A distinct impact of repeated morphine exposure on synaptic plasticity at Schaffer collateral-CA1, temporoammonic-CA1, and perforant pathway-dentate gyrus synapses along the longitudinal axis of the hippocampus

We aimed to study how morphine affects synaptic transmission in the dentate gyrus and CA1 regions along the hippocampal long axis. For this, recording and measuring of field excitatory postsynaptic potentials (fEPSPs) were utilized to test the effects of repeated morphine exposure on paired-pulse evoked responses and long-term potentiation (LTP) at Schaffer collateral-CA1 (Sch-CA1), temporoammonic-CA1 (TA-CA1) and perforant pathway-dentate gyrus (PP-DG) synapses in transverse slices from the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus in adult male rats. After repeated morphine exposure, the expression of opioid receptors and the α1 and α5 GABA_A subunits were also examined. We found that repeated morphine exposure blunt the difference between the DH and the VH in their basal levels of synaptic transmission at Sch-CA1 synapses that were seen in the control groups. Significant paired-pulse facilitation of excitatory synaptic transmission was observed at Sch-CA1 synapses in slices taken from all three hippocampal segments as well as at PP-DG synapses in slices taken from the VH segment in the morphine-treated groups as compared to the control groups. Interestingly, significant paired-pulse inhibition of excitatory synaptic transmission was observed at TA-CA1 synapses in the DH slices from the morphine-treated group as compared to the control group. While primed-burst stimulation (a protocol reflecting normal neuronal firing) induced a robust LTP in hippocampal subfields in all control groups, resulting in a decaying LTP at TA-CA1 synapses in the VH slices and at PP-DG synapses in both the IH and VH slices taken from the morphine-treated rats. In the DH of morphine-treated rats, we found increased levels of the mRNAs encoding the α1 and α5 GABA_A subunits as compared to the control group. Taken together, these findings suggest the potential mechanisms through which repeated morphine exposure causes differential changes in circuit excitability and synaptic plasticity in the dentate gyrus and CA1 regions along the hippocampal long axis.     

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses

Hippocampus is importantly involved in dopamine‐dependent behaviors and dopamine is a significant modulator of synaptic plasticity in the hippocampus. Moreover, the dopaminergic innervation appears to be disproportionally segregated along the hippocampal longitudinal (dorsoventral) axis with unknown consequences for synaptic plasticity. In this study we examined the actions of endogenously released dopamine and the effects of exogenous D1/D5 dopamine receptor agonists on theta‐burst stimulation‐induced long‐term potentiation (LTP) of field excitatory synaptic potential (fEPSP) at Schaffer collateral‐CA1 synapses in slices from dorsal (DH) and ventral hippocampus (VH). Furthermore, we quantified D1 receptor mRNA and protein expression levels in DH and VH. We found that blockade of D1/D5 receptors by SCH 23390 (20 μM) significantly reduced the magnitude of LTP in both DH and VH similarly suggesting that dopamine endogenously released during TBS, presumably mimicking low activity of DA neurons, exerts a homogeneous modulation of LTP along the hippocampal long axis. Moderate to high concentrations of the selective partial D1/D5 receptor agonist SKF 38393 (50‐150 μM) did not significantly change LTP in either hippocampal segment. However, the full D1 receptor selective agonist SKF 82958 (10 μM) significantly enhanced LTP in VH but not DH. Furthermore, the expression of D1 receptor mRNA and protein was considerably higher in VH compared with DH. These results suggest that the dynamic range of D1/D5 receptor‐mediated dopamine effects on LTP may be higher in VH than DH and that VH may be specialized to acquire information about behaviorally relevant strong stimuli signaled by the dopamine system.     

Forebrain NR2B overexpression enhancing fear acquisition and long‐term potentiation in the lateral amygdala

N‐methyl‐d ‐aspartic acid (NMDA) receptor‐dependent long‐term potentiation (LTP) at the thalamus–lateral amygdala (T‐LA) synapses is the basis for acquisition of auditory fear memory. However, the role of the NMDA receptor NR2B subunit in synaptic plasticity at T‐LA synapses remains speculative. In the present study, using transgenic mice with forebrain‐specific overexpression of the NR2B subunit, we have observed that forebrain NR2B overexpression results in enhanced LTP but does not alter long‐term depression (LTD) at the T‐LA synapses in transgenic mice. To elucidate the cellular mechanisms underlying enhanced LTP at T‐LA synapses in these transgenic mice, AMPA and NMDA receptor‐mediated postsynaptic currents have been measured. The data show a marked increasing in the amplitude and decay time of NMDA receptor‐mediated currents in these transgenic mice. Consistent with enhanced LTP at T‐LA synapses, NR2B‐transgenic mice exhibit better performance in the acquisition of auditory fear memory than wild‐type littermates. Our results demonstrate that up‐regulation of NR2B expression facilitates acquisition of auditory cued fear memory and enhances LTP at T‐LA synapses.     

The α5GABAA receptor modulates the induction of long‐term potentiation at ventral but not dorsal CA1 hippocampal synapses

The hippocampal synapses display conspicuous ability for long‐term plasticity which is thought to underlie learning and memory. Growing evidence shows that this ability differs along the long axis of the hippocampus, with the ventral CA1 hippocampal synapses displaying remarkably lower ability for long‐term potentiation (LTP) compared with their dorsal counterpart when activated with high‐frequency stimulation. Here, we show that low frequency, 10 Hz stimulation induced LTP more reliably in dorsal than in ventral CA1 field. Blockade of alpha5 subunit‐containing GABA_A receptors eliminated the difference between dorsal and ventral hippocampus. We propose that α5GABA_A receptor‐mediated activity plays a crucial role in regulating the threshold for induction of LTP especially at the ventral CA1 hippocampal synapses. This might have important implications for the functional specialization along the hippocampus. Synapse, 2014. © 2014 Wiley Periodicals, Inc.     

Ischemic LTP: NMDA‐dependency and dorso/ventral distribution within the hippocampus

A transient ischemic episode causes a reduction in evoked EPSPs in hippocampal slices, followed by an NMDA dependent LTP. We explored the relations between ischemic LTP (iLTP) and the more conventional tetanic LTP (tLTP) in CA1 region of slices along the dorsal/ventral axis of the hippocampus. Dorsal hippocampal (DH) slices produced a much larger iLTP than their ventral hippocampal (VH) counterparts. In both regions, iLTP and tLTP shared the same NMDA mediated potentiation, such that one LTP saturated the ability of the other treatment to generate LTP. The smaller LTP in VH was correlated with a lower NMDA‐mediated EPSP, and a parallel lower density of NMDA receptors. Calcium permeable AMPA receptors did not contribute to the DH/VH disparity. We conclude that a differential distribution of NMDA receptor subunits along the septotemporal axis of the hippocampus controls the diverse ability to evoke iLTP and tLTP in the two regions and may underlie their characteristic behavioral outputs as well as their differential sensitivity to ischemia. © 2015 Wiley Periodicals, Inc.     

GABAergic inhibition gates excitatory LTP in perirhinal cortex

The perirhinal cortex (PRh) is a key region downstream of auditory cortex (ACx) that processes familiarity linked mnemonic signaling. In gerbils, ACx‐driven EPSPs recorded in PRh neurons are largely shunted by GABAergic inhibition (Kotak et al., 2015, Frontiers in Neural Circuits, 9). To determine whether inhibitory shunting prevents the induction of excitatory long‐term potentiation (e‐LTP), we stimulated ACx‐recipient PRh in a brain slice preparation using theta burst stimulation (TBS). Under control conditions, without GABA blockers, the majority of PRh neurons exhibited long‐term depression. A very low concentration of bicuculline increased EPSP amplitude, but under this condition TBS did not significantly increase e‐LTP induction. Since PRh synaptic inhibition included a GABA_B receptor‐mediated component, we added a GABA_B receptor antagonist. When both GABA_A and GABA_B receptors were blocked, TBS reliably induced e‐LTP in a majority of PRh neurons. We conclude that GABAergic transmission is a vital mechanism regulating e‐LTP induction in the PRh, and may be associated with auditory learning.     

Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP

Enlargement of dendritic spines and synapses correlates with enhanced synaptic strength during long‐term potentiation (LTP), especially in immature hippocampal neurons. Less clear is the nature of this structural synaptic plasticity on mature hippocampal neurons, and nothing is known about the structural plasticity of inhibitory synapses during LTP. Here the timing and extent of structural synaptic plasticity and changes in local protein synthesis evidenced by polyribosomes were systematically evaluated at both excitatory and inhibitory synapses on CA1 dendrites from mature rats following induction of LTP with theta‐burst stimulation (TBS). Recent work suggests dendritic segments can act as functional units of plasticity. To test whether structural synaptic plasticity is similarly coordinated, we reconstructed from serial section transmission electron microscopy all of the spines and synapses along representative dendritic segments receiving control stimulation or TBS‐LTP. At 5 min after TBS, polyribosomes were elevated in large spines suggesting an initial burst of local protein synthesis, and by 2 h only those spines with further enlarged synapses contained polyribosomes. Rapid induction of synaptogenesis was evidenced by an elevation in asymmetric shaft synapses and stubby spines at 5 min and more nonsynaptic filopodia at 30 min. By 2 h, the smallest synaptic spines were markedly reduced in number. This synapse loss was perfectly counterbalanced by enlargement of the remaining excitatory synapses such that the summed synaptic surface area per length of dendritic segment was constant across time and conditions. Remarkably, the inhibitory synapses showed a parallel synaptic plasticity, also demonstrating a decrease in number perfectly counterbalanced by an increase in synaptic surface area. Thus, TBS‐LTP triggered spinogenesis followed by loss of small excitatory and inhibitory synapses and a subsequent enlargement of the remaining synapses by 2 h. These data suggest that dendritic segments coordinate structural plasticity across multiple synapses and maintain a homeostatic balance of excitatory and inhibitory inputs through local protein‐synthesis and selective capture or redistribution of dendritic resources. ©2010 Wiley‐Liss, Inc.     

Less means more: The magnitude of synaptic plasticity along the hippocampal dorso‐ventral axis is inversely related to the expression levels of plasticity‐related neurotransmitter receptors

The dorsoventral axis of the hippocampus exhibits functional differentiations with regard to (spatial Vs emotional) learning and information retention (rapid encoding Vs long‐term storage), as well as its sensitivity to neuromodulation and information received from extrahippocampal structures. The mechanisms that underlie these differentiations remain unclear. Here, we explored neurotransmitter receptor expression along the dorsoventral hippocampal axis and compared hippocampal synaptic plasticity in the CA1 region of the dorsal (DH), intermediate (IH) and ventral hippocampi (VH). We observed a very distinct gradient of expression of the N‐methyl‐D‐aspartate receptor GluN2B subunit in the Stratum radiatum (DH< IH< VH). A similar distribution gradient (DH< IH< VH) was evident in the hippocampus for GluN1, the metabotropic glutamate receptors mGlu1 and mGlu2/3, GABA_B and the dopamine‐D1 receptor. GABA_A exhibited the opposite expression relationship (DH > IH > VH). Neurotransmitter release probability was lowest in DH. Surprisingly, identical afferent stimulation conditions resulted in hippocampal synaptic plasticity that was the most robust in the DH, compared with IH and VH. These data suggest that differences in hippocampal information processing and synaptic plasticity along the dorsoventral axis may relate to specific differences in the expression of plasticity‐related neurotransmitter receptors. This gradient may support the fine‐tuning and specificity of hippocampal synaptic encoding.     

A postsynaptic G-protein in hippocampal long-term potentiation

The effects of guanosine triphosphate (GTP)-binding protein (G-protein) blockade on hippocampal LTP at stratum radiatum-CA₁ synapses was studied. Bath application of 20 mM lithium chloride (LiCl) inhibited long-term potentiation (LTP) of extracellularly-recorded excitatory postsynaptic potentials (EPSPs). Inclusion of 100 mM LiCl in intracellular recording electrodes was shown to block postsynaptic G-proteins by bath-application of baclofen, an agonist at the G-protein linked γ-aminobutyric acid (GABA_B) receptor. Under normal conditions, GABA_B receptor activation causes a hyperpolarization postsynaptically, and a decrease in neurotransmitter release presynaptically. With LiCl in the recording electrodes, the postsynaptically-mediated hyperpolarization was blocked, while the presynaptically-mediated depression of EPSPs was unaffected. With postsynaptic G-proteins blocked in this manner, LTP at these synapses was inhibited. These studies provide evidence for the involvement of a postsynaptic G-protein in LTP of stratum radiatum-CA₁ synapses.     

Effect of bromophenacyl bromide, a phospholipase A2 inhibitor, on the induction and maintenance of LTP in hippocampal slices

The effect of bromophenacyl bromide (BPB), a phospholipase A₂ (PLA₂) inhibitor, on both the induction and the maintenance of long-term potentiation (LTP) was investigated in field CA₁ of the hippocampal slice preparation. One hour of BPB application (50 μM) caused a large reduction in the magnitude of LTP induced by a theta burst stimulation (TBS) paradigm. BPB had no significant effect on either the degree of paired-pulse facilitation or the amount of pre-established LTP. Furthermore, the facilitation of postsynaptic responses occuring during TBS and in the first minute following TBS was not reduced by the PLA₂ inhibitor. These results indicate that the inhibition of LTP produced by BPB is not due to an effect of the drug on a physiological event that triggers LTP. The data also suggest that PLA₂ activation plays a critical role in the expression of LTP, but is not required for the maintenance of the potentiation.     

Stress‐induced dynamic routing of hippocampal connectivity: A hypothesis

Recent observations have caused a drastic shift in the conception of the hippocampus as a homogeneous structure that subserves cognitive functions, either spatial maps or short term episodic memory, to a structure that is associated with both cognitive and emotional functions. In fact, the assignment of cognitive functions to the hippocampus is restricted to its dorsal sector. In contrast, the ventral hippocampus (VH) appears to be associated with control of behavioral inhibition, stress and emotional memory, but not with strictly cognitive functions. Curiously, the VH but not the dorsal hippocampus (DH) is associated with the development of affective disorders. In line with these collective observations, we and others have found that the ability to evoke a sustained long term potentiation (LTP), a cellular correlate of learning and memory, is much lower in the VH compared to the DH. Strikingly, acute stress as well as direct exposure to corticosterone affect DH and VH in an opposite manner; causing facilitation of LTP in the VH and its suppression in the DH. This double dissociative action results from activation of different steroid receptor species in the DH and VH. Since the DH and VH differ in efferent connectivity, and since the strength of LTP can be considered as an indicator of strength of synaptic connectivity, these results suggest that stress regulates the routes by which the hippocampus is functionally linked to the rest of the brain such that under stress, the ventral route to the amygdala is enabled while the dorsal route to the neocortex is suppressed. This selective routing may underlie the complex outcome of stress on hippocampal and amygdala physiology and behavior. © 2009 Wiley‐Liss, Inc.     

Cellular basis of a rapid effect of mineralocorticosteroid receptors activation on LTP in ventral hippocampal slices

The ventral hippocampus (VH) was recently shown to express lower magnitude LTP compared to the dorsal hippocampus (DH). Exposure to acute stress reversed this difference, and VH slices from stressed rats expressed larger LTP than that produced in the DH, which was reduced by stress. In an attempt to uncover the mechanisms responsible for this differential action, we found that activation of mineralocorticosteroid receptors (MR) by aldosterone mimics the effects of stress in the VH, to facilitate LTP. We also found that aldosterone reduces GABAergic inhibition in both the DH and VH. We now examined if the reduction in inhibition caused by MRs can underlie the altered LTP in the VH. Rat hippocampal slices were recorded before and after exposure to the GABA antagonist bicuculline and to aldosterone. As expected, blockade of GABA with bicuculline enhanced LTP in both DH and VH. However, its effect did not occlude that of aldosterone in the VH, indicating that the latter drug does not operate by blockade of inhibition. Furthermore, the NMDA receptor antagonist APV blocked LTP induced in the presence of bicuculline, but did not block LTP facilitation by aldosterone, indicating that the effect of aldosterone is not mediated by the conventional NMDA-dependent LTP generating mechanism. Furthermore, rapid effects of aldosterone on LTP were blocked by the L-type calcium channel antagonist nifedipine, indicating that aldosterone facilitates calcium influx via nifedipine-sensitive channels, to enhance LTP in the VH. The locus of effect of aldosterone may be the presynaptic terminal, as it caused a marked facilitation of paired pulse potentiation in the VH but not in the DH. These experiments confirm and extend previous suggestions for the effects of MRs on neuronal plasticity in the hippocampus.     

Different pools of postsynaptic GABAA receptors mediate inhibition evoked by low‐ and high‐frequency presynaptic stimulation at hippocampal synapses

Patterns of short‐term synaptic plasticity could considerably differ between synapses of the same axon. This may lead to separation of synaptic receptors transmitting either low‐ or high‐frequency signals and, therefore, may have functional consequences for the information transfer in the brain. Here, we estimated a degree of such separation at hippocampal GABAergic synapses using a use‐dependent GABA_A receptor antagonist, picrotoxin, to selectively suppress a pool of GABA_A receptors monosynaptically activated during the low‐frequency stimulation. The relative changes in postsynaptic responses evoked by the high‐frequency stimulation before and after such block were used to estimate the contribution of this GABA_A receptor pool to synaptic transmission at high frequencies. Using this approach, we have shown that IPSCs evoked by low‐frequency (0.2 Hz) stimulation and asynchronous currents evoked by high‐frequency (20–40 Hz) stimulation are mediated by different pools of postsynaptic GABA_A receptors. Thus, our findings suggest that inhibition produced by a single hippocampal interneuron may be selectively routed to different postsynaptic targets depending on the presynaptic discharge frequency. Synapse 68:344–354, 2014 . © 2014 Wiley Periodicals, Inc.     

A brief, but repeated, swimming protocol is sufficient to overcome amyloid beta-protein inhibition of hippocampal long-term potentiation

Alzheimer's disease starts as an almost imperceptible malady, first observed clinically as a mild memory problem. Accumulating genetic and biochemical data have suggested that amyloid β‐protein (Aβ) plays an important role in this memory loss, and Aβ has been shown to suppress long‐term potentiation (LTP), a cellular model for memory and learning. Here we show that a very brief (3 min) swimming, twice daily for 2 weeks, rescues LTP inhibition in the CA1 region of hippocampal slices caused by Aβ₄₂ or Aβ₄₀ carrying the Arctic mutation using a theta burst stimulation (TBS) protocol. Whereas the input–output curve was not affected, the paired‐pulse ratio was reduced in mice receiving our repeated swimming protocol, suggesting a possible involvement of presynaptic facilitation. Similar to swimming, Aβ's inhibition of LTP could be rescued with the adenylyl cyclase, forskolin. Interestingly, this swimming protocol produced conditions in which a weak‐TBS could invoke LTP not observed in naïve mice, which again was mimicked by forskolin. In contrast, the protein kinase A (PKA) inhibitor, H89, blocked both the forskolin and swimming potentiation of LTP; these data implicate cAMP/PKA signaling in the protective effect of swimming and mediating Aβ′ detrimental effects. Our data add a new simple behavior paradigm that shows the importance of an environmental factor in reversing the pathophysiological effects of Aβ, and suggest new therapeutic avenues.     

Presynaptic Ultrastructural Plasticity Along CA3→CA1 Axons During Long‐Term Potentiation in Mature Hippocampus

In area CA1 of the mature hippocampus, synaptogenesis occurs within 30 minutes after the induction of long‐term potentiation (LTP); however, by 2 hours many small dendritic spines are lost, and those remaining have larger synapses. Little is known, however, about associated changes in presynaptic vesicles and axonal boutons. Axons in CA1 stratum radiatum were evaluated with 3D reconstructions from serial section electron microscopy at 30 minutes and 2 hours after induction of LTP by theta‐burst stimulation (TBS). The frequency of axonal boutons with a single postsynaptic partner was decreased by 33% at 2 hours, corresponding perfectly to the 33% loss specifically of small dendritic spines (head diameters <0.45 μm). Docked vesicles were reduced at 30 minutes and then returned to control levels by 2 hours following induction of LTP. By 2 hours there were fewer small synaptic vesicles overall in the presynaptic vesicle pool. Clathrin‐mediated endocytosis was used as a marker of local activity, and axonal boutons containing clathrin‐coated pits showed a more pronounced decrease in presynaptic vesicles at both 30 minutes and 2 hours after induction of LTP relative to control values. Putative transport packets, identified as a cluster of less than 10 axonal vesicles occurring between synaptic boutons, were stable at 30 minutes but markedly reduced by 2 hours after the induction of LTP. APV blocked these effects, suggesting that the loss of axonal boutons and presynaptic vesicles was dependent on N‐methyl‐D‐aspartic acid (NMDA) receptor activation during LTP. These findings show that specific presynaptic ultrastructural changes complement postsynaptic ultrastructural plasticity during LTP. J. Comp. Neurol. 521:3898–3912, 2013. © 2013 Wiley Periodicals, Inc.     

Induction and reversal of long-term potentiation by repeated high-frequency stimulation in rat hippocampal slices

Field potential recordings were made from area CA1 of hippocampal slices from young adult rats to study the effects of repeated tetanic stimulation on the development of LTP. Stimulation was applied to the Schaffer collateral afferents, and field excitatory postsynaptic potentials were recorded in stratum radiatum. Theta-burst stimulation (TBS) resulted in variable amounts of long-term potentiation (LTP), depending on how many trains of stimulation were delivered. Peak amounts of LTP occurred after 8–16 trains of TBS, but virtually no LTP occurred after 24 or 32 trains of TBS. There was thus an inverted U-shaped relation between the amount of TBS and the degree of LTP. The temporal spacing of TBS trains was important for observing the lack of LTP after 32 trains (“over-stimulation”). If the trains were grouped into blocks of 8, with 10 min between blocks, LTP occurred normally. This finding suggests that a time-dependent LTP reversal process was occurring during the massed presentation of TBS trains. Over-stimulation inhibited for 60–90 min the subsequent induction of LTP by a normally efficient LTP-inducing protocol. This effect was input specific and dependent on activation of N-methyl-D-aspartate (NMDA) receptors. Lowering extracellular [CA²⁺] from 2.5 to 2.0 mM, or adding the L-type calcium channel antagonist nimodipine, had only a small protective effect on the lack of LTP induced by 32 trains of TBS. Addition of an NMDA receptor antagonist to the bath solution shortly after the beginning of the over-stimulation protocol gave significantly more protection. Administration of an adenosine (A₁) receptor antagonist during over-stimulation permitted robust LTP to occur, indicating that A₁ receptor activation during TBS contributes to the depotentiation process. These findings confirm previous findings in the dentate gyrus that repeated afferent tetanization within a narrow time frame can lead to a loss or reversal of LTP. Activation of adenosine receptors appears to trigger this effect. Hippocampus 7:137–145, 1997. © 1997 Wiley-Liss, Inc.     

Effect of bromophenacyl bromide, a phospholipase A2 inhibitor, on the induction and maintenance of LTP in hippocampal slices

The effect of bromophenacyl bromide (BPB), a phospholipase A2 (PLA2) inhibitor, on both the induction and the maintenance of long-term potentiation (LTP) was investigated in field CA1 of the hippocampal slice preparation. One hour of BPB application (50 microM) caused a large reduction in the magnitude of LTP induced by a theta burst stimulation (TBS) paradigm. BPB had no significant effect on either the degree of paired-pulse facilitation or the amount of pre-established LTP. Furthermore, the facilitation of postsynaptic responses occurring during TBS and in the first minute following TBS was not reduced by the PLA2 inhibitor. These results indicate that the inhibition of LTP produced by BPB is not due to an effect of the drug on a physiological event that triggers LTP. The data also suggest that PLA2 activation plays a critical role in the expression of LTP, but is not required for the maintenance of the potentiation.     

Critical Role of Presynaptic Nicotinic ACh Receptor in the Formation of Long-Term Potentiation: Implications for Development of Anti-Dementia Drugs

Background : Since neuronal nicotinic ACh receptors are involved in the cognitive function, they have been studied as a target of anti‐dementia drugs. The present study was designed to understand the role of nicotinic ACh receptors in the expression of long‐term potentiation (LTP), a cellular model of learning and memory. Methods : The ultrastructural localization of neuronal nicotinic ACh receptors in the rat hippocampus was examined electron‐immunohistochemically using an antibody against the α7 subunit, forming a brain‐type nicotinic ACh receptor. Miniature excitatory postsynaptic currents (mEPSCs) were monitored in cultured rat hippocampal neurons. Schaffer collateral‐CA1 LTP and perforant path LTP were analyzed by recording field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) in the CA1 region and the dentate gyrus of rat hippocampal slices or in the intact mouse hippocampus. Results : α7 receptors are preferentially localized on presynaptic terminals, where the receptors are employed in the release of the excitatory neurotransmitter, glutamate. The probability of LTP development was markedly reduced in the presence of the neuronal nicotinic ACh receptor antagonists, α‐bungarotoxin and mecamylamine, in both the CA1 region and the dentate gyrus of rat hippocampal slices. Perforant path LTP was never induced in slices with selective cholinergic denervation using 192 IgG‐saporin, while it was not affected by atropine, a selective muscarinic ACh receptor antagonist, in normal slices. Nicotine facilitated hippocampal neurotransmission with the saturation occluding the potentiation induced by tetanic stimulation, and vice versa. A similar occlusion was also obtained with an intact mouse hippocampus. These types of LTP, which are dependent upon N‐methyl‐D‐aspartate (NMDA) receptors, were still induced by treatment with nicotine in the presence of D‐2‐amino‐5‐phosphonovaleric acid (APV), a selective NMDA receptor antagonist. Conclusion : The results of the present study suggest that presynaptic nicotinic ACh receptors play a critical role as a target of retrograde messengers in the formation of NMDA receptor‐dependent LTP. This may account for the involvement of nicotinic ACh receptors in cognitive function. Drugs enhancing the activity of neuronal nicotinic ACh receptors, therefore, are capable of expressing LTP, conversely, ameliorating dementia.     

Role of N-methyl-D-aspartate receptors in the induction of synaptic potentiation by burst stimulation patterned after the hippocampal theta-rhythm

Short bursts of high frequency stimulation produce maximal long-term potentiation (LTP) at Schaffer-commissural synapses on CA1 neurons in hippocampal slices when the bursts are spaced 200 ms apart. A burst to one input (S1) does not induce LTP but 'primes' the postsynaptic neurons such that 200 ms later the postsynaptic response to a burst to a second input (S2) is greatly enhanced and LTP is induced. The role of N-methyl-D-aspartate (NMDA) receptors in this response enhancement and LTP induction was studied by perfusing slices with the NMDA antagonist, 2-amino-5-phosphonovalerate (AP5). AP5 (100 microM) had no effect on the field excitatory postsynaptic potential evoked by single pulse stimulation, but completely eliminated both the decremental short-term potentiation (lasting less than 10 min) and stable LTP effects elicited by burst stimulation. AP5 reduced the response to a non-primed burst by about 10% and reduced the relative enhancement of a primed burst response by about 35%. These results indicate that part of the postsynaptic response to a primed burst is mediated by NMDA receptors and that this component is necessary for all forms of synaptic potentiation (including LTP) resulting from burst stimulation. The similarity of the short bursts with the complex-spike discharges of hippocampal neurons as well as the 200 ms optimal interval with the period of the hippocampal theta-rhythm suggest links between theta and the NMDA receptor in the induction of hippocampal synaptic plasticity.     

Selective facilitation of LTP in the ventral hippocampus by calcium stores

The effects of low concentrations of caffeine and ryanodine on field excitatory postsynaptic potentials (EPSPs) and long‐term potentiation (LTP) were studied in CA1 region of slices of dorsal and ventral hippocampus (DH and VH, respectively). There was a striking difference between the two regions in the magnitude of effect of both drugs, as well as the ability to interact with a tetanic stimulation to produce LTP. Low concentration of caffeine (1 mM) produced a postsynaptic increase in the slope of population EPSPs in VH, and facilitated LTP in this region. Low concentration of ryanodine (0.2 μM) was able to convert short‐term potentiation (STP) to LTP in VH only. These effects are postsynaptic and they reflect a higher concentration of ryanodine receptors (RyRs) in the VH compared to the DH. © 2012 Wiley Periodicals, Inc.