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PubMed1996

Ethanol effects on synaptic neurotransmission and tetanus-induced synaptic plasticity in hippocampal slices of chronic in vivo lead-exposed adult rats.

The interaction of chronic in vivo lead exposure and acute in vitro ethanol treatment on synaptic neurotransmission and plasticity were studied using extracellular electrophysiological techniques in CA1 region of hippocampal brain slices from adult rats. Neither chronic lead exposure nor acute ethanol treatment had any significant effect on field excitatory postsynaptic potentials (EPSPs). In vivo lead exposure enhanced short-term potentiation (STP, potentiation that decays within 30 min) by 21% shortly after 'weak' tetanus, but had no effect on long-term potentiation (LTP, sustained at least 1 h). In vitro bath application of 60 mM ethanol inhibited STP by 35% and blocked LTP induced by 'weak' tetanus in slices from Pb exposed rats (500 ppm lead acetate, 56-70 days), while having no effect on STP or LTP in slices from control counterpart Na-exposed rats (pair-fed 216 ppm sodium acetate). In contrast, 'strong'-tetanus-induced LTP was abolished in Pb-exposed slices, and 60 mM ethanol slightly inhibited STP and blocked LTP in slices from Na-exposed rats. These differences could not be explained by differences in ethanol inhibition of NMDA-mediated field EPSPs because they were similarly reduced in slices from Na-exposed (30%) and Pb-exposed (25%) rats. These findings suggest that the strength of the tetanus used determines whether or not synaptic plasticity is blocked by either chronic lead exposure or acute ethanol treatment, and that even in adult rats, hippocampal synaptic LTP can be compromised by combined exposure to ethanol and lead. More importantly, these findings suggest the consequences of combined lead exposure and alcohol abuse in the adult human population may not be fully recognized yet.

Animals↗
PubMed1999

Dendritic spine changes associated with hippocampal long-term synaptic plasticity.

Long-term enhancement of synaptic efficacy in the hippocampus is an important model for studying the cellular mechanisms of neuronal plasticity, circuit reorganization, and even learning and memory. Although these long-lasting functional changes are easy to induce, it has been very difficult to demonstrate that they are accompanied or even caused by morphological changes on the subcellular level. Here we combined a local superfusion technique with two-photon imaging, which allowed us to scrutinize specific regions of the postsynaptic dendrite where we knew that the synaptic changes had to occur. We show that after induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrite or in slices where long-term potentiation was blocked, no significant spine growth occurred.

Animals↗
PubMed1999

Synaptic plasticity and the organization of behaviour after early and late brain injury.

Hebb proposed that synaptic change underlies behavioural and cognitive plasticity. When applied to recovery from brain injury, the general hypothesis is that if there is recovery following brain injury, then there ought to be a correlated synaptic change, which is presumed to be responsible for recovery. In contrast, if recovery fails to occur, or expected recovery is blocked in some manner, then the synaptic change will likely not be present. Systematic study of functional recovery and synaptic change following brain injury at different ages supports these predictions. Good recovery is always correlated with enhanced connectivity whereas poor recovery is always correlated with an absence of reorganized connectivity. Furthermore, factors that stimulate recovery, such as neurotrophins or experience, stimulate synaptic change and functional recovery. Factors that retard recovery, such as depletion of neuromodulators, also block synaptic change. These results thus support Hebb's general idea that synaptic plasticity is related to behavioural change.

Age of Onset↗
PubMed2003

Age-related differences in synaptic plasticity following muscle unloading.

The objective of the present investigation was to determine the effects of muscle unloading-a form of subtotal disuse- on the morphology of the neuromuscular junction (NMJ) in younger and aged animals. Sixteen aged (22 months) and 16 young adult (8 months) male Fischer 344 rats were assigned to control and hindlimb suspension (HS) conditions (n=8/group). At the conclusion of the 4 week experimental period, soleus muscles were collected, and immunofluorescent procedures were used to visualize acetylcholine (ACh) vesicles and receptors, nerve terminal branching, as well as NCAM and NT-4 expression. Quantitative analyses revealed that aged controls displayed significant (p<0.05) reductions in area and perimeter length of ACh vesicle and receptor regions, without affecting nerve terminal branch number or length. In contrast to younger NMJs, which were resilient to the effects of unloading, NMJs of aged HS rats demonstrated significant expansion of ACh vesicle and receptor dimensions compared to aged controls. Qualitative analyses of NCAM staining indicated that aging alone somewhat increased this molecule's expression (aged controls>young controls). Among the four groups, however, the greatest amount of NCAM content was detected among aged HS muscles, matching the degree of synaptic plasticity exhibited in those muscles. Unlike NCAM, the expression of NT-4 did not appear to differ among the treatment groups. These data suggest that although young adult muscle maintains normal NMJ structure during prolonged exposure to unloading, aged NMJs experience significant adaptation to that stimulus.

Acetylcholine↗
PubMed2005

Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity.

Amyloid-beta (Abeta), a peptide thought to play a crucial role in Alzheimer's disease (AD), has many targets that, in turn, activate different second-messenger cascades. Interestingly, Abeta has been found to markedly impair hippocampal long-term potentiation (LTP). To identify a new pathway that might be responsible for such impairment, we analyzed the role of the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK)/cAMP-responsive element-binding protein (CREB) cascade because of its involvement in LTP. The use of the NO donor 2-(N,N-dethylamino)-diazenolate-2-oxide diethylammonium salt (DEA/NO), the sGC stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine, or the cGMP-analogs 8-bromo-cGMP and 8-(4-chlorophenylthio)-cGMP reversed the Abeta-induced impairment of CA1-LTP through cGK activation. Furthermore, these compounds reestablished the enhancement of CREB phosphorylation occurring during LTP in slices exposed to Abeta. We also found that Abeta blocks the increase in cGMP immunoreactivity occurring immediately after LTP and that DEA/NO counteracts the effect of Abeta. These results strongly suggest that, when modulating hippocampal synaptic plasticity, Abeta downregulates the NO/cGMP/cGK/CREB pathway; thus, enhancement of the NO/cGMP signaling may provide a novel approach to the treatment of AD and other neurodegenerative diseases with elevated production of Abeta.

Alzheimer Disease↗
PubMed2000

Dopamine and synaptic plasticity in the neostriatum.

After the unilateral destruction of the dopamine input to the neostriatum there are enduring changes in rat behaviour. These have been ascribed to the loss of dopamine and the animals are often referred to as 'hemiparkinsonian'. In the denervated neostriatum, we have shown that not only are the tyrosine hydroxylase positive boutons missing, but also the medium sized densely spiny output cells have fewer spines. Spines usually have asymmetric synapses on their heads. In a recent stereological study we were able to show that there is a loss of approximately 20% of asymmetric synapses in the lesioned neostriatum by 1 mo after the lesion. Current experiments are trying to establish the specificity of this loss. So far we have evidence suggesting that there is no obvious preferential loss of synapses from either D1 or D2 receptor immunostained dendrites in the neostriatum with damaged dopamine innervation. These experiments suggest that dopamine is somehow necessary for the maintenance of corticostriatal synapses in the neostriatum. In a different series of experiments slices of cortex and neostriatum were maintained in vitro in such a way as to preserve at least some of the corticostriatal connections. In this preparation we have been able to show that cortical stimulation results in robust excitatory postsynaptic potentials (EPSPs) recorded from inside striatal neurons. Using stimulation protocols derived from the experiments on hippocampal synaptic plasticity we have shown that the usual consequence of trains of high frequency stimulation of the cortex is the depression of the size of EPSPs in the striatal cell. In agreement with similar experiments by others, the effect seems to be influenced by NMDA receptors since the unblocking of these receptors with low Mg++ concentrations in the perfusate uncovers a potentiation of the EPSPs after trains of stimulation. Dopamine applied in the perfusion fluid round the slices has no effect but pulsatile application of dopamine, close to the striatal cell being recorded from, and in temporal association with the cortical trains, leads to a similar LTP like effect. The reduction of K+ channel conductance in the bath with TEA also has the effect of making cortical trains induce potentiation of corticostriatal transmission. TEA applied only to the cell being recorded from has no similar effect; the cortical stimulation again depresses the EPSP amplitude, so the site of action of TEA may well be presynaptic to the striatal cell. The morphological and physiological experiments may not necessarily be related but it is tempting to suggest that dopamine protects some corticostriatal synapses by potentiating them but that in the absence of dopamine others simply disconnect and are no longer detectable on electron microscopy.

Animals↗
PubMed2006

Caspase-like activity is essential for long-term synaptic plasticity in the terrestrial snail Helix.

Although caspase activity in the nervous system of mollusks has not been described before, we suggested that these cysteine proteases might be involved in the phenomena of neuroplasticity in mollusks. We directly measured caspase-3 (DEVDase) activity in the Helix lucorum central nervous system (CNS) using a fluorometrical approach and showed that the caspase-3-like immunoreactivity is present in the central neurons of Helix. Western blots revealed the presence of caspase-3-immunoreactive proteins with a molecular mass of 29 kDa. Staurosporin application, routinely used to induce apoptosis in mammalian neurons through the activating cleavage of caspase-3, did not result in the appearance of a smaller subunit corresponding to the active caspase in the snail. However, it did increase the enzyme activity in the snail CNS. This suggests differences in the regulation of caspase-3 activity in mammals and snails. In the snail CNS, the caspase homolog seems to possess an active center without activating cleavage typical for mammals. In electrophysiological experiments with identified snail neurons, selective blockade of the caspase-3 with the irreversible and cell-permeable inhibitor of caspase-3 N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp-(OMe)-fluoro-methylketone prevented development of the long-term stage of synaptic input sensitization, suggesting that caspase is necessary for normal synaptic plasticity in snails. The results of our study give the first direct evidence that the caspase-3-like activity is essential for long-term plasticity in the invertebrate neurons. This activity is presumably involved in removing inhibitory constraints on the storage of long-term memory.

Animals↗
PubMed1999

Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression.

Streptozotocin-diabetic rats, an animal model for diabetes mellitus, show learning deficits and impaired long-term potentiation in the CA1-field of the hippocampus. The present study aimed to further characterize the effects of streptozotocin-diabetes on N-methyl-D-aspartate receptor-dependent long-term potentiation in the CA1-field, to extend these findings to N-methyl-D-aspartate receptor-dependent and independent long-term potentiation in other regions of the hippocampus and to examine effects on long-term depression. First, the effect of diabetes duration on long-term potentiation in the CA1-field was determined. A progressive deficit was observed after a diabetes duration of six to eight weeks, which reached a maximum after 12 weeks of diabetes and remained stable thereafter. Next, long-term potentiation was examined in the dentate gyrus and in the CA3-field after 12 weeks of diabetes. Both were found to be impaired compared to controls. Finally, long-term depression was examined in the CA1-field of the hippocampus after 12 weeks of diabetes and found to be enhanced in slices from diabetic rats compared to controls. Changes in synaptic plasticity were observed in hippocampal slices from streptozotocin-diabetic rats. Expression of N-methyl-D-aspartate receptor-dependent long-term potentiation was impaired in the CA1-field and dentate gyrus and expression of N-methyl-D-aspartate receptor-independent long-term potentiation was impaired in the CA3-field. In contrast, expression of long-term depression was facilitated in CA1. It is suggested that this combination of changes in plasticity may reflect alterations in intracellular signalling pathways.

Animals↗
PubMed2001

Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor.

NMDA receptor, Ca(2+)/calmodulin-dependent protein kinase II (alphaCaMKII), and postsynaptic density 95 (PSD-95) are three major components of the PSD fraction. Both alphaCaMKII and PSD-95 have been shown previously to bind NR2 subunits of the NMDA receptor complex. The nature and mechanisms of targeting to the NMDA receptor subunits are, however, not completely understood. Here we report that the C-terminal NR2A(S1389-V1464) sequence was sufficient to guarantee the association of both native and recombinant alphaCaMKII and PSD-95. PSD-95(54-256) was able to compete with the binding of both native and recombinant alphaCaMKII to the NR2A C-tail. Accordingly, alphaCaMKII(1-325) competes with both the native PSD-95 and the native kinase itself for the binding to NR2A. In addition, Ser/Ala1289 and Ser/Asp1289 point mutations on the unique CaMKII phosphosite of NR2A did not significantly influence the binding of native alphaCaMKII and PSD-95 to the NR2A C-tail. Finally, the association-dissociation of alphaCaMKII and PSD-95 to and from the NR2A C-tail was significantly modulated by activation of NMDA receptor achieved by either pharmacological tools or long-term potentiation induction, underlining the importance of dynamic and reciprocal interactions of NMDA receptor, alphaCaMKII, and PSD-95 in hippocampal synaptic plasticity.

Animals↗
PubMed1997

Synaptic plasticity of 5-hydroxytryptamine-immunoreactive terminals in the phrenic nucleus following spinal cord injury: a quantitative electron microscopic analysis.

The present study was conducted to examine the plasticity of 5-hydroxytryptamine (5-HT)-immunoreactive terminals in the rat phrenic nucleus following an ipsilateral C2 spinal cord hemisection and 30-day survival period. A retrograde horseradish peroxidase (HRP) labeling technique was used to identify the phrenic motoneurons at the electron microscopic (EM) level. After employing a pre-embedding immunocytochemical technique, the ultrastructural characteristics of 5-HT-immunoreactive terminals were qualitatively and then quantitatively analyzed with a computerized morphometric system before and after injury in separate groups of rats. The results indicated that the majority of the 5-HT-labeled terminals formed axodendritic contacts, but some 5-HT-labeled terminals made axosomatic contacts. 5-HT terminals were associated with either asymmetrical or symmetrical synapses, and some displayed postsynaptic dense bodies. Approximately 2% of the 5-HT terminals had dense-core vesicles. Although the total number of labeled and unlabeled terminals in the phrenic nucleus was reduced after hemisection, the number of 5-HT terminals in the hemisected group was greater than that of the control group. Moreover, the total number and length of asymmetrical and symmetrical synaptic active zones per 5-HT terminal were significantly greater after injury. Finally, the total number of 5-HT terminals with multiple synapses was significantly greater in the hemisected group as compared to controls. It is possible that 5-HT synaptic plasticity may be part of the morphological substrate for the unmasking of the latent crossed phrenic pathway which mediates recovery of the ipsilateral hemidiaphragm paralyzed by C2 spinal cord hemisection.

Animals↗
PubMed2000

Cell-specific changes in expression of mRNAs encoding splice variants of aplysia cell adhesion molecule accompany long-term synaptic plasticity.

Aplysia neurons express several splice variants of apCAM, a member of the Ig superfamily of cell adhesion molecules. The major transmembrane isoform is endocytosed in sensory neurons (SNs) during the early phases of long-term facilitation (LTF) of SN synapses evoked by serotonin (5-HT) or in the motor neuron L7 during the early phases of long-term depression (LTD) of SN synapses evoked by Phe-Met-Arg-Phe-amide (FMRFa). We used single cell RT-PCR to evaluate whether expression of mRNAs encoding for different apCAM isoforms in SNs and L7 is regulated during LTF produced by 5-HT, and LTD produced by FMRFa. Single SNs and L7s express mRNAs encoding for all major isoforms, but the proportion of each isoform expressed differs for the two cells. SN expresses more mRNA encoding for GPI-linked isoforms, while L7 expresses more mRNA encoding for the major transmembrane isoform. The neuromodulators produced significant changes in the proportional levels of mRNAs encoding for specific apCAM isoforms during the first 4 h after treatments without affecting overall levels of apCAM mRNA. 5-HT evoked changes that exaggerated cell-specific differences in isoform expression. FMRFa evoked changes that reduced cell-specific differences in isoform expression. The effects of the neuromodulators on apCAM mRNA expression were not detected when cells were cultured alone or when SNs were cocultured with another motor cell that failed to induce synapse formation (L11). The results suggest that rapid cell-specific regulation of splice variant expression may contribute to different forms of long-term synaptic plasticity.

Alternative Splicing↗
PubMed1997

Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring.

Prenatal ethanol exposure has been associated with long-lasting intellectual impairments in children. Previous studies using animal models of fetal ethanol exposure suggest that these deficits are, at least in part, linked to neurochemical abnormalities in the hippocampal formation. We explored whether prenatal exposure to moderate quantities of ethanol produced functional deficits at the entorhinal cortical perforant path-dentate granule cell connection by examining some electrophysiological properties, including the induction of long-term potentiation (LTP). Rat dams consumed one of three diets throughout gestation: 1) a BioServ liquid diet containing 5% (v/v) ethanol (26% ethanol-derived calories), which produces a maternal peak blood ethanol concentration of 83 mg/dl; 2) pair-fed an isocalorically equivalent amount of 0% ethanol liquid diet; or 3) Purina rat chow ad libitum. Adult offspring (120-150 days of age) from each experimental diet group were anesthetized with urethane and field excitatory postsynaptic potentials (EPSPs) and population spikes were measured in the dentate gyrus in response to ipsilateral perforant path stimulation. We examined input-output functions using a wide range of single pulse stimulation intensities and induction of LTP using high-frequency stimulation. In the 50-500 microA range of single pulse intensities, there were no significant differences among the diet groups in dentate gyrus evoked potentials. In response to high-frequency stimulation, prenatal ethanol-exposed rats showed a smaller increase in field EPSPs and population spikes compared with rats from either of the two control groups. Thus, prenatal exposure to moderate ethanol levels can produce a long-lasting deficit in synaptic enhancement in a neural pathway believed to be critical in certain forms of learning and memory. This deficit in hippocampal synaptic plasticity may, in part, account for cognitive impairments seen in children whose mothers consumed ethanol during pregnancy.

Analysis of Variance↗
PubMed1989

Synaptic plasticity in the hippocampus is modulated by behavioral state.

The possible influence of the sleep-waking cycle on evoked neurotransmission and on the induction of long-term potentiation (LTP) and depression (LTD) was studied in the perforant path-granule cell system. Freely moving rats received a high-frequency stimulus train (8 bursts at 400 Hz) during slow-wave sleep (SWS), rapid eye movement (REM) sleep, and a still-alert (SAL) behavioral state. Trains applied during SAL and REM reliably elicited LTP of the excitatory postsynaptic potential (EPSP) slope, population spike height, and spike onset latency. Granule cell excitability was also enhanced, as indicated by a leftward shift of the EPSP-population spike (E-S) relation. In contrast, tetanization in SWS rarely produced 'classical' LTP and often failed to elicit any lasting change in field potentials. Furthermore, the following types of E-S change occurred almost exclusively after tetanization in SWS: (1) LTP of the EPSP accompanied by depression of the population spike, and (2) E-S potentiation without a change in EPSP. When LTP occurred, however, its magnitude was independent of the animal's behavioral state at the time of the train. In agreement with previous reports, the efficacy of low-frequency neurotransmission varied with behavioral state. A modulation index (MI) was introduced to quantify the difference between field potentials evoked in SAL and SWS. Interestingly, both the occurrence and magnitude of LTP were related to the strength of the MI, as determined in each rat before the train. After trains, the state-dependent modulation of transmission was maintained and was superimposed on LTP and LTD. The results suggest that synaptic plasticity is dynamically modulated during the sleep-wakefulness cycle.

Animals↗
PubMed2002

Synaptic plasticity in the pathway from the medial geniculate body to the lateral amygdala is induced by seizure repetition.

Repeated induction of generalized audiogenic seizures (AGS) (AGS kindling) induces expansion of the seizure network and evokes additional convulsive behaviors. The medial geniculate body (MGB) and amygdala are implicated in the network expansion induced by AGS kindling, although these sites are not required for AGS before kindling. A recent study indicated that amygdala neuronal responses are greatly increased by AGS kindling. The present study examined the effects of AGS kindling on the thalamo-amygdala pathway in genetically epilepsy-prone rats (GEPR-9s) by examining the neuronal responses in lateral amygdala (LAMG) to electrical stimulation in MGB in vivo. AGS kindling in GEPR-9s involved 14 AGS in response to twice daily acoustic stimulation. Sham-kindled normals received the mean stimulation parameters presented to kindled animals. Spontaneous LAMG extracellular action potentials (APs) and APs evoked by electrical stimuli in the MGB were examined in ketamine-anesthetized rats. The mean spontaneous LAMG firing in kindled GEPR-9s was significantly elevated as compared to non-kindled GEPRs, sham-kindled and non-kindled normals. LAMG firing evoked by MGB stimuli in kindled GEPR-9s was significantly elevated, and a significant mean threshold reduction was also observed in kindled GEPR-9s, as compared to other animal groups. These changes may be due to enhanced glutamate receptor-mediated excitation and/or compromised GABA receptor-mediated inhibition in AMG, as previously reported in electrical kindling in the amygdala. These findings indicate that AGS kindling increases the efficacy of the thalamo-amygdala pathway in GEPR-9s, suggesting that synaptic plasticity in this portion of the expanded neuronal network is an important pathophysiological mechanism subserving AGS kindling.

Acoustic Stimulation↗
PubMedDate not supplied

Synaptic plasticity: keeping synapses under control.

Recent studies have confirmed that a retrograde signal is produced at the neuromuscular junction that can adjust the efficacy of transmission to meet long-term changing needs. Genetic manipulations in Drosophila have begun to define the circumstances in which such signals are generated and how they act.

Animals↗