Cortico-striatal synaptic plasticity in endothelial nitric oxide synthase deficient mice

Nitric oxide (NO) is a retrograde messenger involved in the processes of learning and memory. The role of the endothelial isoform of nitric oxide synthase (eNOS) in striatal synaptic plasticity was investigated in eNOS-deficient (eNOS(-/-)) and wild type (WT) mice. Tetanic stimulation of cortical afferents in WT mice evoked either long-term potentiation (LTP), or long-term depression (LTD) of cortico-striatal transmission. Both these plasticity related phenomena were NMDA-receptor-dependent; LTD was blocked by sulpiride, a dopamine D2-receptor antagonist. LTP occurrence in slices from eNOS(-/-) mice was significantly reduced when compared with WT mice. The NOS inhibitor NL-ARG reduced the occurrence of LTP and increased the occurrence of LTD in WT mice, resembling the balance of LTP/LTD in eNOS(-/-) mice. Impairment of NO-synthesis thus shifts striatal plasticity towards LTD. This indicates a possible involvement of eNOS from endothelia in neuronal modulation.     

Vasopressin reverses aluminum-induced impairment of synaptic plasticity in the rat dentate gyrus in vivo

Aluminum (Al), an important neurotoxin, contributes to a variety of cognitive dysfunction and mental diseases. Previous studies have demonstrated that Al impairs hippocampal long-term potentiation (LTP) in vitro and in vivo. In the present study, both LTP and LTD (long-term depression) were recorded in the same animal to investigate the Al-induced impairment of synaptic plasticity. Another aim of the present research was to verify whether the impairment of synaptic plasticity induced by Al could be reversed by vasopressin (VP) treatment. Neonatal Wistar rats were exposed to Al from parturition through adulthood (pre- and post-weaning) by the drinking of 0.3% aluminum chloride (AlCl(3)) solution. The input-output (I/O) function, paired-pulse reaction (PPR), excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) of adult rats (60-90 days) in response to stimulation applied to the lateral perforant path. The results showed: (1) Al reduced the amplitudes of both EPSP LTP (control: 132+/-7%, n=7; Al-exposed: 115+/-10%, n=8, P<0.05) and PS LTP (control: 242+/-18%, n=7; Al-exposed: 136+/-7%, n=8, P<0.01) significantly. The amplitudes of EPSP LTD (control: 82+/-6%, n=7; Al-exposed: 92+/-7%, n=8, P<0.05) and PS LTD (control: 81+/-4%, n=7; Al-exposed: 98+/-5%, n=8, P<0.05) were also decreased by Al treatment. The Al-induced impairments of PS LTP and PS LTD were more serious than that of EPSP LTP and EPSP LTD. (2) In control rats, VP had an increase in the PS LTP amplitude (control: 242+/-18%, n=7; control+VP: 358+/-23%, n=6, P<0.01), while it had no significant effects on PS LTD (control: 81+/-4%, n=7; control+VP: 76+/-7%, n=6, P>0.05). (3) In Al-exposed rats, VP had a significant increase in the amplitudes of both PS LTP (Al-exposed: 136+/-7%, n=8, Al-exposed+VP: 255+/-16%, n=6, P<0.01) and PS LTD (Al-exposed: 98+/-5%, n=8; Al-exposed+VP: 81+/-6%, n=6, P<0.05). After the application of VP, the range of synaptic plasticity (PS LTP+PS LTD) in Al-exposed rats increased from 38% to 174%, which surpassed that in control rats (161%). It was suggested that VP could reverse Al-induced impairment of synaptic plasticity and might be an effective medicine to cure Al-induced neurological disorders.     

不同刺激对条件性恐惧大鼠行为及海马CA1区突触可塑性的影响

目的研究不同刺激对条件性恐惧大鼠的行为、海马CA1区兴奋性突触后电位（EPSP）的长时程增强（LTP）及长时程抑制（LTD）的影响。方法将106只大鼠分为7个实验组和4个行为对照组，检测其活体海马CA1区EPSP的LTP和LTD。（1）应激：①空白对照组（11只）除外，将6个实验组大鼠分别在A箱（应激箱）和B箱（非应激箱）中适应2d，第3天在A箱中给予20个条件性光刺激（CS）和足底电击（应激），将②急性应激组（8只）在应激后立即检测，③无暴露组（11只）在应激后24h后检测；（2）行为学观察：第4天将其余4组分别暴露于A箱（④A暴露组，17只）和B箱（⑤B暴露组，11只）中，并在不同刺激下（⑥A暴露＋1CS组，10只；⑦B暴露＋1CS组，11只）观察其僵住行为（共1h，分3个连续时相，每个时相20min；自第3个时相开始时给予或不给予1次CS）。随后进行检测。相应的4个行为对照组大鼠接受与④一⑦组同样的处理，但不予电击和EPSP检测。结果（1）僵住行为：各实验组在3个时相中的僵住时间比例均高于各自的对照组（P≤O．01）。在第3个时相中，A暴露组、A暴露＋1CS组、B暴露＋1CS组的僵住时间比例均高于B暴露组（P≤0．01）。（2）EPSP：经高频刺激，除急性应激组和A暴露＋1CS组外，空白对照组、无暴露组、A暴露组、B暴露组和B暴露＋1CS组均诱导出m（P〈0．01和P〈0．05）。经低频刺激后，急性应激组和A暴露＋1CS组大鼠的海马CA1区可稳定地诱导出LTD（P〈O．01和P〈0．05）。结论不同刺激可引起条件性恐惧大鼠长时间的僵住行为，其海马CA1区突触可塑性发生异质性改变。     

A role for monomeric G-proteins in synaptic plasticity in the rat dentate gyrus in vitro

Recent studies have implicated Ras signalling in synaptic plasticity. In this study we have investigated a role for the low molecular weight G proteins Ras, Rap, Ra1 and Rac in long-term potentiation and depression using Clostridium Sordelli Lethal Toxin-82 (LT-82), which inactivates Ras, Rap, Ra1 and Rac, and manumycin A, a Ras inhibitor. Perfusion of hippocampal slices with LT-82 (200 ng/ml) attenuated LTP (83±10%, n=5, P<0.01, compared with controls of 160±11% at 60 min post HFS, n=5). LT-82 had no effect on LTD (63±1% at 100 ng/ml, n=5 and 66±1% at 200 ng/ml, n=4, compared to controls of 56±6%, n=6). Manumycin A (2μM) had no effect on LTP (162±2%, n=5, compared to controls of 167±13%, n=5), but significantly attenuated LTD (88±6%, n=5, P<0.01, compared to controls of 63±9%, n=7). LT-82 (200 ng/ml) significantly increased the amplitude of the isolated NMDA-EPSP at 60 min post-drug application (240±40%, n=5, P<0.01, compared with controls of 100±4%, n=5). However, manumycin A, had no significant effect on NMDAR-EPSP amplitude (92±2%, n=5, compared with controls). These results demonstrate an important role for Ras in LTD and a role for Rap, Ra1 and Rac in LTP.     

COX-2 oxidative metabolism of endocannabinoids augments hippocampal synaptic plasticity

Endocannabinoids (eCBs) are important endogenous lipid mediators in synaptic transmission and plasticity and are oxygenated by cyclooxygenase-2 (COX-2) to form new types of prostaglandins. However, little is known about whether COX-2 oxidative metabolism of eCBs and their metabolites alter synaptic signaling. Here we demonstrate that increased COX-2 expression significantly enhances basal synaptic transmission and augments long-term potentiation (LTP) in the mouse hippocampus. This augmentation was inhibited in the presence of a selective COX-2 inhibitor or with deletion of the COX-2 gene. The CB₁ receptor-mediated depolarization-induced suppression of inhibition (DSI) was diminished when COX-2 expression was increased either with lipopolysaccharide (LPS) stimulation or transgenic neuronal over-expression of COX-2. Conversely, DSI was potentiated when COX-2 activity was pharmacologically or genetically inhibited. Interestingly, COX-2 oxidative metabolites of eCBs elevated LTP, an effect opposite to that of their parent molecules 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA). In addition, the ERK/MAPK and IP₃ pathways were found to mediate PGE₂-G-induced enhancement of LTP. Our results indicate that COX-2 oxidative metabolism of eCBs is an important signaling pathway in modulation of synaptic transmission and plasticity.     

Associative synaptic potentiation and depression: quantification of dissociable modifications in the hippocampal dentate gyrus favors a particular class of synaptic modification equations

This report further characterizes associative long-term synaptic modification of the ipsilateral and contralateral synapses formed by the bilateral entorhinal cortical (EC) projection to the dentate gyrus (DG). The experimental model is the anesthetized hooded rat. The quantitative results qualify this system as a model for studying the rules of associative synaptic modification formulated in terms of individual synapses. Bilateral DG microelectrodes recorded both ipsilateral and contralateral EC-DG responses before and after brief, high-frequency EC conditioning stimulation. The weak contralateral pathway received high-frequency conditioning before, during, or after similar conditioning of the strong, converging ipsilateral pathway. Statistical analyses revealed two types of significant, dissociated synaptic modifications, which depend on the relationship of the ipsilateral and contralateral afferents. First, contralateral EC-DG responses potentiated or depressed when the converging ipsilateral responses concurrently either potentiated or remained unchanged. Second, contralateral EC-DG responses potentiated, depressed, or showed no change when the collateral ipsilateral responses concurrently either potentiated or remained unchanged. Correlation and contingency table analyses indicated that changes in the contralateral synaptic responses are not well predicted by changes at either neighboring synapses of the converging ipsilateral pathway or at synapses of the collateral ipsilateral pathway. The contingencies of associated pre- and postsynaptic activation determined by the conditioning paradigm, however, accurately predicted the altered synaptic responses of both ipsilateral and contralateral EC-DG pathways. The results imply that associative synaptic modification in the EC-DG system is specific to individual synapses and requires both appropriate presynaptic and postsynaptic activation. Because this system provides suitable controls for nonspecific effects of conditioning stimulation and because modification of neighboring synapses is dissociable, the EC-DG system can be used to study further those rules of activity-dependent associative modification that are formulated in terms of individual synapses. The discussion briefly considers published rules of synaptic modification, pointing out several rules that are not consistent with the experimental observations and one that agrees with the present results.     

Age-related changes in the synaptic plasticity of rat superior cervical ganglia

A few seconds of tetanic preganglionic stimulation of rat sympathetic ganglia results in potentiation of cholinergic synaptic transmission lasting several hours. However, ganglia from aged (28-32 months) rats did not develop as much potentiation as did ganglia from young (3-6 months) rats. This potentiation appears to decay exponentially but in two phases. The early component decays in 15 minutes, a time course consistent with the phenomenon of post-tetanic potentiation (PTP). The later component decays over several hours and is a form of long-term potentiation (LTP). A double exponential decay model was employed to quantitatively resolve the decay of potentiation and allow quantitative comparison of the decay parameters in both aged and young rats. It is clear that the magnitude and duration of PTP was the same in both age groups. However both the magnitude and decay time-constant for LTP were 30-50% smaller in the aged group of rats. Several agents which mimic cyclic AMP or stimulate cyclic AMP production in the ganglion enhance nicotinic transmission for several hours. However, these agents, 8-bromo cAMP, forskolin, isoproterenol, and secretin were equally effective in potentiating transmission in ganglia from both young and aged rats. Previous studies demonstrated that stimulus induced LTP and cyclic AMP induced potentiation was the result of enhanced release of acetylcholine (ACh) and not from increased postsynaptic responsiveness. Presumably these agents act through the same pathway and by the same mechanism that generates LTP following preganglionic tetany. These observations demonstrate that there is a selective age-dependent decline in the capacity for sympathetic ganglia to generate long-term changes in synaptic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)     

应激和吗啡对不同周龄大鼠海马CA1区突触可塑性的影响

目的研究慢性应激和(或)吗啡对不同周龄Wistar大鼠海马CA1区突触可塑性的影响。方法将4周龄和10周龄(各51只)雄性Wistar大鼠分别随机分为对照组(分别为14只)、慢性应激组(分别为13只和11只)、吗啡组(分别为14只和13只)和慢性应激加吗啡组(分别为10只和13只)。以场兴奋性后电位(fEPSP)的幅值观察两个年龄段各组大鼠的突触可塑性变化。结果(1)长时程增强(LTP)：对照组、慢性应激组和吗啡组均为10周龄鼠大于4周龄鼠(P＜0.01)；慢性应激削弱了4周龄和10周龄大鼠LTP[分别为(106.8±0.3)%,(115.6±0.2)％]；吗啡易化了10周龄大鼠的LTP(135.7±0.4)%,却削弱了4周龄大鼠的LTP(105.0±0.2)%；慢性应激加吗啡组削弱了10周龄大鼠的LTP(116.7±0.3)%,却易化了4周龄的LTP(117.7±0.5)%,均P＜0.05。(2)长时程抑制(LTD)：慢性应激后10周龄大鼠不能诱导出LTD(103.9±0.3)%,却易化4周龄大鼠的LTD(88.6±0.3)%；吗啡对10周龄和4周龄大鼠的LTD均起易化作用[分别为(77.5±0.2)%,(86.4±0.5)%]；10周龄慢性应激的大鼠使用吗啡后不能诱导出LTD(110.4±0.3)%,但对4周龄大鼠的LTD起易化作用(79.1±0.2)%,均P＜0.05。结论慢性应激和(或)急性吗啡暴露分别对4周龄与10周龄大鼠海马CA1区的LTP和LTD有不同作用,存在明显的年龄差异。     

Long-term synaptic plasticity in the spinal dorsal horn and its modulation by electroacupuncture in rats with neuropathic pain

Our previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, we investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). We found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from our present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz.     

Multideterminant role of calcium in hippocampal synaptic plasticity

Hippocampal CA1 cells possess several varieties of long-lasting synaptic plasticity: two different forms of long-term potentiation (LTP) and at least one form of long-term depression (LTD). All forms of synaptic plasticity are induced by afferent activation, all involve Ca²⁺ influx, all can be blocked by Ca²⁺ chelators, and all activate Ca²⁺-dependent mechanisms. The question arises as how different physiological responses can be initiated by activation of the same second messenger. We consider two hypotheses which could account for these phenomena: voltage-dependent differences in cytosolic Ca²⁺ concentration acting upon Ca²⁺ substrates of differing Ca²⁺ affinities and compartmentalization of the Ca²⁺ and its substrates. © 1994 Wiley-Liss, Inc.     

Dopamine-mediated regulation of corticostriatal synaptic plasticity

The striatum represents the main input into the basal ganglia. Neurons projecting from the striatum receive a large convergence of afferents from all areas of the cortex and transmit neural information to the basal ganglia output structures. Corticostriatal transmission is essential in the regulation of voluntary movement, in addition to behavioural control, cognitive function and reward mechanisms. Long-term potentiation (LTP) and long-term depression (LTD), the two main forms of synaptic plasticity, are both represented at corticostriatal synapses and strongly depend on the activation of dopamine receptors. Here, we discuss possible feedforward and feedback mechanisms by which striatal interneurons, in association with striatal spiny neurons and endogenous dopamine, influence the formation and maintenance of both LTP and LTD. We also propose a model in which the spontaneous membrane oscillations of neurons projecting from the striatum (named 'up' and 'down' states), in addition to the pattern of release of endogenous dopamine, bias the synapse towards preferential induction of LTP or LTD. Finally, we discuss how endogenous dopamine crucially influences changes in synaptic plasticity induced by pathological stimuli, such as energy deprivation.     

Target-cell-specific bidirectional synaptic plasticity at hippocampal output synapses

It is commonly accepted that the hippocampus is critically involved in the explicit memory formation of mammals. The subiculum is the principal target of CA1 pyramidal cells and thus serves as the major relay station for the outgoing hippocampal information. Pyramidal cells in the subiculum can be classified according to their firing properties into burst-spiking and regular-spiking cells. In the present study we demonstrate that burst-spiking and regular-spiking cells show fundamentally different forms of low frequency-induced synaptic plasticity in rats. In burst-spiking cells, low-frequency stimulation (at 0.5–5 Hz) induces frequency-dependent long-term depression (LTD) with a maximum at 1 Hz. This LTD is dependent on the activation of NMDAR and masks an mGluR-dependent long-term potentiation (LTP). In contrast, in regular-spiking cells low-frequency stimulation induces an mGluR-dependent LTP that masks an NMDAR-dependent LTD. Both processes depend on postsynaptic Ca²⁺-signaling as BAPTA prevents the induction of synaptic plasticity in both cell types. Thus, mGluR-dependent LTP and NMDAR-dependent LTD occur simultaneously at CA1-subiculum synapses and the predominant direction of synaptic plasticity relies on the cell type investigated. Our data indicate a novel mechanism for the sliding-threshold model of synaptic plasticity, in which induction of LTP and LTD seems to be driven by the relative activation state of NMDAR and mGluR. Our observation that the direction of synaptic plasticity correlates with the discharge properties of the postsynaptic cell reveals a novel and intriguing mechanism of target specificity that may serve in tuning the significance of neuronal information by trafficking hippocampal output onto either subicular burst-spiking or regular-spiking cells.     

Suppression of hippocampal synaptic plasticity during slow-wave sleep

The influence of behavioral state on the induction of long-term enhancement (LTE) of hippocampal synapses was studied in chronically prepared animals. Perforant path evoked field potentials and EEG were recorded from fascia dentata during slow-wave sleep (SWS) and waking. LTE was strongly suppressed during SWS, suggesting that hippocampal information storage may be inactivated at certain phases of the sleep cycle. Normal LTE was observed in the same animals while awake.     

Effects of changes in glucose concentration on synaptic plasticity in hippocampal slices

The effects of a low or high concentration of glucose in the perfusion medium on synaptic activity and plasticity were studied in hippocampal slices from rats. Low-glucose medium depressed the field excitatory post-synaptic potentials (fEPSP) significantly, whereas high-glucose medium had little effect on the fEPSP. Tetanization of the afferent fibres elicited significant potentiation (LTP) of synaptic activity irrespective of the glucose concentration in the medium. This may indicate that LTP induction does not depend on optimal neural transmission. Paired-pulse facilitation (PPF) experiments showed that the medium glucose concentration did not significantly influence potentiation of the second response.     

Age-dependent alterations of long-term synaptic plasticity in thyroid-deficient rats

Thyroid hormone deficiency during a critical period of development profoundly affects cognitive functions such as attention, learning, and memory, but the synaptic alterations underlying these deficits remain unexplored. The present study examines the effect of congenital hypothyroidism on long-term synaptic plasticity. This plasticity is believed to be essential for learning and memory and for activity-dependent regulation of synapse formation in the developing brain. We found that the neonatal expression of long-term potentiation (LTP), long-term depression (LTD), depotentiation, and de-depression in hippocampal slices from hypothyroid animals was similar to that of controls. To examine the postnatal development of these plasticities, we used slices from neonatal (2-3 weeks) and adult (7-8 weeks) rats. This work demonstrates that the ability to express all these forms of synaptic plasticity is reduced in an age-dependent manner in control rats. LTP and depotentiation are also downregulated in adult hypothyroid rats, but we have found that de-depression is not affected during maturation. In addition, these animals express LTD at ages at which controls fail to induce it. In contrast, input/output experiments have shown greater levels of basal synaptic efficacy in hypothyroid adults, and this effect is probably related to the higher probability of release observed by paired-pulse experiments. Nevertheless, these effects appear to be unrelated to the differences observed in long-term synaptic plasticity, as no correlation was found between basal synaptic efficacy and the degree of LTD and de-depression. Furthermore, the NMDA-receptor antagonist amino-phosphonopentanoic acid (APV) completely blocked LTD, which suggests a postsynaptic locus of this alteration. Because LTD has been associated with novelty acquisition, we suggest that the greater LTD observed in adult hypothyroid rats might be related to the hyperactivity of these animals. However, other possibilities such as a retarded maturation of synaptic plasticity must be taken into account.     

Age-associated changes in Ca2+-dependent processes: Relation to hippocampal synaptic plasticity

Altered calcium (Ca²⁺) homeostasis is thought to play a key role in aging and neuropathology resulting in memory deficits. Several forms of hippocampal synaptic plasticity are dependent on Ca²⁺, providing a potential link between altered Ca²⁺ homeostasis and memory deficits associated with aging. The current study reviews evidence for Ca²⁺ dysregulation during aging which could interact with Ca²⁺-dependent synaptic plasticity. The authors suggest that changes in Ca²⁺ regulation could adjust the thresholds for synaptic modification, favoring processes for depression of synaptic strength during aging. Hippocampus 1997;7:602–612.     

Talking to the neighbours: The molecular and physiological mechanisms of clustered synaptic plasticity

Synaptic connectivity forms the basis for neuronal communication and the storage of information. Experiences and learning of new abilities can drive remodelling of this connectivity and promotes the formation of spine clusters; dendritic segments with a higher spine density. Spines located within these segments are frequently co-activated, undergo different dynamics than synapses located outside of this dendritic compartment and have, in general, a longer lifetime.Several lines of evidence have shown that chemical synapses located close to each other share or compete for intracellular signalling molecules and structural resources. This sharing and competition directly influences spine dynamics. Spines can grow, shrink, increase or decrease the surface expression of receptors, channels and adhesion molecules or remain stable and unchanged over extended periods of time. Here we summarize recent discoveries and provide a closer look at spine clustering, dendritic segment-specific signalling and potential molecular mechanisms underlying associative and heterosynaptic plasticity.     

Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory

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.     

The neural cell adhesion molecule in synaptic plasticity and ageing

By mediating cell adhesion and signal transduction, the neural cell adhesion molecule (NCAM) regulates neurite outgrowth, fasciculation and target recognition in the developing nervous system. In addition, a number of studies suggest an important role for the NCAM in regeneration and learning in the adult nervous system. NCAM-deficient mice are impaired in spatial learning. Moreover, by interfering with normal NCAM function by intracranial injections of NCAM-antibodies, long-term potentiation (LTP) in rat hippocampal slices and learning in rats and chicks have been inhibited. In the vertebrate nervous system, NCAM is the dominant carrier of polysialic acid (PSA), an unusual carbohydrate consisting of long homopolymers of sialic acid. The PSA-NCAM expression decreases markedly during development. However, an upregulation of polysialic acid (PSA) in restricted brain areas including the hippocampus has been observed following learning. Moreover, enzymatic removal of PSA results in impaired LTP and learning. In muscle, the PSA-NCAM expression is upregulated following denervation. This response is weakened in aging rats. The expression of NCAM and PSA have been shown to be regulated by neuronal activity suggesting that the NCAM may promote structural remodelling in an activity dependent manner associated with learning and regeneration.