP. It was indicated that glutamine synthetase expression was increased in PNEE females, suggesting that altered excitatory neurotransmitter replenishment may serve as a compensatory mechanism. Ovariectomizing females did not influence LTP in control or PNEE animals, suggesting that circulating estradiol levels do not play a major role in maintaining LTP levels in PNEE females. These results demonstrate the sexually dimorphic effects of PNEE on the ability for the adult brain to elicit LTP in the DG. The mechanisms for these effects are not fully understood, but an increase in glutamine synthetase in females may underlie this phenomenon. © 2013 Wiley Periodicals, Inc.     

Prepubertal castration causes the age‐dependent changes in hippocampal long‐term potentiation

The effects of prepubertal castration on hippocampal CA3‐CA1 synaptic transmission and plasticity were studied at different ages in vitro. The field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) were simultaneously recorded from stratum radiatum and stratum pylamidale of area CA1 following stimulation of Schaffer collaterals in slices taken from sham‐castrated and castrated rats at postnatal days (PND) 28, 35, 45, and 60. Castration had no effect on baseline responses at different ages except at PND 60 that a decrease in the fEPSP slope was seen. Prepubertal castration caused age‐specific changes in CA1‐long term potentiation (LTP) induction. The castration did decrease both fEPSP‐LTP and PS‐LTP at PND 35 but a decrease was seen only in PS‐LTP at PND 60. NMDA receptor antagonist AP5 (25 µM) completely blocked both fEPSP‐LTP and PS‐LTP at PND 60 and only PS‐LTP at PND 35 in both sham‐castrated and castrated groups. Although AP5 blocked fEPSP‐LTP at PND 35 in sham‐castrated group, it failed to inhibit fEPSP‐LTP at PND 35 in castrated one. These findings suggest that prepubertal castration causes the age‐dependent changes in CA1‐LTP induction, which might arise from alterations in the NMDA receptors. Synapse 67:235–244, 2013. © 2013 Wiley Periodicals, Inc.     

Chronic psychosocial stress accelerates impairment of long‐term memory and late‐phase long‐term potentiation in an at‐risk model of Alzheimer's disease

Although it is generally agreed that Aβ contributes to the pathogenesis of AD, its precise role in AD and the reason for the varying intensity and time of onset of the disease have not been elucidated. In addition to genetic factors, environmental issues such as stress may also play a critical role in the etiology of AD. This study examined the effect of chronic psychosocial stress in an at‐risk (treatment with a subpathogenic dose of Aβ; “subAβ”) rat model of AD on long‐term memory by three techniques: memory tests in the radial arm water maze, electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of learning‐ and long‐term memory‐related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD was induced by continuous infusion of 160 pmol/day Aβ_1–42 via a 14‐day i.c.v. osmotic pump. All tests showed that subAβ rats were not different from control rats. Result from behavioral tests and electrophysiological recordings showed that infusion of subAβ in chronically stressed rats (stress/subAβ group) caused significant impairment of cognitive functions and late‐phase long‐term potentiation (L‐LTP). Molecular analysis of various signaling molecules after expression of L‐LTP, revealed an increase in the levels of p‐CREB in control, stress, and subAβ rats, but not in the stress/subAβ rats. These findings suggest that the chronic stress‐induced molecular alteration may accelerate the impairment of cognition and synaptic plasticity in individuals “at‐risk” for AD. © 2010 Wiley‐Liss, Inc.     

Ras‐GRF2 mediates long‐term potentiation,survival, and response to an enriched environment of newborn neurons in the hippocampus

Hippocampal adult neurogenesis contributes to key functions of the dentate gyrus (DG), including contextual discrimination. This is due, at least in part, to the unique form of plasticity that new neurons display at a specific stage of their development when compared with the surrounding principal neurons. In addition, the contribution that newborn neurons make to dentate function can be enhanced by an increase in their numbers induced by a stimulating environment. However, signaling mechanisms that regulate these properties of newborn neurons are poorly understood. Here, we show that Ras‐GRF2 (GRF2), a calcium‐regulated exchange factor that can activate Ras and Rac GTPases, contributes to both of these properties of newborn neurons. Using Ras‐GRF2 knockout mice and wild‐type mice stereotactically injected with retrovirus containing shRNA against the exchange factor, we demonstrate that GRF2 promotes the survival of newborn neurons of the DG at approximately 1–2 weeks after their birth. GRF2 also controls the distinct form of long‐term potentiation that is characteristic of new neurons of the hippocampus through its effector Erk MAP kinase. Moreover, the enhancement of neuron survival that occurs after mice are exposed to an enriched environment also involves GRF2 function. Consistent with these observations, GRF2 knockout mice display defective contextual discrimination. Overall, these findings indicate that GRF2 regulates both the basal level and environmentally induced increase of newborn neuron survival, as well as in the induction of a distinct form of synaptic plasticity of newborn neurons that contributes to distinct features of hippocampus‐derived learning and memory. © 2014 Wiley Periodicals, Inc.     

Unique response of zinc in the hippocampus to behavioral stress and attenuation of subsequent mossy fiber long-term potentiation

Extracellular zinc in the hippocampus is decreased by novelty stress. The significance of zinc movement in acute stress is unknown. In the present study, response of extracellular zinc in the hippocampus was examined after exposure to tail suspension, a behavioral stress. In rats subjected to hippocampal perfusion, thirty-second tail suspension elicited a short increase in extracellular glutamate and a persistent decrease in extracellular zinc, which continued for 60 min. These results suggest that zinc influx into hippocampal cells is facilitated by acute behavioral stress. Furthermore, the influence of the facilitated zinc influx in mossy fiber long-term potentiation (LTP) was evaluated in hippocampal slices prepared from rats 1 h after tail suspension. Mossy fiber LTP was significantly attenuated. Perfusion with 100 μM ZnCl₂ prior to LTP induction was performed to facilitate zinc influx. The zinc perfusion also attenuated mossy fiber LTP. On the other hand, perfusion with 50 μM glutamate did not attenuate it. The attenuation of mossy fiber LTP by tail suspension was completely restored when rats were pretreated with clioquinol (30 mg/kg) to block the action of chelatable zinc. The present study indicates that exposure to tail suspension attenuates subsequent mossy fiber LTP. It is likely that the facilitated zinc influx by tail suspension, which seems to be linked to glutamate signaling, is involved in attenuation of subsequent mossy fiber LTP.     

Hippocampal long‐term potentiation is enhanced in urethane‐anesthetized RGS2 knockout mice

RGS2 is a member of the regulator of G‐protein signaling (RGS) family and has been implicated in cellular mechanisms associated with neuronal plasticity. Long‐term potentiation (LTP) of RGS2 knockout and wild‐type mice was examined at the Schaffer collaterals to CA1 pathway in urethane‐anesthetized mice in vivo to examine RGS2's possible role in the regulation of potentiation. As compared to wild‐type mice, RGS2 knockouts demonstrated much stronger LTP of the extracellular population spikes at the somatic and dendritic layers in CA1 region and more pronounced LTP of the population excitatory postsynaptic current sink. Under baseline conditions, RGS2 knockouts showed lower paired‐pulse facilitation of the excitatory postsynaptic potentials and associated current sinks in vivo as compared with wild‐type mice. The data show for the first time that RGS2 deficient mice in vivo differ from wild‐type mice in both short‐term and long‐term synaptic plasticity suggesting that RGS2 serves as a negative regulator of long‐term synaptic plasticity. © 2009 Wiley‐Liss, Inc.     

A ketogenic diet does not impair rat behavior or long‐term potentiation

The effect of the ketogenic diet on behavior and cognition is unclear. We addressed this issue in rats behaviorally and electrophysiologically. We fed postnatal day 21 rats a standard diet (SD), ketogenic diet (KD), or calorie‐restricted diet (CR) for 2–3 weeks. CR controlled for the slower weight gain experienced by KD‐fed rats. We assessed behavioral performance with a locomotor activity and a conditioned fear test. To evaluate possible parallel effects of diet on synaptic function, we examined paired‐pulse modulation (PPM) and long‐term potentiation (LTP) in the medial perforant path in vivo. KD‐fed rats performed similarly to SD‐fed rats on the behavioral tests and electrophysiologic assays. These data suggest that the KD does not alter behavioral performance or synaptic plasticity.     

The role of Homer1c in metabotropic glutamate receptor‐dependent long‐term potentiation

Group I metabotropic glutamate receptors (mGluR1/5) play a role in synaptic plasticity and they demonstrate direct interactions with the neuronal Homer1c protein. We have previously shown that Homer1c can restore the plasticity deficits in Homer1 knockout mice (H1‐KO). Here, we investigated the role of Homer1c in mGluR‐dependent synaptic plasticity in wild‐type mice, H1‐KO, and H1‐KO mice overexpressing Homer1c (KO+H1c). We used a form of plasticity induced by activation of mGluR1/5 that transforms short‐term potentiaion (STP) induced by a subthreshold theta burst stimulation into long‐term potentiation (LTP). We have shown that although acute hippocampal slices from wild‐type animals can induce LTP using this stimulation protocol, H1‐KO only show STP. Gene delivery of Homer1c into the hippocampus of H1‐KO mice rescued LTP to wild‐type levels. This form of synaptic plasticity was dependent on mGluR5 but not mGluR1 activation both in wild‐type mice and in KO+H1c. mGluR1/5‐dependent LTP was blocked with inhibitors of the MEK‐ERK and PI3K‐mTOR pathways in KO+H1c mice. Moreover, blocking Homer1c–mGluR5 interactions prevented the maintenance of LTP in acute hippocampal slices from KO+H1c. These data indicate that Homer1c–mGluR5 interactions are necessary for mGluR‐dependent LTP, and that mGluR1/5‐dependent LTP involves PI3K and ERK activation. © 2013 Wiley Periodicals, Inc.     

Late phase of long‐term potentiation in the mossy fiber—CA3 hippocampal pathway is critically dependent on metalloproteinases activity

Matrix metalloproteinases (MMPs) are known to play a pivotal role in remodeling of the extracellular matrix and have been implicated in synaptic plasticity, learning and memory. In hippocampus, inhibition of MMPs impairs the maintenance of long term plasticity in Schaeffer collateral‐CA1 (Sch/CA1) synapses while its effect on short term plasticity remains a matter of debate. Surprisingly little is known on the role of MMPs in other hippocampal synapses. In this study we have investigated the impact of a broad spectrum MMPs inhibitor, FN‐439 on synaptic transmission in mossy fiber‐CA3 (MF/CA3) synapses exhibiting profoundly different mechanism of long term potentiation (LTP) as well as robust short‐term plasticity, features that clearly distinguish them from the Sch/CA1 synapses. We report, that MMPs blockade before and up to 30 minutes after LTP induction resulted in a severe disruption of the late phase of tetanically induced LTP. However, LTP time course was not changed when FN439 was administered 60 minutes post LTP induction indicating that MMPs activity is required for the consolidation of the synaptic plasticity within a specific time window. The paired‐pulse facilitation ratio or post‐tetanic potentiation or burst‐like pattern of mossy fiber stimulation were not changed in the presence of FN‐439 administered for 15 minutes suggesting that temporal pattern of presynaptic transmitter release and, in general, the MF‐CA3 fidelity is not significantly affected by MMPs inhibition. We conclude that although the mechanisms of long‐term plasticity in MF/CA3 and in Sch/CA1 are profoundly different, MMPs play a crucial role in both pathways in the maintenance of LTP, which is believed to play an important role in learning and memory in the hippocampus. © 2010 Wiley‐Liss, Inc.     

Acute stress disrupts paired pulse facilitation and long‐term potentiation in rat dorsal hippocampus through activation of glucocorticoid receptors

Cognitive functions such as learning and memory are widely believed to depend on patterns of short‐ and long‐term synaptic plasticity. Factors, such as acute stress, which affect learning and memory, may do so by altering patterns of synaptic plasticity in distinct neural circuits. Numerous studies have examined the effects of acute stress on long‐term synaptic plasticity; however, few have examined its influence on short‐term plasticity. The present experiments directly assessed the effects of acute stress on short‐term synaptic plasticity as measured by paired pulse facilitation (PPF) of excitatory postsynaptic potentials recorded from rat dorsal hippocampus (dHip) in vivo. Long‐term potentiation (LTP) was also examined. Acute stress induced by exposure to an elevated platform impaired PPF and LTP in the dHip. Pretreatment of rats exposed to stress with mifepristone (RU38486; 10 mg kg⁻¹) blocked the stress‐induced impairment of both PPF and LTP. These data demonstrate that activation of glucocorticoid receptors during acute stress disrupts normal patterns of both PPF and LTP in the dHip. © 2009 Wiley‐Liss, Inc.     

Regulation of plasminogen activators and type-1 plasminogen activator inhibitor by cyclic AMP and phorbol ester in rat astrocytes.

Two plasminogen activators (PAs): tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), as well as the type-1 plasminogen activator inhibitor (PAI-1) are synthesized and secreted by rat astrocytes. Preliminary studies suggest that PA activity plays a role in astrocyte development and differentiation. We have examined the regulation of the PA system by the cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in purified rat astrocyte cultures. PKA activity was increased by exposing cultured astrocytes to forskolin or dibutyryl cyclic AMP, whereas PKC activity was stimulated with phorbol-12-myristate 13-acetate (PMA). Activation of both second-messenger pathways produced a time- and dose-dependent increase in the total PA activity. However, based on SDS-PAGE/zymography we found that forskolin increased t-PA activity and reduced u-PA activity, whereas PMA treatment caused a significant increase in u-PA activity without altering t-PA activity. Reverse zymography analysis revealed that astrocyte PAI-1 activity is decreased by forskolin and increased by PMA. Together, these results demonstrate that the components of the PA system in rat astrocytes are independently and reciprocally regulated by PKA and PKC. Our findings raise the possibility that the plasminogen activator system could be involved in some of the actions of growth factors and/or neuromodulators that modulate PKC or PKA in astrocytes.