Synapse-specific mGluR1-dependent long-term potentiation in interneurones regulates mouse hippocampal inhibition

Hippocampal CA1 inhibitory interneurones control the excitability and synchronization of pyramidal cells, and participate in hippocampal synaptic plasticity. Pairing theta-burst stimulation (TBS) with postsynaptic depolarization, we induced long-term potentiation (LTP) of putative single-fibre excitatory postsynaptic currents (EPSCs) in stratum oriens/alveus (O/A) interneurones of mouse hippocampal slices. LTP induction was absent in metabotropic glutamate receptor 1 (mGluR1) knockout mice, was correlated with the postsynaptic presence of mGluR1a, and required a postsynaptic Ca²⁺ rise. Changes in paired-pulse facilitation and coefficient of variation indicated that LTP expression involved presynaptic mechanisms. LTP was synapse specific, occurring selectively at synapses modulated by presynaptic group II, but not group III, mGluRs. Furthermore, the TBS protocol applied in O/A induced a long-term increase of polysynaptic inhibitory responses in CA1 pyramidal cells, that was absent in mGluR1 knockout mice. These results uncover the mechanisms of a novel form of interneurone synaptic plasticity that can adaptively regulate inhibition of hippocampal pyramidal cells.     

Kinase-dependent modification of dendritic excitability after long-term potentiation

Patterns of presynaptic activity properly timed with postsynaptic action potential output can not only increase the strength of synaptic inputs but can also increase the excitability of dendritic branches of adult CA1 pyramidal neurons. Here, we examined the role of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) in the enhancement of dendritic excitability that occurs during theta-burst pairing of presynaptic and postsynaptic firing activity. Using dendritic and somatic whole-cell recordings in rat hippocampal slices, we measured the increase in the amplitude of back-propagating action potentials in the apical dendrite that occurs in parallel with long-term potentiation (LTP) of synaptic inputs. We found that inhibition of the MAPK pathway prevents this enhancement of dendritic excitability using either a weak or strong LTP induction protocol, while synaptic LTP can still be induced by the strong protocol. Both forms of plasticity are blocked by inhibition of PKA and occluded by interfering with cAMP degradation, consistent with a PKA-mediated increase in MAPK activity following induction of LTP. This provides a signalling mechanism for plasticity of dendritic excitability that occurs during neuronal activity and demonstrates the necessity of MAPK activation. Furthermore, this study uncovers an additional contribution of kinase activation to plasticity that may occur during learning.     

Aging effects on the limits and stability of long-term synaptic potentiation and depression in rat hippocampal area CA1

Altered hippocampal synaptic plasticity may underlie age-related memory impairment. In acute hippocampal slices from aged (22-24 mo) and young adult (1-12 mo) male Brown Norway rats, extracellular excitatory postsynaptic field potentials were recorded in CA1 stratum radiatum evoked by Schaffer collateral stimulation. We used enhanced Ca(2+) to Mg(2+) ratio and paired-pulse stimulation protocol to induce maximum changes in the synaptic plasticity. Six episodes of theta-burst stimulation (TBS) or nine episodes of paired low-frequency stimulation (pLFS) were used to generate asymptotic long-term potentiation (LTP) and long-term depression (LTD), respectively. In addition, long-term depotentiation (LTdeP) or de-depression (LTdeD) from maximal LTP and LTD were examined using two episodes of pLFS or TBS. Multiple episodes of TBS or pLFS produced significant LTP or LTD in aged and young adult rats; this was not different between age groups. Moreover, there was no significant difference in the amount of LTdeP or LTdeD between aged and young adult rats. Our results show no age differences in the asymptotic magnitude of LTP or LTD, rate of synaptic modifications, development rates, reversal, or decay after postconditioning. Thus impairment of the basic synaptic mechanisms responsible for expression of these forms of plasticity is not likely to account for decline in memory function within this age range.     

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.     

Enhanced intrinsic excitability and EPSP-spike coupling accompany enriched environment-induced facilitation of LTP in hippocampal CA1 pyramidal neurons

Environmental enrichment (EE) is a well-established paradigm for studying naturally occurring changes in synaptic efficacy in the hippocampus that underlie experience-induced modulation of learning and memory in rodents. Earlier research on the effects of EE on hippocampal plasticity focused on long-term potentiation (LTP). Whereas many of these studies investigated changes in synaptic weight, little is known about potential contributions of neuronal excitability to EE-induced plasticity. Here, using whole-cell recordings in hippocampal slices, we address this gap by analyzing the impact of EE on both synaptic plasticity and intrinsic excitability of hippocampal CA1 pyramidal neurons. Consistent with earlier reports, EE increased contextual fear memory and dendritic spine density on CA1 cells. Furthermore, EE facilitated LTP at Schaffer collateral inputs to CA1 pyramidal neurons. Analysis of the underlying causes for enhanced LTP shows EE to increase the frequency but not amplitude of miniature excitatory postsynaptic currents. However, presynaptic release probability, assayed using paired-pulse ratios and use-dependent block of N-methyl-d-aspartate receptor currents, was not affected. Furthermore, CA1 neurons fired more action potentials (APs) in response to somatic depolarization, as well as during the induction of LTP. EE also reduced spiking threshold and after-hyperpolarization amplitude. Strikingly, this EE-induced increase in excitability caused the same-sized excitatory postsynaptic potential to fire more APs. Together, these findings suggest that EE may enhance the capacity for plasticity in CA1 neurons, not only by strengthening synapses but also by enhancing their efficacy to fire spikes-and the two combine to act as an effective substrate for amplifying LTP.     

Action potential-induced dendritic calcium dynamics correlated with synaptic plasticity in developing hippocampal pyramidal cells.

In hippocampal CA1 pyramidal cells, intracellular calcium increases are required for induction of long-term potentiation (LTP), an activity-dependent synaptic plasticity. LTP is known to develop in magnitude during the second and third postnatal weeks in the rats. Little is known, however, about development of intracellular calcium dynamics during the same postnatal weeks. We investigated postnatal development of intracellular calcium dynamics in the proximal apical dendrites of CA1 pyramidal cells by whole cell patch-clamp recordings and calcium imaging with the Ca(2+) indicator fura-2. Dendritic calcium increases induced by intrasomatically evoked action potentials were slight during the first postnatal week but gradually became robust 3 to 6-fold during the second and third postnatal weeks. These calcium increases were blocked by application of 250 microM CdCl(2), a nonspecific blocker for high-threshold voltage-dependent calcium channels (VDCCs). Under the voltage-clamp condition, both calcium currents and dendritic calcium accumulations induced by depolarization were larger at the late developmental stage (P15-18) than the early stage (P4-7), indicating developmental enhancement of calcium influx mediated by high-threshold VDCCs. Moreover, theta-burst stimulation (TBS), a protocol for LTP induction, induced large intracellular calcium increases at the late developmental stage, in synchrony with maturation of TBS-induced LTP. These results suggest that developmental enhancement of intracellular calcium increases induced by action potentials may underlie maturation of calcium-dependent functions such as synaptic plasticity in hippocampal neurons.     

Induction of long-term potentiation at hippocampal mossy-fiber synapses follows a Hebbian rule

1. The induction of long-term potentiation (LTP) at hippocampal mossy-fiber synapses requires an increase in postsynaptic [Ca2+]i but is independent of N-methyl-D-aspartate (NMDA) receptor activation. Voltage-gated Ca2+ channels have been proposed as one alternative source for raising [Ca2+]i during the induction of LTP. We tested the hypothesis that voltage-gated Ca2+ channel activation could mediate the induction of LTP by examining whether 1) the induction of mossy-fiber LTP was dependent on postsynaptic depolarization and 2) depolarization alone, of a magnitude presumably capable of activating Ca2+ channels, was sufficient to induce LTP. 2. Intracellular recordings were made from rat CA3 pyramidal cells in the hippocampal slice preparation under both current- and voltage-clamp conditions. Mossy-fiber postsynaptic potentials and currents were recorded before and after high-frequency stimulation (HFS) in the presence of 20-50 microM D-2-amino-5-phosphonovaleric acid (D-APV), an NMDA-receptor antagonist. 3. Voltage clamping of CA3 neurons between -80 and -100 mV during HFS reversibly blocked the induction of mossy-fiber LTP. Conversely, HFS paired with depolarizing-current steps under current clamp increased the magnitude of LTP compared with controls. These results indicate that mossy-fiber LTP is dependent on postsynaptic depolarization, and presynaptic activation alone was not sufficient to induce mossy-fiber LTP. 4. Depolarizing-current injections, which presumably depolarized CA3 cells to potentials sufficient to activate voltage-gated Ca2+ channels, had no effect on mossy-fiber synaptic responses. These results suggest that synaptic activation, in addition to postsynaptic depolarization, is required for the induction of mossy-fiber LTP. 5. Single mossy-fiber afferent volleys were also paired with depolarizing-current pulses. In the presence of APV, pairing of single-mossy-fiber excitatory postsynaptic potentials (EPSPs) with postsynaptic depolarization did not potentiate synaptic responses, suggesting that some form of HFS is also required for mossy-fiber LTP. In the absence of APV, however, the contamination of mossy-fiber synaptic responses by CA3-recurrent inputs resulted in some potentiation. 6. These results suggest that the induction of mossy-fiber LTP is dependent on both pre- and postsynaptic activity and thus follows a Hebbian rule for synaptic modification. In contrast to that demonstrated at Schaffer-collateral-commissural synapses, however, the induction of mossy-fiber LTP may require HFS in addition to postsynaptic depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)     

Requirement of dendritic calcium spikes for induction of spike-timing-dependent synaptic plasticity

Spike-timing-dependent synaptic plasticity (STDP) by definition requires the temporal association of pre- and postsynaptic action potentials (APs). Yet, in cortical pyramidal neurons pairing unitary EPSPs with single APs at low frequencies is ineffective at generating plasticity. Using recordings from synaptically coupled layer 5 pyramidal neurons, we show here that high-frequency (200 Hz) postsynaptic AP bursts, rather than single APs, are required for both long-term potentiation (LTP) induction and NMDA channel activation during EPSP–AP pairing at low frequencies. Furthermore, we find that AP bursts can lead to LTP induction and NMDA channel activation during EPSP–AP pairing at both positive and negative times. High-frequency AP bursts generated supralinear calcium signals in basal dendrites suggesting the generation of dendritic calcium spikes, as has been observed previously in apical dendrites during AP burst firing at frequencies greater than 100 Hz. Consistent with a role of these dendritic calcium spikes in LTP induction, pairing EPSPs with low frequency (50 Hz) AP bursts was ineffective in generating LTP. Furthermore, supralinear calcium signals in basal dendrites during AP bursts were blocked by low concentrations of the T- and R-type calcium channel antagonist nickel, which also blocked LTP and NMDA channel activation. These data suggest an important role of dendritic calcium spikes during AP bursts in determining both the efficacy and time window for STDP induction.     

Inhibition of the slow afterhyperpolarization restores the classical spike timing-dependent plasticity rule obeyed in layer 2/3 pyramidal cells of the prefrontal cortex

The induction of long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic currents was investigated in proximal synapses of layer 2/3 pyramidal cells of the rat medial prefrontal cortex. The spike timing-dependent plasticity (STDP) induction protocol of negative timing, with postsynaptic leading presynaptic stimulation of action potentials (APs), induced LTD as expected from the classical STDP rule. However, the positive STDP protocol of presynaptic leading postsynaptic stimulation of APs predominantly induced a presynaptically expressed LTD rather than the expected postsynaptically expressed LTP. Thus the induction of plasticity in layer 2/3 pyramidal cells does not obey the classical STDP rule for positive timing. This unusual STDP switched to a classical timing rule if the slow Ca(2+)-dependent, K(+)-mediated afterhyperpolarization (sAHP) was inhibited by the selective blocker N-trityl-3-pyridinemethanamine (UCL2077), by the β-adrenergic receptor agonist isoproterenol, or by the cholinergic agonist carbachol. Thus we demonstrate that neuromodulators can affect synaptic plasticity by inhibition of the sAHP. These findings shed light on a fundamental question in the field of memory research regarding how environmental and behavioral stimuli influence LTP, thereby contributing to the modulation of memory.     

Network interactions mediated by new excitatory connections between CA1 pyramidal cells in rats with kainate-induced epilepsy

Axon sprouting and synaptic reorganization in the hippocampus are associated with the development of seizures in temporal lobe epilepsy. Synaptic interactions among CA1 pyramidal cells were examined in fragments of hippocampal slices containing only the CA1 area from saline- and kainate-treated rats. Glutamate microapplication to the pyramidal cell layer increased excitatory postsynaptic current (EPSC) frequency, but only in rats with kainate-induced epilepsy. In bicuculline, action potentials evoked in single pyramidal cells increased the frequency of network bursts only in slices from rats with kainate-induced epilepsy. These data further support the hypothesis that excitatory connections between CA1 pyramidal cells increase after kainate-induced status epilepticus.     

Competitive Hebbian learning through spike-timing-dependent synaptic plasticity

Hebbian models of development and learning require both activity-dependent synaptic plasticity and a mechanism that induces competition between different synapses. One form of experimentally observed long-term synaptic plasticity, which we call spike-timing-dependent plasticity (STDP), depends on the relative timing of pre- and postsynaptic action potentials. In modeling studies, we find that this form of synaptic modification can automatically balance synaptic strengths to make postsynaptic firing irregular but more sensitive to presynaptic spike timing. It has been argued that neurons in vivo operate in such a balanced regime. Synapses modifiable by STDP compete for control of the timing of postsynaptic action potentials. Inputs that fire the postsynaptic neuron with short latency or that act in correlated groups are able to compete most successfully and develop strong synapses, while synapses of longer-latency or less-effective inputs are weakened.     

Spike timing-dependent plasticity: a learning rule for dendritic integration in rat CA1 pyramidal neurons

Long-term plasticity of dendritic integration is induced in parallel with long-term potentiation (LTP) or depression (LTD) based on presynaptic activity patterns. It is, however, not clear whether synaptic plasticity induced by temporal pairing of pre- and postsynaptic activity is also associated with synergistic modification in dendritic integration. We show here that the spike timing-dependent plasticity (STDP) rule accounts for long-term changes in dendritic integration in CA1 pyramidal neurons in vitro . Positively correlated pre- and postsynaptic activity (delay: +5/+50 ms) induced LTP and facilitated dendritic integration. Negatively correlated activity (delay: −5/−50 ms) induced LTD and depressed dendritic integration. These changes were not observed following positive or negative pairing with long delays (> ±50 ms) or when NMDA receptors were blocked. The amplitude–slope relation of the EPSP was facilitated after LTP and depressed after LTD. These effects could be mimicked by voltage-gated channel blockers, suggesting that the induced changes in EPSP waveform involve the regulation of voltage-gated channel activity. Importantly, amplitude–slope changes induced by STDP were found to be input specific, indicating that the underlying changes in excitability are restricted to a limited portion of the dendrites. We conclude that STDP is a common learning rule for long-term plasticity of both synaptic transmission and dendritic integration, thus constituting a form of functional redundancy that insures significant changes in the neuronal output when synaptic plasticity is induced.     

Photolysis of postsynaptic caged Ca2+ can potentiate and depress mossy fiber synaptic responses in rat hippocampal CA3 pyramidal neurons

The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+ ([Ca2+]i). Ca2+ is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+ compounds to test whether a postsynaptic rise in [Ca2+]i is sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]i to approximately 1 microm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+ buffer capacity than CA1 neurons, limiting the rise in [Ca2+]i achievable by photolysis. This [Ca2+]i rise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.     

Differential maintenance and frequency-dependent tuning of LTP at hippocampal synapses of specific strains of inbred mice

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be "tuned" to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.     

Spike-Dependent Intrinsic Plasticity Increases Firing Probability in Rat Striatal Neurons In Vivo

The collision of pre- and postynaptic activity is known to provide a trigger for controlling the gain of synaptic transmission between neurons. Here, using in vivo intracellular recordings of rat striatal output neurons, we analyse the effect of a single action potential, generated by ongoing synaptic activity, on subsequent excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the cerebral cortex. This pairing induced a short-term increase in the probability that cortically evoked EPSPs caused striatal cells to fire. This enhanced EPSP-spike coupling was associated with a decrease in the voltage firing threshold with no apparent change in the synaptic strength itself. Antidromic action potentials in striatal cells were also able to induce the facilitation while subthreshold EPSPs were ineffective, indicating that the postsynaptic spike was necessary and sufficient for the induction of the plasticity. A prior spontaneous action potential also enhanced the probability with which directly applied current pulses elicited firing, suggesting that the facilitation originated from changes in the intrinsic electrical properties of the postsynaptic cell. Using whole-cell recordings in cortico-striatal slices, we found that the increase in membrane excitability as well as in EPSP-spike coupling was abolished by low concentration of 4-aminopyridine. This suggests that the intrinsic plasticity results from a time-dependent modulation of a striatal voltage-dependent potassium current available close to the firing threshold. Action potentials thus provide a postsynaptic signal, not only for associative synaptic plasticity but also for activity-dependent intrinsic plasticity, which directly controls the efficacy of coupling between pre- and postsynaptic neurons.     

Inhibitory control of LTP and LTD: stability of synapse strength

Although much is known about the induction of synaptic plasticity, the persistence of memories suggests the importance of understanding factors that maintain synaptic strength and prevent unwanted synaptic changes. Here we present evidence that recurrent inhibitory connections in the CA1 region of hippocampus may contribute to this task by modulating the relative ability to induce long-term potentiation and depression (LTP and LTD). Bath application of the gamma-aminobutyric acid (GABA) type A agonist muscimol to hippocampal slices increased the range of frequencies that produce LTD, whereas in the presence of the GABA type A antagonist picrotoxin LTD was induced only at very low stimulation frequencies (0.25-0.5 Hz). Because one source of GABAergic input to CA1 pyramidal cells is via recurrent inhibition, we tested the prediction that elevated postsynaptic spike activity would increase feedback GABA inhibition and favor the induction of LTD. By using an induction stimulation of 8 Hz, which alone produced no net change in synaptic strength, we found that stimulation presented during antidromic activation of pyramidal cell spikes induced LTD. This effect was blocked by picrotoxin. The influence of recurrent inhibition on LTP and LTD displays properties that may decrease the potential for self-reinforcing, runaway changes in synapse strength. A mechanism of this sort may help maintain patterns of synaptic strengths despite the ongoing opportunities for plasticity produced by synapse activation.     

葡萄糖浓度降低对幼龄鼠及成年鼠海马长时程增强的影响

目的:观察葡萄糖浓度降低对幼龄鼠15-16日龄及成年鼠56-63日龄海马CA1区长时程增强(LTP)诱发的影响。方法:采用脑片灌流及电生理学技术,以场兴奋性突触后电位的初始斜率(S-EPSP)为观测指标。结果:当将灌流液中葡萄糖浓度降为3或1.5mmol/L时,S-EPSP显著减小。在葡萄糖浓度为3或1.5mmol/L的介质中,以高频刺激(HFS)作用于成年鼠脑片仅出现短时程增强反应;但在葡萄糖浓度为3mmol/L的介质中,HFS仍可在幼龄鼠脑片上诱导出LTP。结论:低糖可使突触的传递活动减弱;在突触可塑性方面,幼龄鼠对低糖的耐受性要强于成年鼠。     

Subthreshold contribution of N-methyl-d-aspartate receptors to long-term potentiation induced by low-frequency pairing in rat hippocampal CA1 pyramidal cells

Long-term potentiation (LTP) is a use-dependent and persistent enhancement of synaptic strength. In the CA1 region of the hippocampus, LTP has Hebbian characteristics and requires precisely timed interaction between presynaptic firing and postsynaptic depolarization. Although depolarization is an absolute requirement for plasticity, it is still not clear whether the postsynaptic response during LTP induction should be subthreshold or suprathreshold for the generation of somatic action potential. Here, we use the whole-cell patch-clamp technique and different pairing protocols to examine systematically the postsynaptic induction requirements for LTP. We induce LTP by changes only in membrane potential while keeping the afferent stimulation constant and at minimal levels. This approach permits differentiation of two types of LTP: LTP induced with suprathreshold synaptic responses (LTP(AP)) and LTP induced with subthreshold excitatory postsynaptic current (EPSCs; LTP(EPSC)). We found that LTP(AP) (>40%) required pairing of depolarization (V(m)>or=-40 mV, for 40-60 s) with four to six (0.1 Hz) single synaptically initiated action potentials. LTP(EPSC) was of smaller magnitude (<30%) and required pairing of depolarization to -50 mV (60 s) with six subthreshold EPSCs. The N-methyl-d-aspartate receptor (NMDAR) antagonists aminophosphonovaleric acid and 7-chlorokynurenic acid consistently blocked LTP(EPSC) but were ineffective in preventing LTP(AP). Robust, NMDAR-independent LTP is obtained by stronger postsynaptic depolarization that converts the EPSCs to suprathreshold somatic action potentials. Purely NMDAR-dependent LTP is obtained by pairing mild somatic depolarization with subthreshold afferent pulses to the postsynaptic cell. Our results indicate that the degree of postsynaptic depolarization in the presence of single afferent pulses determines the type and magnitude of LTP.     

Visualization of changes in presynaptic function during long-term synaptic plasticity.

Controversy exists regarding the site of modification of synaptic transmission during long-term plasticity in the mammalian hippocampus. Here we used a fluorescent marker of presynaptic activity, FM 1-43, to directly image changes in presynaptic function during both short-term and long-term forms of plasticity at presynaptic boutons of CA3-CA1 excitatory synapses in acute hippocampal slices. We demonstrated enhanced presynaptic function during long-term potentiation (LTP) induced either chemically (with tetraethylammonium), or by high-frequency (200-Hz) electrical stimulation. Both of these forms of LTP required activation of L-type voltage-gated calcium channels and NMDA receptors in the postsynaptic CA1 neuron. These results thus implied that a long-lasting increase in the efficacy of synaptic transmission is likely to depend, at least in part, on enhanced transmitter release from the presynaptic neuron.     

Group I mGluR agonist DHPG facilitates the induction of LTP in rat prelimbic cortex in vitro.

Long-term potentiation (LTP) of synaptic transmission is a favored neural model for learning and memory. In isolated slices of rat prelimbic cortex, glutamatergic activation of metabotropic receptors (mGluRs) is required for the production of LTP at synapses on layer V neurons. Group I mGluRs are found in neocortex, and in prelimbic cortex they have been located on layer V neurons. We have now investigated whether application of the selective group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine (DHPG) facilitates the induction of LTP. We recorded field potentials in layer V in response to test shocks applied to layer II and measured the population spike peak amplitude and slope. Intracellular recording was used to examine the correspondence between excitatory postsynaptic potentials (EPSPs) and action potentials with components of the field potential, and to further investigate the action of DHPG. Repetitive bursts of stimulation at theta frequencies (TBS) did not consistently alter the magnitude or slope of the population spike (mean response 105+/-4%, mean+/-SE of control at 30 min after TBS ended, n = 9 slices, no significant difference). When DHPG was added to the bathing medium for 10 min during continued test stimulation, the slope and amplitude of the population spike were significantly reduced, but 30 min after wash out of the DHPG, they recovered (mean response 89+/-10% of control, n = 6 slices, no significant difference). However, when TBS was administered in conjunction with bath application of DHPG, LTP of the population spike was induced (mean response 147+/-12% of control at 30 min after TBS ended, P = 0.004, paired t-test, n = 9 slices). We conclude that co-application of DHPG with TBS facilitates the induction of LTP of the population spike, which supports a role for group I mGluRs in the activity-dependent induction of LTP in the prelimbic cortex.