Expression Of Long-term Potentiation Research Articles

Involvement of multiple phosphatidylinositol 3-kinase-dependent pathways in the persistence of late-phase long term potentiation expression

The mechanisms responsible for the stabilization and persistence of synaptic plasticity remain largely unknown. In this study, we investigated the time course of the dependence of late-phase long term potentiation of field excitatory post-synaptic potential on phosphatidylinositol 3-kinase and its downstream effectors mTOR and AKT. In agreement with our previous results obtained on an early-phase long-term potentiation paradigm we observed that application of a nanomolar concentration of wortmannin (100nM) 1 h after late-phase long term potentiation induction reversed potentiation completely. However, application of wortmannin 4 h after late-phase long term potentiation induction resulted in a more limited reduction of field excitatory post-synaptic potential suggesting that the dependence of late-phase long term potentiation expression on phosphatidylinositol 3-kinase decreases over time. Application of a nanomolar concentration of rapamycin (200nM) during the tetanization paradigm prevented the induction of late-phase long term potentiation consistent with our earlier results. Application of rapamycin 1 h after late-phase long term potentiation induction resulted in a less pronounced though significant decline of field excitatory post-synaptic potential. Immunohistological analysis demonstrated that the concentration of rapamycin used was effective in inhibiting the phosphorylation of p70S6K at Thr389, the main determinant of its pro-translational activity, and that Thr389 phosphorylation recovered after washout. Lastly, a transient application of Akt inhibitor I (10μM) one hour after late-phase long term potentiation induction also induced a partial although significant reduction of potentiated field excitatory post-synaptic potential that stabilized at a level of approximately 114% of baseline three hours after application, suggesting that AKT also contributes to the stabilization of late-phase long term potentiation expression. These results confirm and extend previous observations that the expression of long term potentiation in the CA1 of rat hippocampus involves several elements of the phosphatidylinositol 3-kinase signaling pathway.

Deletion of the nuclear receptor Nr2e1 impairs synaptic plasticity and dendritic structure in the mouse dentate gyrus

The spontaneous or targeted deletion of the nuclear receptor transcription factor Nr2e1 produces a mouse that shows hypoplasia of the hippocampal formation and reduced neurogenesis in adult mice. In these studies we show that hippocampal synaptic transmission appears normal in the dentate gyrus and cornu ammonis 1 subfields of adult mice that lack Nr2e1 ( Nr2e1 −/−), and that fEPSP shape, paired-pulse responses, and short-term plasticity are not substantially altered in either subfield. In contrast, the expression of long-term potentiation is selectively impaired in the dentate gyrus, and not in the cornu ammonis 1 subfield. Golgi analysis revealed that there was a significant reduction in both dendritic branching and dendritic length that was specific to dentate gyrus granule cells in the Nr2e1 −/− mice. These results indicate that Nr2e1 deletion can significantly alter both synaptic plasticity and dendritic structure in the dentate gyrus.

Rapid eye movement sleep deprivation in post-critical period, adolescent rats alters the balance between inhibitory and excitatory mechanisms in visual cortex

Suppression of rapid eye movement sleep (REMS) in developing animals has both anatomical and physiological consequences. We have recently shown that initiating REMS deprivation (REMSD) prior to the end of the critical period in young rats delays termination of the critical period (CP) in visual cortex, and, consequently, the synaptic plasticity mechanisms that support a developmentally regulated form of long-term potentiation (LTP) are maintained in an immature state [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431–443]. In CP animals, high-frequency, theta burst stimulation (TBS) directed at the white matter (WM) below visual cortex produces LTP in the post-synaptic cells in layer II/III (LTPWM-III). However, LTPWM-III can be induced in cortical tissue taken from REMS-deprived animals for up to a week beyond the usual end of the CP [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431–443]. Further, in post-CP, adolescent animals (as late as postnatal day 60), REMSD appears to unmask synaptic plasticity mechanisms that allow for production of developmentally regulated LTPWM-III [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. It has been proposed that REMSD's effects on production of LTPWM-III result from a reduction in efficiency of the inhibitory mechanisms thought to precipitate termination of the CP of brain development [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. In this study we tested the hypothesis that low-frequency stimulation (LFS) of the fibers of the WM, which usually produces the related form of synaptic plasticity, long-term depression (LTD), will also reflect the reduction in inhibitory tone. We report here that LFS protocols, which in normally sleeping, adolescent rats usually produce either LTD or no change in response magnitude, in REMS-deprived, adolescent rats are more likely to produce LTP.

LTP Regulates Burst Initiation and Frequency at Mossy Fiber–Granule Cell Synapses of Rat Cerebellum: Experimental Observations and Theoretical Predictions

Long-term potentiation (LTP) is a synaptic change supposed to provide the cellular basis for learning and memory in brain neuronal circuits. Although specific LTP expression mechanisms could be critical to determine the dynamics of repetitive neurotransmission, this important issue remained largely unexplored. In this paper, we have performed whole cell patch-clamp recordings of mossy fiber-granule cell LTP in acute rat cerebellar slices and studied its computational implications with a mathematical model. During LTP, stimulation with short impulse trains at 100 Hz revealed earlier initiation of granule cell spike bursts and a smaller nonsignificant spike frequency increase. In voltage-clamp recordings, short AMPA excitatory postsynaptic current (EPSC) trains showed short-term facilitation and depression and a sustained component probably generated by spillover. During LTP, facilitation disappeared, depression accelerated, and the sustained current increased. The N-methyl-d-aspartate (NMDA) current also increased. In agreement with a presynaptic expression caused by increased release probability, similar changes were observed by raising extracellular [Ca(2+)]. A mathematical model of mossy fiber-granule cell neurotransmission showed that increasing release probability efficiently modulated the first-spike delay. Glutamate spillover, by causing tonic NMDA and AMPA receptor activation, accelerated excitatory postsynaptic potential (EPSP) temporal summation and maintained a sustained spike discharge. The effect of increasing neurotransmitter release could not be replicated by increasing receptor conductance, which, like postsynaptic manipulations enhancing intrinsic excitability, proved very effective in raising granule cell output frequency. Independent regulation of spike burst initiation and frequency during LTP may provide mechanisms for temporal recoding and gain control of afferent signals at the input stage of cerebellar cortex.

The birth (and adolescence) of LTP

The birth (and adolescence) of LTP

Expression of the mu‐opioid receptor is induced in dentate gyrus granule cells after focal cerebrocortical ischaemia and stimulation of entorhinal afferents

Focal ischaemia in the cerebral cortex affects the inducibility of long-term potentiation (LTP) in the hippocampus. This impairment of hippocampal function may result from excessive activation of cortico-hippocampal afferents and subsequent perturbation of hippocampal LTP-relevant transmitter systems, which include opioids. Here, we tested if permanent focal ischaemia and electrical afferent stimulation influence the expression of the mu-opioid receptor (MOR) in the rat hippocampus. In the applied ischaemia model, the entire ipsilateral cortical hemisphere and hippocampus experienced sustained excitation as indicated by a long-lasting increase in the expression of arg 3.1/arc (ARG) mRNA, a marker for neuronal activity. Expression of MOR mRNA and protein was strongly increased in granule cells, which contain very low MOR levels under normal conditions, but not in gamma-aminobutyric acid (GABA)ergic neurons, which express the MOR constitutively. In the molecular layer, which contains the dendrites of granule cells, focal ischaemia caused a redistribution of MOR-like immunoreactivity. In contrast to the dentate gyrus, MOR expression was unaltered in the hippocampus proper and in non-infarcted cortical areas. Repetitive high-frequency stimulation of cortico-hippocampal perforant path afferents induced strong MOR mRNA expression throughout the granular layer. However, weak tetanization sufficient to induce LTP and ARG expression did not influence MOR mRNA levels. Taken together, we provide direct evidence for the induction of MOR expression in granule cells experiencing sustained excitation by cortical afferents. In activated, MOR-expressing granule cells, inhibitory opioids may counter-regulate glutamatergic excitation by the perforant path.

Homosynaptic and Heterosynaptic Inhibition of Synaptic Tagging and Capture of Long-Term Potentiation by Previous Synaptic Activity

Long-term potentiation (LTP) is an enhancement of synaptic strength that may contribute to information storage in the mammalian brain. LTP expression can be regulated by previous synaptic activity, a process known as "metaplasticity." Cell-wide occurrence of metaplasticity may regulate synaptic strength. However, few reports have demonstrated metaplasticity at synapses that are silent during activity at converging synaptic inputs. We describe a novel form of cell-wide metaplasticity in hippocampal area CA1. Low-frequency stimulation (LFS) decreased the stability of long-lasting LTP ["late" LTP (L-LTP)] induced later at the same inputs (homosynaptic inhibition) and at other inputs converging on the same postsynaptic cells (heterosynaptic inhibition). Significantly, heterosynaptic inhibition of L-LTP also occurred across basal and apical dendrites ("heterodendritic" inhibition). Because transient early LTP (E-LTP) was not affected by previous LFS, we examined the effects of LFS on the consolidation of E-LTP to L-LTP. The duration of E-LTP induced at one set of inputs can be extended by capturing L-LTP-associated gene products generated by previous activity at other inputs to the same postsynaptic neurons. LFS applied homosynaptically or heterosynaptically before L-LTP induction did not impair synaptic capture by subsequent E-LTP stimulation, suggesting that LFS does not impair L-LTP-associated transcription. In contrast, LFS applied just before E-LTP (homosynaptically or heterosynaptically) prevented synaptic tagging, and capture of L-LTP expression. Thus, LFS inhibits synaptic tagging to impair expression of subsequent L-LTP. Such anterograde inhibition represents a novel way in which synaptic activity can regulate the expression of future long-lasting synaptic plasticity in a cell-wide manner.

Interaction between paired-pulse facilitation and long-term potentiation in the projection from hippocampal area CA1 to the entorhinal cortex

The hippocampus communicates with the neocortex via the entorhinal cortex and is thought to be critically involved in the consolidation of memories. This paper contains in vivo evidence of a projection from the hippocampal area CA1 to the entorhinal cortex. Current theories of memory formation suggest that the backprojections from the hippocampus to the neocortex should undergo some form of plastic change in order that memories become consolidated. Paired-pulse facilitation (PPF) and long-term potentiation (LTP) are forms of short- and long-term plasticity, respectively. We show that the CA1 to entorhinal cortex projection is capable of sustaining PPF over a wide range of stimulus intervals. In addition we demonstrate that following high frequency stimulation of this pathway the evoked response in the entorhinal cortex remains potentiated for at least 30 min. Finally, we demonstrate that PPF changes following LTP depending on the initial ratio of PPF, suggesting that LTP expression on this pathway may contain a presynaptic component. These findings should provide insight into the hippocampal function in memory formation.

Psychosocial stress-induced hypertension results from in vivo expression of long-term potentiation in rat sympathetic ganglia

Long-term potentiation in sympathetic ganglia (gLTP) is an activity-dependent unique form of synaptic plasticity in that it is serotonin-dependent and can be completely inhibited by 5-HT3 receptor antagonists. Long lasting enhancement of the basal tone of ganglionic transmission seen with gLTP results in a sustained increase in peripheral resistance that leads to elevated blood pressure. We examined the possibility that, in sympathetic ganglia, stress-induced gLTP may be responsible for the expression of stress hypertension. Chronic treatment of male and female Wistar rats with a 5-HT3 receptor antagonist, tropisetron (ICS; 5 mg/kg/day) or ondansetron (0.5 mg/kg/day), prevented or reversed psychosocial stress-induced increases in blood pressure in stressed rats with no significant effect on blood pressure of unstressed control rats. Pharmacological and electrophysiological evidence that supports the presence of gLTP in ganglia isolated from stressed hypertensive rats includes inhibition of basal synaptic transmission by 5-HT3 antagonists, failure to induce gLTP with repetitive stimulation indicating occlusion of gLTP due to saturation and a left hand shift of the input/output curve. We suggest that a sustained stress-induced increase in central sympathetic efferent impulses to ganglia may provide the repeated high frequency presynaptic activity required to induce gLTP in sympathetic ganglia, thereby enhancing sympathetic tone to blood vessels resulting in hypertension.

Agonists of peroxisome proliferator-activated receptor-γ attenuate the Aβ-mediated impairment of LTP in the hippocampus in vitro

The data we present here suggest that agonists of peroxisome proliferator-activated receptor-γ (PPARγ) can attenuate the effects of beta-amyloid peptide (Aβ). Alzheimer's disease is associated with elevated levels of Aβ, and enhanced expression of PPARγ. In this study, we determined that application of Aβ [1–40] could impair hippocampal post-tetanic potentiation (PTP) and long-term potentiation (LTP) in vitro. We investigated the effects of PPARγ agonists; troglitazone, ciglitazone and 15-deoxy-Δ 12,14 prostaglandin J 2 (PGJ 2) on synaptic transmission and plasticity in area CA1. Both ciglitazone and PGJ 2 increased baseline synaptic transmission significantly, without altering paired-pulse facilitation. PGJ 2 produced a significant reduction in LTP, whereas ciglitazone and troglitazone had no significant effect. In addition, prior application of each ligand attenuated the previously observed Aβ [1–40]-mediated impairment of LTP. The effect of troglitazone on the Aβ [1–40]-mediated impairment of LTP was not reversed by the PPARγ antagonist, GW-9662. These findings demonstrate that PPARγ agonists attenuate the effects of Aβ on LTP, and support the potential use of these agents to alleviate the symptoms of Alzheimer's disease. We also suggest that PPARγ agonists may regulate expression of hippocampal LTP in vitro.

Memory consolidation of Pavlovian fear conditioning requires nitric oxide signaling in the lateral amygdala

Nitric oxide (NO) has been widely implicated in synaptic plasticity and memory formation. In studies of long-term potentiation (LTP), NO is thought to serve as a 'retrograde messenger' that contributes to presynaptic aspects of LTP expression. In this study, we examined the role of NO signaling in Pavlovian fear conditioning. We first show that neuronal nitric oxide synthase is localized in the lateral nucleus of the amygdala (LA), a critical site of plasticity in fear conditioning. We next show that NO signaling is required for LTP at thalamic inputs to the LA and for the long-term consolidation of auditory fear conditioning. Collectively, the findings suggest that NO signaling is an important component of memory formation of auditory fear conditioning, possibly as a retrograde signal that participates in presynaptic aspects of plasticity in the LA.

The Metabotropic Glutamate Receptor mGluR3 is Critically Required for Hippocampal Long-term Depression and Modulates Long-term Potentiation in the Dentate Gyrus of Freely Moving Rats

Group II metabotropic glutamate receptors (mGluRs) play an important role in the regulation of hippocampal synaptic plasticity in vivo: long-term potentiation (LTP) is inhibited and long-term depression (LTD) is enhanced by activation of these receptors. The contribution, in vivo, of the individual group II mGluR subtypes has not been characterized. We analysed the involvement of the subtype mGluR3 in LTD and LTP. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path-dentate gyrus synapses. Neither the selective mGluR3 agonist, N-acetylaspartylglutamate (NAAG), nor the antagonist beta-NAAG, given intracerebrally, affected basal synaptic transmission. beta-NAAG significantly inhibited LTD expression. NAAG exhibited transient inhibitory effects on the intermediate phase of LTD. Whereas NAAG altered paired-pulse responses, beta-NAAG had no effect, suggesting that antagonism of mGluR3 prevents LTD via a postsynaptic mechanism, whereas agonist activation of mGluR3 modulates LTD at a presynaptic locus. NAAG impaired the expression of LTP, whereas beta-NAAG had no effect. NAAG effects on LTP were blocked by EGLU, a selective group II mGluR antagonist. Our data suggest an essential role for mGluR3 in LTD, and a modulatory role for mGluR3 in LTP, with effects being mediated by distinct pre- and post-synaptic loci.

Pharmacological antagonism of metabotropic glutamate receptor 1 regulates long‐term potentiation and spatial reference memory in the dentate gyrus of freely moving rats via N‐methyl‐d‐aspartate and metabotropic glutamate receptor‐dependent mechanisms

Group I metabotropic glutamate receptors (mGluRs) are critically required for multiple forms of hippocampal synaptic plasticity in vivo. The role of the receptor subtype mGluR1 in long-term potentiation (LTP) and learning is unclear. We examined the contribution of mGluR1 to hippocampal LTP and spatial learning using the selective antagonist (S)-(+)-alpha-amino-4carboxy-2-methylbenzene-acetic acid (LY367385). Male Wistar rats were chronically implanted with recording and stimulating electrodes to enable measurement of evoked potentials from medial perforant path-dentate gyrus granule cell synapses. An injection cannula was inserted into the ipsilateral cerebral ventricle to enable drug application. Experiments were begun 10 days after the implantation procedure. We induced a robust LTP which lasted over 25 h with a 200-Hz tetanization. Injections of LY367385 at all concentrations under investigation (4-32 nmol in a 5-microL injection volume) did not affect basal synaptic transmission. In contrast, we observed a dose-dependent impairment of LTP expression: LY367385 (4 nmol) had no effect on LTP induction, whereas 8 and 16 nmol LY367385 reduced both LTP induction and expression, suggestive of an interaction with N-methyl-d-aspartate receptors. We assessed the effects of daily LY367385 application (8 nmol) on performance in an eight-arm radial maze. LY367385-treated rats showed deficits in reference but not working memory performance compared with vehicle-treated controls. Rearing, grooming and locomotor activity were unaffected by LY367385. These data suggest an important role for mGluR1 in LTP and learning and highlight the specific significance of this mGluR subtype for reference memory.

Epileptogenic insult causes a shift in the form of long-term potentiation expression

The relationship between epilepsy, modeled here by pentylenetetrazol kindling, and learning deficits, modeled here by long-term potentiation (LTP), was studied. The field excitatory postsynaptic potentials and population spikes (PS) were recorded from strata radiatum and pyramidale, respectively, in urethane-anesthetized rat dorsal hippocampus CA1 area upon stimulation of Schaffer collaterals. To induce LTP, a 100Hz primed-burst stimulation protocol was used. Experiments were carried out at approximately 30 days after the last pentylenetetrazol dose. The effects of voltage dependent calcium channel blocker verapamil and N-methyl- d-aspartate receptor antagonist MK-801 on LTP expression were examined. Tetanic stimulation elicited both field excitatory postsynaptic potential LTP and PS LTP in control animals, and LTP-induction of the PS in control animals was attenuated by MK-801, but not by verapamil. By contrast, kindled rats showed LTP of the PS only. MK-801 reduced the extent of potentiation of PS amplitude and verapamil inhibited the PS amplitude potentiation, completely. The results suggest that seizure induction modifies mechanisms underlying LTP induction and causes a shift in the form of LTP expression. The pentylenetetrazol-kindling-induced increase in PS LTP is sensitive to verapamil and not to MK-801 and therefore primarily dependent on activation of voltage dependent calcium channels rather N-methyl- d-aspartate receptors. Kindling may lead to a shift in synaptic plasticity thresholds much like the shift that occurs during aging, and such alterations may contribute to deficits in learning and memory.

Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus

Late fetal and early postnatal iron deficiency (ID) is a common condition that causes learning and memory impairments in humans while they are iron deficient and following iron repletion. Rodent models of fetal ID demonstrate significant short- and long-term hippocampal structural and biochemical abnormalities that may predispose hippocampal area CA1 to abnormal electrophysiology. Rat pups made iron deficient during the fetal and early postnatal period were assessed for basal synaptic transmission, paired-pulse facilitation (PPF), and long-term potentiation (LTP) in CA1 at postnatal days (P)15 and P30 while iron deficient and at P65 following iron repletion. Our results showed no differences in basal synaptic transmission between iron sufficient and iron deficient pups at P15 or P30, but the ID group did fail to demonstrate the expected developmental increase in synaptic strength by P65 (P < 0.05). Similarly, PPF ratios from iron deficient slices also failed to demonstrate the characteristic developmental changes seen in the iron sufficient group (P < 0.001). Iron deficient slices retained a developmentally immature P15 pattern of LTP expression at P30 and after iron repletion, and LTP expression was lower (P < 0.05) in the iron deficient group at P65. Thus, ID in the fetal and early postnatal period delays or abolishes the developmental maturation of electrophysiological components of synaptic efficacy and plasticity, resulting in abnormalities beyond the period of deficiency. These findings provide a functional corroboration to previous structural and biochemical abnormalities found in the iron deficient rat hippocampus and provide a potential model for learning and memory deficits seen in humans exposed to fetal and early postnatal ID.

Synergistic effects of the peptide fragment D-NAPVSIPQ on ethanol inhibition of synaptic plasticity and NMDA receptors in rat hippocampus

The L1 cell adhesion molecule has been implicated in ethanol teratogenesis as well as NMDAR-dependent long-term potentiation (LTP) of synaptic transmission, a process thought to be critical for neural development. Ethanol inhibits LTP at least in part by interacting with NMDA receptors. Ethanol also inhibits L1-mediated cell adhesion in a manner that is prevented by an octapeptide, D-NAPVSIPQ (D-NAP), as well as long chain alcohols such as 1-octanol. Here we analyzed the effects of D-NAP and 1-octanol on ethanol modulation of LTP induced by theta burst stimulation in two subfields of the rat hippocampus, the dentate gyrus and area CA1. When theta burst stimulation was delivered in ethanol (50mM), LTP was inhibited by about 50%. Surprisingly, when D-NAP (10 −7M) and ethanol were co-applied or applied sequentially, LTP was completely absent. The effects of D-NAP were persistent, since delivery of a second theta burst stimulation following washout of D-NAP and ethanol elicited minimal plasticity. Application of D-NAP alone had no effect on LTP induction or expression. The synergistic effect of D-NAP on ethanol inhibition of LTP was concentration-dependent since D-NAP (10 −10M) had an intermediate effect, while D-NAP (10 −13M) had no effect on ethanol suppression of LTP. These observations were also replicated with a different ethanol antagonist, 1-octanol, in area CA1. To address the mechanisms underlying this long-lasting suppression of LTP, the sensitivity of pharmacologically isolated NMDAR extracellular field potentials to combinations of D-NAP and ethanol was determined. D-NAP (10 −7M) alone had no effect on NMDA extracellular field potentials; however, the peptide significantly increased the inhibitory action of ethanol on NMDA extracellular field potential. The findings suggest that D-NAP and 1-octanol selectively interact with NMDA receptors in an ethanol-dependent manner, further implicating the L1 cell adhesion molecule in alcohol-related brain disorders.

The neuro-biomolecular basis of alertness in sleep disorders

Sleep is present in all species in which it has been studied, but its functions remain unknown. Identification of the molecular correlates of sleep and wakefulness is essential if we are to understand the restorative processes that occur during sleep, the cellular mechanisms that underlie sleep regulation, and the functional consequences of sleep loss and poor quality sleep. To address the questions of how we know whether sleep has performed its functions and whether treatment has improved sleep quality, we have proposed a synaptic homeostasis hypothesis about the significance of slow wave activity (SWA) during sleep and its homeostatic regulation. Briefly, the hypothesis states that (1) wakefulness is associated with potentiation in several cortical circuits; (2) synaptic potentiation is then tied to the homeostatic regulation of SWA; (3) SWA is associated with synaptic downscaling; and (4) synaptic downscaling is tied to the beneficial effects of sleep on performance. According to this hypothesis, the potentiation of neural circuits that results from synaptic plasticity during alert wakefulness is responsible for SWA homeostasis. Increasing noradrenergic activity increases the expression of long-term potentiation (LTP)-related genes, and interference with these changes block the induction of markers of synaptic potentiation during alert wakefulness. Inducing local LTP-like changes during alert wakefulness also results in increased local slow wave homeostasis. Thus, as SWA homeostasis can be induced on a local level or can be triggered by a learning task, and is strongly correlated with postsleep performance enhancement, plasticity during alert wakefulness depends on good sleep, which, in turn, depends on efficient synaptic downscaling.

Autonomous activity of CaMKII is only transiently increased following the induction of long‐term potentiation in the rat hippocampus

A major role has been postulated for a maintained increase in the autonomous activity of CaMKII in the expression of long-term potentiation (LTP). However, attempts to inhibit the expression of LTP with CaMKII inhibitors have yielded inconsistent results. Here we compare the changes in CaMKII autonomous activity and phosphorylation at Thr286 of alphaCaMKII in rat hippocampal slices using chemical or tetanic stimulation to produce either LTP or short-term potentiation (STP). Tetanus-induced LTP in area CA1 requires CaMKII activation and Thr286 phosphorylation of alphaCaMKII, but we did not observe an increase in autonomous activity. Next we induced LTP by 10 min exposure to 25 mM tetraethyl-ammonium (TEA) or 5 min exposure to 41 mM potassium (K) after pretreatment with calyculin A. Exposure to K alone produced STP. These protocols allowed us to monitor temporal changes in autonomous activity during and after exposure to the potentiating chemical stimulus. In chemically induced LTP, autonomous activity was maximally increased within 30 s whereas this increase was significantly delayed in STP. However, in both LTP and STP the two-fold increase in autonomous activity measured immediately after stimulation was short-lived, returning to baseline within 2-5 min after re-exposure to normal ACSF. In LTP, but not in STP, the phosphorylation of alphaCaMKII at Thr286 persisted for at least 60 min after stimulation. These results confirm that LTP is associated with a maintained increase in autophosphorylation at Thr286 but indicate that a persistent increase in the autonomous activity of CaMKII is not required for the expression of LTP.

The 5-Hydroxytryptamine4 Receptor Exhibits Frequency-dependent Properties in Synaptic Plasticity and Behavioural Metaplasticity in the Hippocampal CA1 Region In vivo

Long-term plasticity, in the forms of long-term depression (LTD) and long-term potentiation (LTP), of synaptic transmission are thought to underlie memory. Biogenic amino acids modulate the expression of LTD and LTP. The serotonergic 5-hydroxytryptamine4 (5-HT4) receptor has been shown to influence learning and memory. However, little is known about the role of this receptor in synaptic plasticity. Here we show that although induction of LTP is unaffected by either pharmacological activation or inhibition of 5-HT4, application of the 5-HT4 receptor agonist, RS67333, completely blocks learning-induced depotentiation of LTP in the hippocampal CA1 region of freely moving rats, suggesting a role for 5-HT4 receptors in behavioural metaplasticity. In addition, the 5-HT4 antagonist RS39604 enhances the intermediate phase of LTD and converts short-term depression into persistent LTD (>24 h), suggesting a significant role for 5-HT4 receptors in the expression of LTD in CA1. Stimulation at 10 Hz causes transient synaptic depression. However, 5-HT4 antagonist application prior to 10 Hz stimulation leads to LTD, whereas agonist application leads to LTP expression. 5-HT4 receptors thus shift the frequency-response relationship for induction of plasticity. Together, these findings suggest a key role for 5-HT4 receptors in the regulation of synaptic plasticity and the determination of the particular properties of stored synaptic information.

Changes in the paired-pulse ratio after long-term potentiation induced by 2- and 100-Hz tetanus in rat visual cortical slices

The effects of 2- and 100-Hz tetanus on long-term potentiation (LTP) of field potentials recorded from layers II/III and induced in layer IV in rat visual cortical slices were examined. Paired-pulse stimulation was used to probe the different mechanisms of LTP induced by 2- and 100-Hz tetanus. The paired-pulse ratio (PPR) decreased after the LTP induced by 2-Hz tetanus, with the changes in PPR being correlated with LTP amplitude. However, in the LTP induced by 100-Hz tetanus, the changes in PPR were not correlated with LTP expression. These experiments suggest that an enhanced probability of presynaptic transmitter release underlies LTP induced by 2-Hz tetanus, but not LTP induced by 100-Hz tetanus.