Activity-dependent plasticity in descending synaptic inputs to respiratory spinal motoneurons

This review focuses on recent evidence for short- and long-term activity-dependent plasticity in descending synaptic inputs to respiratory spinal motoneurons. In anesthetized rats, application of high frequency (100 Hz) conditioning stimulation to descending inputs to phrenic motoneurons elicits short-term potentiation of spontaneous inspiratory bursts. In turtle brainstem-spinal cords in vitro, 10-100 Hz conditioning stimulation elicits short-term potentiation in descending inputs to inspiratory-related serratus motoneurons; 100 Hz stimulation also elicits long-term potentiation in some preparations. In contrast, 1-10 Hz stimulation of descending synaptic inputs to expiratory-related pectoralis motoneurons elicits depression during conditioning stimulation (temporal depression), and long-term depression following stimulation. We hypothesize that inspiratory descending pathways to spinal motoneurons express short-term potentiation, with little evidence for long-term activity-dependent plasticity; other forms of long-lasting plasticity (e.g. serotonin-dependent long-term facilitation) may predominate in these pathways. In contrast, expiratory descending pathways appear biased towards activity-dependent depression possibly to conserve resources during passive expiration.     

Age-related changes in theta frequency stimulation-induced long-term potentiation

Several signaling mechanisms that are crucial for the induction of long-term potentiation (LTP) by theta frequency (5 Hz) trains of synaptic stimulation are altered in aged animals. To determine whether theta frequency stimulation-induced LTP is particularly sensitive to changes in synaptic function that occur in aged animals, we examined whether activating synapses in the hippocampal CA1 region with three different trains of theta pulse stimulation (TPS) has different effects on synaptic strength in hippocampal slices from aged and young mice. Our results indicate that TPS-induced LTP is not diminished in the aged hippocampus but does show a dependence on L-type voltage-sensitive calcium channels that is not seen in young animals. Moreover, we found that the facilitation of TPS-induced LTP by co-activation of beta-adrenergic and cholinergic receptors is strongly reduced in slices from aged animals. Together, these results suggest that memory impairments in aged animals might arise, at least in part, from deficits in the ability of modulatory transmitters to regulate activity-dependent forms of synaptic plasticity.     

Priming-induced shift in synaptic plasticity in the rat hippocampus

The activity history of a given neuron has been suggested to influence its future responses to synaptic input in one prominent model of experience-dependent synaptic plasticity proposed by Bienenstock, Cooper, and Munro (BCM theory). Because plasticity of synaptic plasticity (i.e., metaplasticity) is similar in concept to aspects of the BCM proposal, we have tested the possibility that a form of metaplasticity induced by a priming stimulation protocol might exhibit BCM-like characteristics. CA1 field excitatory postsynaptic potentials (EPSPs) obtained from rat hippocampal slices were used to monitor synaptic responses before and after conditioning stimuli (3-100 Hz) of the Schaffer collateral inputs. A substantial rightward shift (>5-fold) in the frequency threshold between long-term depression (LTD) and long-term potentiation (LTP) was observed <1 h after priming. This change in the LTD/P crossover point occurred at both primed and unprimed synaptic pathways. These results provide new support for the existence of a rapid, heterosynaptic, experience-dependent mechanism that is capable of modifying the synaptic plasticity phenomena that are commonly proposed to be important for developmental and learning/memory processes in the brain.     

Stress-facilitated LTD induces output plasticity through synchronized-spikes and spontaneous unitary discharges in the CA1 region of the hippocampus

Long-term potentiation (LTP) and long-term depression (LTD) of the excitatory synaptic inputs plasticity in the hippocampus is believed to underlie certain types of learning and memory. Especially, stressful experiences, well known to produce long-lasting strong memories of the event themselves, enable LTD by low frequency stimulation (LFS, 3 Hz) but block LTP induction by high frequency stimulation (HFS, 200 Hz). However, it is unknown whether stress-affected synaptic plasticity has an impact on the output plasticity. Thus, we have simultaneously studied the effects of stress on synaptic plasticity and neuronal output in the hippocampal CA1 region of anesthetized Wistar rats. Our results revealed that stress increased basal power spectrum of the evoked synchronized-spikes and enabled LTD induction by LFS. The induction of stress-facilitated LTD but not LFS induced persistent decreases of the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges; However, HFS induced LTP in non-stressed animals and increased the power spectrum of the synchronized-spikes, without affecting the frequency of the spontaneous unitary discharges, but HFS failed to induce LTP in stressed animals without affecting the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges. These observations that stress-facilitated LTD induces the output plasticity through the synchronized-spikes and spontaneous unitary discharges suggest that these types of stress-related plasticity may play significant roles in distribution, amplification and integration of encoded information to other brain structures under stressful conditions.     

Differential induction of long-lasting potentiation of inhibitory postsynaptic potentials by theta patterned stimulation versus 100-Hz tetanization in hippocampal pyramidal cells in vitro

Tetanization of Schaffer collaterals, which induces long-term potentiation of excitatory transmission in the hippocampus of the rat, also affects local inhibitory circuits. Mechanisms controlling plasticity of early and late components of inhibitory postsynaptic potentials in CA1 pyramidal cells were studied using intracellular recordings and Ca2+ imaging in rat hippocampal slices. High-frequency stimulation (100 Hz/s) of Schaffer collaterals resulted in no change in the mean amplitude of early or late inhibitory postsynaptic potentials 30 min post-tetanus. However, intracellular injection of the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetate unmasked a significant increase in mean amplitude of both inhibitory postsynaptic potentials 30 min post-tetanus and the induction of this potentiation was blocked by the N-methyl-D-aspartate receptor antagonist(+/-)-2-amino-5-phosphopentanoic acid. In contrast to high-frequency tetanization, "theta-burst" stimulation in normal medium resulted in a significant potentiation of the mean amplitude of both early and late inhibitory postsynaptic potentials 30 min post-tetanus. This potentiation was blocked by the N-methyl-D-aspartate receptor antagonist. The more physiological tetanization pattern, which mimics the endogenous theta rhythm, therefore resulted in an N-methyl-D-aspartate-dependent increase in inhibition 30 min post-tetanus. Calcium imaging during whole-cell recordings from pyramidal cells revealed differences in the Ca2+ signal associated with high-frequency and theta-burst stimulations. During theta-burst stimulation of Schaffer collaterals, the mean time to peak of Ca2+ signals was significantly longer, and the mean peak amplitude and area under the Ca2+ response were larger than during high-frequency stimulation. These results indicate that tetanization induces long-lasting synaptic plasticity in hippocampal inhibitory circuits. This plasticity involves an interaction between a Ca2(+)-mediated postsynaptic depression and an N-methyl-D-aspartate-mediated potentiation of GABAA and GABAB inhibition, and these processes are differentially sensitive to tetanization parameters.     

Involvement of inositol-1,4,5-trisphosphate receptors in the bidirectional synaptic plasticity induced in hippocampal CA1 neurons by 1–10 Hz low-frequency stimulation

In the present study, both potentiation and depression of the synaptic response were induced in hippocampal CA1 neurons by systematically varying the frequency of low frequency afferent stimulation (LFS) between 0.5 and 25 Hz and the pulse number between 40 and 1000. The input–response relationship for CA1 synapses showed that LFS at a higher frequency or with a smaller pulse number increased the magnitude of potentiation of the synaptic response by increasing the contribution of N-methyl-d-aspartate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs) to induction of potentiation. One possible mechanism for this bidirectional plasticity was that specific patterns of LFS differentially activate a uniform receptor population in producing depression or potentiation of synaptic responses. However, a pharmacological study indicated that, despite their opposite effects, both the synaptic depression induced by LFS at 1 Hz and the synaptic potentiation induced by LFS at 10 Hz were triggered by co-activation of NMDARs and mGluRs at CA1 synapses. We suggest that activation of protein kinase C or inositol-1,4,5-trisphosphate receptors, both coupled to group 1 mGluRs, is involved in the bidirectional synaptic plasticity induced in hippocampal CA1 neurons by 1–10 Hz LFS.     

Inhibitory synaptic plasticity regulates pyramidal neuron spiking in the rodent hippocampus

Spike-timing modifies the efficacy of both excitatory and inhibitory synapses onto CA1 pyramidal neurons in the rodent hippocampus. Repetitively spiking the presynaptic neuron before the postsynaptic neuron induces inhibitory synaptic plasticity, which results in a depolarization of the reversal potential for GABA (E(GABA)). Our goal was to determine how inhibitory synaptic plasticity regulates CA1 pyramidal neuron spiking in the rat hippocampus. We demonstrate electrophysiologically that depolarizing E(GABA) by 24.7 mV increased the spontaneous action potential firing frequency of cultured hippocampal neurons 254% from 0.12+/-0.07 Hz to 0.44+/-0.13 Hz (n=11; P<0.05). Next we used a single compartment model of a CA1 pyramidal neuron to explore in detail how inhibitory synaptic plasticity of feedforward and feedback inhibition regulates the generation of action potentials, spike latency, and the minimum excitatory conductance required to generate an action potential; plasticity was modeled as a depolarization of E(GABA), which effectively weakens inhibition. Depolarization of E(GABA) at feedforward and feedback inhibitory synapses decreased the latency to the 1st spike by 2.27 ms, which was greater that the sum of the decreases produced by depolarizing E(GABA) at feedforward (0.85 ms) or feedback inhibitory synapses (0.02 ms) alone. In response to a train of synaptic inputs, depolarizing E(GABA) decreased the inter-spike interval and increased the number of output spikes in a frequency dependent manner, improving the reliability of input-output transmission. Moreover, a depolarizing shift in E(GABA) at feedforward and feedback synapses triggered by spike trains recorded from CA1 pyramidal layer neurons during field theta from anesthetized rats, significantly increased spiking on the up- and down-strokes of the first half of the theta rhythm (P<0.05), without changing the preferred phase of firing (P=0.783). This study provides the first explanation of how depolarizing E(GABA) affects pyramidal cell output within the hippocampus.     

Regional differences in GABAergic modulation for TEA-induced synaptic plasticity in rat hippocampal CA1, CA3 and dentate gyrus

Tetraethylammonium (TEA), a K(+)-channel blocker, reportedly induces long-term potentiation (LTP) of hippocampal CA1 synaptic responses, but at CA3 and the dentate gyrus (DG), the characteristics of TEA-induced plasticity and modulation by inhibitory interneurons remain unclear. This study recorded field EPSPs from CA1, CA3 and DG to examine the involvement of GABAergic modulation in TEA-induced synaptic plasticity for each region. In Schaffer collateral-CA1 synapses and associational fiber (AF)-CA3 synapses, bath application of TEA-induced LTP in the presence and absence of picrotoxin (PTX), a GABA(A) receptor blocker, whereas TEA-induced LTP at mossy fiber (MF)-CA3 synapses was detected only in the absence of GABA(A) receptor blockers. MF-CA3 LTP showed sensitivity to Ni(2+), but not to nifedipine. In DG, synaptic plasticity was modulated by GABAergic inputs, but characteristics differed between the afferent lateral perforant path (LPP) and medial perforant path (MPP). LPP-DG synapses showed TEA-induced LTP during PTX application, whereas at MPP-DG synapses, TEA-induced long-term depression (LTD) was seen in the absence of PTX. This series of results demonstrates that TEA-induced DG and CA3 plasticity displays afferent specificity and is exposed to GABAergic modulation in an opposite manner.     

Local circuit plasticity in the rat dentate gyrus: characterization and aging-related impairment

We have used frequency-dependent inhibition, a form of short-term plasticity mediated by the activation of inhibitory interneurons, to characterize in vivo alterations in local circuit activity and plasticity in the dentate gyrus of the anesthetized rat. The application of the GABA-A receptor blocker, bicuculline, induced a transient reduction in frequency-dependent inhibition, indicating that this form of local circuit activity is GABA-mediated. Delivering theta burst stimulation to the perforant pathway of the hippocampus induced long-term potentiation of the population excitatory post-synaptic potential, reflecting the potentiation of the perforant path-dentate gyrus granule cell synapses. Concomitantly, theta burst stimulation caused a lasting reduction in frequency-dependent inhibition. In aged rats, long-term potentiation could be induced to the same level as in young rats, but while in young rats frequency-dependent inhibition was concomitantly reduced, frequency-dependent inhibition in the old rats did not show this form of plasticity.Our results indicate that theta burst stimulation induces a form of local circuit plasticity independently of its known capacity to induce synaptic plasticity, and that this form of local circuit plasticity is compromised in aging. Based on these results we propose a potential role for plasticity at the level of the local circuit in learning and memory.     

Activity-dependent synaptic plasticity in the supraoptic nucleus of the rat hypothalamus

Activity-dependent long-term synaptic changes were investigated at glutamatergic synapses in the supraoptic nucleus (SON) of the rat hypothalamus. In acute hypothalamic slices, high frequency stimulation (HFS) of afferent fibres caused long-term potentiation (LTP) of the amplitude of AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) recorded with the whole-cell patch-clamp technique. LTP was also obtained in response to membrane depolarization paired with mild afferent stimulation. On the other hand, stimulating the inputs at 5 Hz for 3 min at resting membrane potential caused long-term depression (LTD) of excitatory transmission in the SON. These forms of synaptic plasticity required the activation of NMDA receptors since they were abolished in the presence of d -AP5 or ifenprodil, two selective blockers of these receptors. Analysis of paired-pulse facilitation and trial-to-trial variability indicated that LTP and LTD were not associated with changes in the probability of transmitter release, thereby suggesting that the locus of expression of these phenomena was postsynaptic. Using sharp microelectrode recordings in a hypothalamic explant preparation, we found that HFS also generates LTP at functionally defined glutamatergic synapses formed between the organum vasculosum lamina terminalis and SON neurons. Taken together, our findings indicate that glutamatergic synapses in the SON exhibit activity-dependent long-term synaptic changes similar to those prevailing in other brain areas. Such forms of plasticity could play an important role in the context of physiological responses, like dehydration or lactation, where the activity of presynaptic glutamatergic neurons is strongly increased.     

内侧隔核注射Aβ25-35抑制大鼠海马CA1区theta节律

目的:研究内侧隔核(MS)注射淀粉样蛋白25-35片段(Aβ25-35)对大鼠海马CA1区theta节律和长时程增强(LTP)的影响。方法:选用成年雄性SD大鼠,在其MS分别注射Aβ25-35和生理盐水,经一周恢复后,乌拉坦麻醉状态下进行海马CA1区theta节律和场兴奋性突触后电位的在体记录。结果:MS注射Aβ25-35后,经夹尾诱发的大鼠海马CA1区theta节律(3-4 Hz)的功率(22.7±1.84 dB)明显较对照组(30.6±1.91 dB)降低(P<0.01),但与对照组相比Aβ25-35不影响海马CA1区基础性突触传递和高频刺激诱发的LTP(P>0.05)。结论:MS注射Aβ25-35可显著抑制海马CA1区theta节律,提示这可能会影响动物的探索行为,但Aβ对MS造成的伤害尚不足以改变海马CA1区的突触可塑性。     

GABAB Receptor- and Metabotropic Glutamate Receptor-Dependent Cooperative Long-Term Potentiation of Rat Hippocampal GABAA Synaptic Transmission

Repetitive stimulation of Schaffer collaterals induces activity-dependent changes in the strength of polysynaptic inhibitory postsynaptic potentials (IPSPs) in hippocampal CA1 pyramidal neurons that are dependent on stimulation parameters. In the present study, we investigated the effects of two stimulation patterns, theta-burst stimulation (TBS) and 100 Hz tetani, on pharmacologically isolated monosynaptic GABAergic responses in adult CA1 pyramidal cells. Tetanization with 100 Hz trains transiently depressed both early and late IPSPs, whereas TBS induced long-term potentiation (LTP) of early IPSPs that lasted at least 30 min. Mechanisms mediating this TBS-induced potentiation were examined using whole-cell recordings. The paired-pulse ratio of monosynaptic inhibitory postsynaptic currents (IPSCs) was not affected during LTP, suggesting that presynaptic changes in GABA release are not involved in the potentiation. Bath application of the GABA_B receptor antagonist CGP55845 or the group I/II metabotropic glutamate receptor antagonist E4-CPG inhibited IPSC potentiation. Preventing postsynaptic G-protein activation or Ca²⁺ rise by postsynaptic injection of GDP-β-S or BAPTA, respectively, abolished LTP, indicating a G-protein- and Ca²⁺-dependent induction in this LTP. Finally during paired-recordings, activation of individual interneurons by intracellular TBS elicited solely short-term increases in average unitary IPSCs in pyramidal cells. These results indicate that a stimulation paradigm mimicking the endogenous theta rhythm activates cooperative postsynaptic mechanisms dependent on GABA_BR, mGluR, G-proteins and intracellular Ca²⁺, which lead to a sustained potentiation of GABA_A synaptic transmission in pyramidal cells. GABAergic synapses may therefore contribute to functional synaptic plasticity in adult hippocampus.     

Heterosynaptic correlates of long-term potentiation induction in hippocampal CA3 neurons

Previous studies have demonstrated that tetanization of hippocampal mossy fibers induces a long-term potentiation of non-tetanized (heterosynaptic) non-mossy fiber afferents (Schaffer collateral/commissural and fimbrial fibers). Tetanization of these non-mossy fiber afferents, in contrast, does not induce mossy fiber long-term potentiation, but induces a long-term depression of mossy fiber responses (Bradler and Barrionuevo, Synapse 4, 132-142, 1989). The synaptic activity necessary to evoke these heterosynaptic alterations of efficacy is not known. Specifically, the dependence of heterosynaptic efficacy on the activation of N-methyl-D-aspartate receptors has not been assessed. In addition, the capability of different afferents to CA3 neurons to support alterations in heterosynaptic efficacy remains largely unknown. In the present study, heterosynaptic alterations of efficacy in the rat did not require the activation of N-methyl-D-aspartate receptors. Mossy fibers supported N-methyl-D-aspartate receptor-independent heterosynaptic long-term depression, and N-methyl-D-aspartate receptor-independent long-term potentiation. In contrast, non-mossy fiber afferents expressed N-methyl-D-aspartate receptor-independent heterosynaptic long-term potentiation induced by a mossy fiber tetanus, and an N-methyl-D-aspartate receptor-independent long-term depression, in addition to N-methyl-D-aspartate receptor-dependent homosynaptic long-term potentiation. The possibility that non-N-methyl-D-aspartate receptor activity in non-tetanized afferents is necessary for heterosynaptic long-term potentiation induction is discussed. Heterosynaptic long-term depression was induced in the absence of homosynaptic long-term potentiation, suggesting that these concomitant forms of synaptic plasticity rely on different mechanisms.     

State-dependent plasticity of the corticostriatal pathway

Plasticity at corticostriatal synapses is thought to underlie both normal and aberrant forms of reinforcement-driven learning. Studies in brain slices have found bidirectional, spike-timing dependent plasticity in striatum; however it is not known whether similar rules govern corticostriatal plasticity in awake behaving animals. To assess whether behavioral state is a key regulator of plasticity in this pathway, we examined the effects of 5 Hz cortical stimulation trains on evoked striatal field potentials, in either anesthetized or awake, unrestrained rats. Consistent with prior studies we observed long-term potentiation in intact, barbiturate-anesthetized animals. However, when an identical stimulation pattern was applied to the same animals while awake, long-term depression was observed instead. Our results demonstrate that the rules governing corticostriatal plasticity depend critically on behavioral state, and suggest that the dynamic context of cortical-basal ganglia loops must be considered while investigating synaptic mechanisms underlying reinforcement learning and neurological disorders.     

GABA(B) receptor activation mediates frequency-dependent plasticity of developing GABAergic synapses

Activity-induced long-term modification of glutamatergic synapses depends on the frequency of synaptic activation. We found that long-term modification of developing rat hippocampal GABAergic synapses that was induced by repetitive coincident pre- and postsynaptic spiking was also frequency dependent. Spiking at 20-50 Hz resulted in synaptic potentiation, whereas spiking at 5 Hz led to synaptic depression. The potentiation was abolished by blocking GABA(B) receptors (GABA(B)Rs), whereas the depression was independent of GABA(B)R activation and could be converted to potentiation by elevating GABA(B)R activity. The potentiation could be attributed to a local postsynaptic increase in Na(+)/K(+)/2Cl(-) co-transporter activity near activated synapses. The activity of postsynaptic Ca(2+)/calmodulin-dependent protein kinase II was necessary for long-term potentiation of these developing GABAergic synapses and its phosphorylation at Thr286 could be enhanced by activating GABA(B)Rs with baclofen. Together with our finding that activation of GABA(B)Rs is frequency dependent, these results indicate that postsynaptic GABA(B)R activation mediates frequency-dependent potentiation of developing GABAergic synapses.     

The potassium channel modulator flupirtine shifts the frequency-response function of hippocampal synapses to favour LTD in mice

Flupirtine is a centrally acting nonopioid analgesic with muscle-relaxant properties. Flupirtine has been found to activate inwardly rectifying potassium conductances and hence to indirectly inhibit the activation of NMDA receptors. NMDA receptor activation is crucial for the induction of long-term potentiation (LTP) of synaptic transmission, which is considered as cellular correlate of learning and memory and of central sensitization in chronic pain states. Although flupirtine has been widely used for the management of pain, its effects on synaptic plasticity have not yet been investigated. We, therefore, performed extracellular and whole-cell patch-clamp recordings in hippocampal slices of mice to examine the effects of flupirtine on synaptic plasticity and neuronal membrane properties. Excitatory postsynaptic potentials (EPSPs) in the CA1 region were evoked alternately by stimulating two independent Schaffer collateral-commissural inputs. LTP and long-term depression (LTD) were induced by different stimulation paradigms (100 Hz, 10 Hz, 5 Hz, and 1 Hz). Flupirtine (30 μM) diminished the degree of LTP and enhanced LTD. This effect is most likely due to the hyperpolarization of CA1 pyramidal neurons and the reduction of their input resistance found after application of flupirtine. The observed effects on synaptic strength could underly the beneficial effects of flupirtine on different types of chronic pain.     

A possible mechanism for the effect of modifiable lateral inhibition in the striatum on the selection of conditioned reflex motor responses

A mechanism is proposed for the effects of striatal dopamine-modifiable lateral inhibition on the selection of conditioned reflex motor responses. According to this mechanism, activation of dopamine D1 (D2) receptors on strionigral (striopallidal) neurons facilitates long-term depression (potentiation) of the inhibitory inputs simultaneously with potentiation (depression) of the excitatory inputs, of sufficient strength to open NMDA channels. For “ weak” excitation, insufficient to open NMDA channels, the modification rules were of the opposite sign. Activation of presynaptic D2 (D1) receptors leads to decreases (increases) in GABA release from strionigral (striopallidal) axon terminals innervating strionigral (striopallidal) cells. As a result, dopamine-modifiable lateral inhibition simultaneously increases both the potentiation (depression) of the excitatory inputs to “strongly” activated strionigral (striopallidal) neurons, increasing (decreasing) their activity, and increases the depression (potentiation) of the excitatory inputs to the “weakly” activated strionigral (striopallidal) neurons, decreasing (increasing) their activity. Subsequent reorganization of neuron activity in the cortex-basal ganglia-thalamus-cortex circuit facilitates selection of conditioned reflex motor responses by further increasing (decreasing) the activity of those motor cortex neurons which were “strongly” (“weakly”) excited by the striatum in conditions of dopamine release in response to the conditioned stimulus. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 55, No. 4, pp. 444–458, July–August, 2005.     

Hippocampal CA1 synaptic plasticity as a gamma transfer function

The capacity of activity-dependent synaptic modification is essential in processing and storing information, yet little is known about how synaptic plasticity alters the input-output conversion efficiency at the synapses. In the adult mouse hippocampus in vivo, we carefully compared the input-output relationship, in terms of presynaptic activity levels versus postsynaptic potentials, before and after the induction of synaptic plasticity and found that synaptic plasticity led synapses to respond more robustly to inputs, that is, synaptic gain was increased as a function of synaptic activity with an expansive, power-law nonlinearity, i.e. conforming to the so-called gamma curve. In extreme cases, long-term potentiation and depression coexist in the same synaptic pathway with long-term potentiation dominating over long-term depression at higher levels of presynaptic activity. These findings predict a novel function of synaptic plasticity, i.e. a contrast-enhancing filtering of neural information through a gamma correction-like process.     

Long-term depression in the sensorimotor cortex induced by repeated delivery of 10 Hz trains in vivo

Memory consolidation in the neocortex is thought to be mediated in part by bi-directional modifications of synaptic strength. The sensorimotor cortex shows marked spontaneous activity near 10 Hz during both waking and sleep in the form of electroencephalographic spindle waves, and is also sensitive to electrical activation of inputs at 10 Hz. Induction of long-term synaptic depression in corpus callosum inputs to layer V of the sensorimotor cortex of the awake, adult rat requires repeated low-frequency stimulation over many days. To determine if 10 Hz stimulation may facilitate the induction of long-term depression, we compared the amounts of long-term depression induced by conventional 1 Hz trains, repeated delivery of 450 pairs of stimulation pulses using a 100 ms interpulse interval, and 45 short, 2 s, 10 Hz trains. Each pattern was delivered daily for 10 days and was matched for total duration and number of pulses. Changes in synaptic responses were assessed by monitoring field potentials evoked by stimulation of the corpus callosum. A facilitation of synaptic responses in layer V was observed during delivery of both paired-pulse trains and 10 Hz trains. There was no significant difference in long-term depression induced by 1 Hz stimulation and repeated paired-pulse stimulation, but 10 Hz trains induced significantly greater long-term depression than 1 Hz trains in both the early monosynaptic and late polysynaptic field potential components. The effectiveness of short 10 Hz trains for the induction of long-term depression suggests that synchronous population activity at frequencies near 10 Hz such as spindle waves may contribute to endogenous synaptic depression in sensorimotor cortex.     

Glucocorticoid receptor activation selectively hampers N-methyl-D-aspartate receptor dependent hippocampal synaptic plasticity in vitro

Corticosterone and exposure to stressful experiences have been reported to decrease hippocampal synaptic plasticity, in particular when relatively mild stimulation paradigms-presumably activating predominantly N-methyl-d-aspartate receptors-are being used. Using various stimulation paradigms and pharmacological approaches we tested therefore the hypothesis that elevated corticosterone levels, by activating glucocorticoid receptors, predominantly hamper N-methyl-D-aspartate receptor dependent synaptic plasticity in vitro. To address this, mouse hippocampal slices were treated for 20 min with corticosterone (100 nM) or vehicle and synaptic efficacy was examined 1-6 h later. First, we found that primed burst potentiation and synaptic potentiation after 10 Hz stimulation are predominantly N-methyl-D-aspartate receptor dependent, and are significantly suppressed after corticosterone treatment. Second, these latter effects were prevented by treating slices with the glucocorticoid receptor antagonist mifepristone prior to and during corticosterone administration. Third, theta burst potentiation, which was shown to involve activation of both N-methyl-D-aspartate receptors, voltage-dependent calcium channels and possibly other mechanisms, was not affected by corticosterone. However, theta-burst potentiation in the presence of nifedipine-singling out primarily the N-methyl-D-aspartate receptor dependent component-was reduced by corticosterone. These results indicate that corticosterone, via glucocorticoid receptor activation, selectively hampers N-methyl-D-aspartate receptor dependent synaptic plasticity in vitro and leaves more complex forms of long term potentiation unaffected. We speculate that these effects are involved in the impairment of cognitive performance by corticosteroid hormones after exposure to stressful and traumatic experiences.