The NMDA Receptor Antagonist CPP Suppresses Long-term Potentiation in the Rat Hippocampal — accumbens Pathway In Vivo

Excitation of afferent fibres originating in the ventral subiculum of the hippocampus through stimulation of the fimbria elicits field potentials in the nucleus accumbens. When recorded in the dorsomedial aspect of the nucleus accumbens, the evoked field responses consisted of an early, negative-going component (Nl) with a peak latency of 8–10 ms, followed by a second negative-going peak (N2) with a latency of 22–24 ms. The N1 response reflects monosynaptic activation of nucleus accumbens neurons; the N2 component appears to be polysynaptic in origin. In control rats, high-frequency stimulation of the fimbria (three trains at 250 Hz, 250 ms, delivered at 50 min intervals) resulted in a long-lasting potentiation of both the N1 and N2 components. The magnitude of potentiation exhibited by the polysynaptic N2 response was typically greater than that of the monosynaptically evoked N1 response. Following delivery of the first train, the amplitude of the N1 and N2 components was increased by -20 and 50% respectively. Administration of the competitive N-methyl-d -aspartate (NMDA) receptor antagonist 3-[(±)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP, 10 mg/kg i.p.) had no significant effects on the evoked nucleus accumbens responses. High-frequency stimulation failed to produce a significant increase in the amplitude of either the N1 or the N2 response when delivered 45–60 min after CPP administration. To test whether the suppressant effects of CPP were time-dependent, two further high-frequency trains were applied 90 and 180 min after administration of the drug. Significant increases in the amplitude of the N1 and N2 components were observed only after the third train, delivered 180 min after CPP injection. These results demonstrate that high-frequency stimulation of hippocampal afferents to the nucleus accumbens induces LTP in both a monosynaptic and a polysynaptic pathway. In both cases, the induction of LTP is suppressed in a time-dependent manner by the competitive NMDA receptor antagonist CPP. Thus, NMDA receptor activation appears to be prerequisite for the induction of LTP in the hippocampus - accumbens pathway.     

Flip side of synaptic plasticity: Long-term depression mechanisms in the hippocampus

There is growing interest in the phenomenon of long-term depression (LTD) of synaptic efficacy that, together with long-term potentiation (LTP), is a putative information storage mechanism in mammalian brain. In neural network models, multiple learning rules have been used for LTD induction. Similarly, in neurophysiological studies of hippocampal synaptic plasticity, a variety of activity patterns have been effective at inducing LTD, although experimental paradigms are still being optimized. In this review the authors summarize the major experimental paradigms and compare what is known about the mechanisms of LTD induction. Although all paradigms appear to initiate a cascade of events leading to an elevated level of Ca²⁺ postsynaptically, the extent to which these paradigms involve common expression mechanisms has not yet been tested. The authors discuss several critical experiments that would address this latter issue. Numerous questions about the properties and mechanisms of LTD(s) in the hippocampus remain to be answered, but it is clear that LTD has finally arrived, and will soon be attracting attention equal to its flip side, LTP. © 1994 Wiley-Liss, Inc.     

Differential Long-lasting Potentiation of the NMDA and Non-NMDA Synaptic Currents Induced by Metabotropic and NMDA Receptor Coactivation in Cerebellar Granule Cells

Whole-cell patch-clamp recordings in rat cerebellar slices were used to investigate the effect of metabotropic glutamate receptor activation on mossy fibre-granule cell synaptic transmission. Transient application of 20 μM 1 S , 3 R -1 -aminocyclopentane-1,3-dicarboxylic acid simultaneously with low-frequency NMDA receptor activation induced long-lasting non-decremental potentiation of both NMDA and non-NMDA receptor-mediated synaptic transmission. Potentiation could be prevented by application of the metabotropic glutamate receptor antagonist (+)- O -methyl-4-carboxyphenyl-glycine at 500 μM. Characteristically, NMDA potentiation was two to three times as large as non-NMDA current potentiation, occurred only in a slow subcomponent, and was voltage independent. This result demonstrates a pivotal role of NMDA receptors in the metabotropic potentiation of transmission, which may be important in regulating cerebellar information processing.     

The Relative Contribution of NMDA Receptor Channels in the Expression of Long-term Potentiation in the Hippocampal CA1 Region

Long-term potentiation (LTP) was studied in the hippocampal CA1 region of guinea-pigs using a solution containing 0.1 mM magnesium and 10 μM of the non- N -methyl- d -aspartate (non-NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), leaving an NMDA-mediated field excitatory postsynaptic potential (EPSP). Brief high-frequency afferent tetanization induced a substantial synapse-specific potentiation of the NMDA EPSP with a time course closely resembling that previously described for LTP of the non-NMDA-mediated EPSP. This NMDA EPSP potentiation was occluded by prior induction of LTP in normal solution. Using a solution containing 0.1 mM magnesium and 1 μM CNQX, the EPSP was composed of both a non-NMDA- and an NMDA-mediated component which could be measured separately and in parallel. Manipulations that cause increased transmitter release, such as phorbol ester application and changes in stimulation frequency, enhanced the two measures nearly equally. Afferent tetanization induced an increase of both EPSP components, with a similar time course, the NMDA component showing a relative increase of about one-third of that of the non-NMDA one. These results suggest that, to the extent that LTP is based on an increased release of transmitter, the mechanism exhibits features distinct from those underlying other forms of enhanced release.     

Long-term Potentiation and Field EPSPs in the Lateral and Medial Perforant Paths in the Dentate Gyrus In Vitro: a Comparison

The entorhinal cortex projects monosynaptically to the granule cells in the dentate gyrus via the lateral and medial perforant paths. These two subdivisions of the perforant path differ with respect to synaptic properties, and recent studies suggest that they also differ with respect to long-term potentiation (LTP). In the present study, using the in vitro slice preparation of the guinea-pig hippocampus, field excitatory postsynaptic potentials (EPSPs) and LTP in the lateral and medial perforant paths were compared. The two pathways were distinguished on the basis of their different termination in the dendritic layer, their different pharmacology and short-term synaptic facilitation. The field EPSP [obtained in the presence of γ-aminobutyric acid (GABA) A and B receptor antagonists] consisted of a non- N -methyl- d -aspartate (NMDA) component with different time characteristics in the two pathways, the decay being monoexponential in the lateral perforant path and biexponential in the medial one. In addition, the field EPSP in both pathways contained a small NMDA-mediated component that could also be observed after complete blockade of the non-NMDA one. LTP induction in both lateral and medial perforant paths was facilitated by blockade of GABA_A inhibition, showed associative properties, and was blocked by NMDA receptor antagonists. Following the induction event, LTP in both pathways developed to a peak value within 30–40 s, and the stability of LTP was correlated with the amount of postsynaptic, but not presynaptic, activity during the induction event. During blockade of GABA_A inhibition the opioid receptor antagonist naloxone and the β-adrenergic antagonist timolol had no effect on the magnitude or stability of LTP. It is concluded that LTP in the lateral and medial perforant paths does not differ with respect to induction mechanisms and early temporal characteristics.     

Antagonists of the Platelet-activating Factor Receptor Block Long-term Potentiation in Hippocampal Slices

The effects of antagonists and agonists of the platelet-activating factor (PAF) receptor on the formation of long-term potentiation (LTP) were examined in slices of rat hippocampus. The antagonist trans- BTD (trans-2,5-bis-(3,4,5-trimethoxyphenyl)-1,3-dioxolane) at concentrations of 8–16 μM blocked LTP in field CA1 while the same concentration of a stereo isomer ( cis -BTD) with low affinity for PAF receptors was without effect. CV3988, an antagonist structurally related to PAF, also attenuated LTP. The blockade of LTP by trans-BTD was partially reversed by simultaneous application of the non-metabolizable receptor agonist carbamyl-PAF. Trans-BTD did not change the following physiological measures: (i) paired-pulse facilitation, (ii) responses occurring during the short bursts given to induce LTP, (iii) N -methyl- d -aspartate receptor-mediated responses, and (iv) potentiation measured during the first minute after high-frequency stimulation. It thus appears that trans- BTD interferes with LTP at some step after induction and initial expression. These results suggest that activation of PAF receptors contributes to the stabilization of LTP, possibly via an effect on intracellular calcium levels.     

NMDA Receptor-dependent Transient Homo- and Heterosynaptic Depression in Picrotoxin-treated Hippocampal Slices

Extracellular recording was used to study the effects of high-frequency (tetanic) stimulation on excitatory synaptic transmission in the CA1 region of rat hippocampal slices in the presence of the _γ-aminobutyric acid (GABA) type A antagonist, picrotoxin (50 _γM). Under these conditions tetanic stimulation (100 Hz, 1 s) at the test intensity resulted in homosynaptic long-term potentiation (LTP). In contrast, tetanic stimulation of higher intensity (100 Hz, 1 s, double test intensity) resulted in homo- and heterosynaptic depression which recovered within 45 min. A transient (1–3 min) negative shift in DC potential and a transient (5–10 min) depression of the homosynaptic fibre volley occurred immediately following the higher intensity tetanus. The DC shift, induction of homo- and heterosynaptic depression and depression of the fibre volley were reversibly prevented by the N -methyl- d -aspartate (NMDA) receptor antagonist, d -2-amino-5-phosphonopentanoate (AP5; 20 _γM) but were not prevented by a variety of L-type calcium channel antagonists. Transient (30 - 45 min) synaptic depression of pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials also occurred following tetanic stimulation (100 Hz, 1 s) at double test intensity. These results demonstrate an NMDA receptor-dependent form of reversible synaptic depression in the CA1 region of the hippocampus.     

Simultaneous Expression of Long-term Depression of NMDA and Long-term Potentiation of AMPA Receptor-mediated Synaptic Responses in the CA1 Area of the Kainic Acid-lesioned Hippocampus

This study investigates the plasticity of the excitatory synapses in an experimental model of epilepsy, the kainic acid-lesioned rat hippocampus. Stimulation of afferents in the CA1 area of lesioned hippocampi produced an epileptiform burst of action potentials, with an underlying synaptic potential composed of mixed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; 80%) and N -methyl-D-aspartate (NMDA; 20%) receptor-mediated components. Tetanic stimulation yielded a long-term potentiation (LTP) of the mixed AMPA/NMDA receptor-mediated population excitatory postsynaptic potentials. However, the same type of tetanus resulted in a long-term depression (LTD) of pharmacologically isolated NMDA receptor-mediated responses. This LTD occurred independently of the antagonism of AMPA receptors. This suggests that tetanic stimulation produced LTP of AMPA and LTD of NMDA receptor-mediated responses simultaneously. Finally, both LTP and LTD were shown to be NMDA dependent. This property has profound functional implications for the control of excitatory networks in temporal lobe epilepsy. This work was supported by the Wellcome Trust and the Fondation Simone et Cino Del Duca.     

Coactivation of Local Circuit NMDA Receptor Mediated epsps Induces Lasting Enhancement of Minimal Schaffer Collateral epsps in Slices of Rat Hippocampus

Lasting enhancement of minimal Schaffer collateral epsps in CA1 pyramidal neurons was induced when these epsps were coactivated with putative local circuit N-methyl-d-aspartate (NMDA) receptor-mediated epsps. In transverse slices of hippocampus, minimal epsps were evoked by stimulating the Schaffer collateral/commissural pathway within CA3 stratum radiatum and the local circuit axons were stimulated within CA1 stratum oriens or alveus using fine, two barrel glass micropipettes. Minimal Schaffer collateral epsps were insensitive to d-2-amino-5-phosphonovalerate (AP-5) and displayed conventional voltage relations. Local epsps were sensitive to AP-5 and increased in amplitude and duration with membrane depolarization. High frequency tetanic stimulation of the minimal Schaffer collateral epsps induced no lasting enhancement. However, pairing of the Schaffer epsp with a frequency potentiated local epsp resulted in a delayed, but lasting increase in the Schaffer epsp. When the local epsp did not exhibit frequency potentiation during pairing, no enhancement resulted. When either epsp was contaminated with an ipsp, no lasting increase resulted. When transmission through the alveus was blocked by focal application of local anaesthetic, traditional protocols for long-term potentiation (LTP) induction were relatively ineffective. These results indicate that a significant source of the NMDA receptor activation required for the induction of LTP in the Schaffer collateral input to CA1 derives from local circuit connections between CA1 pyramidal neurons and, moreover, that lasting enhancement can be induced with low frequency activation, at postsynaptic resting potential, in the presence of Mg2+ and with local inhibition intact.     

Differential localization of NMDA and AMPA receptor subunits in the lateral and basal nuclei of the amygdala: A light and electron microscopic study

Anatomical and physiological studies indicate that the amino acid L-glutamate is the excitatory transmitter in sensory afferent pathways to the amygdala and in intraamygdala circuits involving the lateral and basal nuclei. The regional, cellular, and subcellular immunocytochemical localizations of N-methyl-D-aspartate (NMDA) and L-α-amino-3–hydroxy-5–methyl- 4–isoxazole propionate (AMPA), two major classes of glutamate receptors, were examined in these areas of the amygdala. A monoclonal antibody and a polyclonal antiserum directed against the R1 subunit of the NMDA receptor were used. Each immunoreagent produced distinct distributions of perikaryal and neuropilar staining. Dendritic immunoreactivity was localized primarily to asymmetric (excitatory) synaptic junctions, mostly on spines, consistent with the conventional view of the organization and function of NMDA receptors. Whereas the anti-NMDAR1 antiserum produced sparse presynaptic axon terminal labeling and extensive glial labeling, the anti-NMDAR1 antibody labeled considerably fewer glia and many more presynaptic axon terminals. Labeled presynaptic terminals formed asymmetric and symmetric synapses, suggesting presynaptic regulation of both excitatory and inhibitory transmission. Immunoreactivity for different subunits of the AMPA receptor (GluR1, GluR2/3, and GluR4) was uniquely distributed across neuronal populations, and some receptor subunits were specific to certain cell types. Immunoreactivity for GluR1 and Glu2/3 was predominately localized to dendritic shafts and was more extensive than that of GluR4 due to heavy labeling of proximal portions of dendrites. The distribution of GluR4 immunoreactivity was similar to NMDAR1: GluR4 was seen in presynaptic terminals, glia, and dendrites and was primarily localized to spines. The presynaptic localization of GluR4 in the absence of GluR2 suggests glutamate. mediated modulation of presynaptic Ca⁺⁺ concentrations. These data add to our understanding of the morphological basis of pre- and postsynaptic transmission mechanisms and synaptic plasticity in the amygdala. © Wiley-Liss, Inc.     

Reparatory effects of nicotine on NMDA receptor-mediated synaptic plasticity in the hippocampal CA1 region of chronically lead-exposed rats

Activation of neuronal nicotinic acetylcholine receptors (nAChRs) modulates the induction of long-term potentiation (LTP): a possible cellular mechanism of learning. To investigate the effect of nicotine on synaptic plasticity in chronically lead-exposed rats, field excitatory postsynaptic potentials and paired-pulse facilitation (PPF) were recorded in the CA1 area of hippocampal slices from chronically lead-exposed 23-30-day-old rats. The results showed the following. (1) Nicotine (1 microm) facilitated the induction of LTP in CA1 by a weak tetanic stimulation (100 Hz, 20 pulses), which does not by itself produce LTP in lead-exposed rats. This effect was significantly suppressed by mecamylamine, a nicotinic antagonist, suggesting that the facilitation of LTP was through nAChRs. (2) The nicotine-facilitated LTP was blocked by dihydro-beta-erythroidine (DHbetaE), a non-alpha7 nAChR antagonist, whereas long-term depression (LTD) was produced by the combination of nicotine and methyllycaconitine, a alpha7-nAChR antagonist. This type of LTD was blocked by DHbetaE. This suggested that several nAChR subtypes were involved in the nicotine-facilitated synaptic plasticity. (3) Nicotine enhanced PPF in the hippocampal CA1 region, and the nicotine-facilitated LTP in lead-exposed rats was blocked by either d-(-)-2-amino-5-phosphonopentanoic acid, the N-methyl-d-aspartate (NMDA) receptor antagonist, or picrotoxin, an antagonist of gamma-aminobutyric acid(A) receptors. We suggest that nicotine-facilitated synaptic plasticity was due to the activation of NMDARs by disinhibition of pyramidal cells through presynaptic nAChRs. This may represent the cellular basis of nicotine-facilitated cognitive enhancement observed in chronically lead-exposed rats.     

Steroid pregnenolone sulfate enhances NMDA-receptor-independent long-term potentiation at hippocampal CA1 synapses: role for L-type calcium channels and sigma-receptors

Severe stress elevates plasma and CNS levels of endogenous neuroactive steroids that can contribute to the influence of stress on memory formation. Among the neuroactive steroids, pregnenolone sulfate (PREGS) reportedly strengthens memories and is readily available as a memory-enhancing supplement. PREGS actions on memory may reflect its ability to produce changes in memory-related neuronal circuits, such as long-term potentiation (LTP) of excitatory transmission in hippocampus. Here, we report a previously undiscovered pathway by which PREGS exposure promotes activity-dependent LTP of field excitatory postsynaptic potentials at CA1 synapses in hippocampal slices. Thus, application of PREGS, but not the phosphated conjugate of the steroid, selectively facilitates the induction of a slow-developing LTP in response to high-frequency (100 Hz) afferent stimulation, which is not induced in the absence of the steroid. The slow-developing LTP is independent of NMDA-receptor function (i.e., dAP5 insensitive) but dependent on functional L-type voltage-gated calcium channels (VGCC) and sigma-receptors. By contrast, PREGS at the highest concentration tested produces a depression in NMDA-receptor-dependent LTP, which is evident when sigma-receptor function is compromised by the presence of a sigma-receptor antagonist. We found that at early times during the induction phase of L-type VGCC-dependent LTP, PREGS via sigma-receptors transiently enhances presynaptic function. As well, during the maintenance phase of L-type VGCC-dependent LTP, PREGS promotes a further increase in presynaptic function downstream of LTP induction, as evidenced by a decrease in paired-pulse facilitation. The identification of complex regulatory actions of PREGS on LTP, involving sigma-receptors, L-type VGCCs, NMDA-receptors, and inhibitory circuits will aid future research endeavors aimed at understanding the precise mechanisms by which this stress-associated steroid may engage multiple LTP-signaling pathways that alter synaptic transmission at memory-related synapses.     

Characterization of the single-channel properties of NMDA receptors in laminae I and II of the dorsal horn of neonatal rat spinal cord

The single-channel properties of native NMDA receptors in laminae I and II of the dorsal horn of the neonatal rat spinal cord were studied using outside-out patch-clamp techniques. These receptors were found to have several features that distinguish them from native NMDA receptors elsewhere in the CNS. Single-channel currents activated by NMDA (100 nm) and glycine (10 microm) exhibited five distinct amplitude components with slope-conductance values of 19.9 +/- 0.8, 32.9 +/- 0.6, 42.2 +/- 1.1, 53.0 +/- 1.0 and 68.7 +/- 1.5 pS. Direct transitions were observed between all conductance levels but transitions between 69-pS openings and 20-, 33- and 42-pS openings were rare. There was no significant difference in the frequency of direct transitions from 42- to 20-pS compared to 20- to 42-pS transitions. The Kb (0 mV) for Mg2+ was 89 microm. The Mg2+ unblocking rate constant was similar to other reported values. However, the Mg2+ blocking rate constant was larger than other reported values, suggesting an unusually high sensitivity to Mg2+. The NR2B subunit-selective antagonist, ifenprodil, had no significant effect on overall channel activity but significantly decreased the mean open time of 53-pS openings. These results suggest neonatal laminae I and II NMDA receptors are not simply composed of NR1 and NR2B subunits or NR1 and NR2D subunits. It is possible that these properties are due to an as yet uninvestigated combination of two NR2 subunits with the NR1 subunit or a combination of NR3A, NR2 and NR1 subunits.     

Long-term Depression in the Hippocampal CA1 Region is Associated with Equal Changes in AMPA and NMDA Receptor-mediated Synaptic Potentials

In the CA1 hippocampal region low-frequency (1-2 Hz) afferent activation leads to a long-term depression of excitatory synaptic potentials that is induced by calcium influx through postsynaptic N -methyl- d -aspartate receptor channels. In the present experiments using 2- to 3-week-old rats, long-term depressions of field excitatory postsynaptic potentials mediated by amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and by N -methyl- d -aspartate receptor channels were examined in parallel, using a perfusion solution containing low concentrations of an AMPA receptor antagonist and of magnesium (0.1 mM). These experiments revealed that long-term depression was associated with equal relative changes in the two components of the field potential, compatible with a presynaptic location of the expression mechanism for the long-term depression.     

Long-term plasticity of visually evoked potentials in humans is altered in major depression.

BACKGROUND: Long-term synaptic plasticity is a ubiquitous form of neuronal plasticity that regulates the strength of synaptic transmission in many brain areas. However, most data on long-term potentiation and long-term depression rely on research in animal brain slices. The role of synaptic plasticity in physiology and pathology of the functioning human brain remains obscure. Considering recent studies that provided evidence for a dysfunction of brain plasticity as the neurobiological basis of affective disorders, we assessed neural transmission and its plastic modulation in the visual pathway in healthy control subjects and patients with major depression. METHODS: Recordings of visually evoked potentials (VEPs) in humans. RESULTS: Prolonged visual presentation of checkerboard reversals resulted in a sustained amplitude modulation of early components of subsequent VEPs. After a 10-min block of visual stimulation (two checkerboard reversals per second), the C1 component was reduced, whereas P1 and N1 were both significantly increased for >30 min. Chronic application of the selective serotonin reuptake inhibitor sertraline in healthy control subjects augmented these effects, whereas the polarity of the modulation was inverted in patients with severe major depression. Moreover, early VEP amplitudes were decreased in depressed patients when compared with matched control subjects and increased in normal control subjects after chronic intake of an antidepressant. CONCLUSIONS: Our results demonstrate that stimulus-induced response plasticity of VEPs can be induced in the human brain and is sharing properties with hebbian forms of synaptic plasticity. Major depression and antidepressant treatment of healthy control subjects differentially modulate amplitude and plasticity of evoked potentials. This study provides direct evidence in humans for a central role of synaptic plasticity in the pathophysiology of depression.     

Tyrosine phosphorylation of the GluR2 subunit is required for long-term depression of synaptic efficacy in young animals in vivo

The study of the intracellular mechanics that underlay changes in synaptic efficacy is a rapidly evolving field of research. It is currently believed that NMDA receptors play a significant role in the induction of synaptic plasticity, whereas AMPA receptors play a significant role in its expression. For AMPA receptors, it has been shown that tyrosine phosphorylation of the GluR2 carboxyl termini is required for the expression of long-term depression of synaptic efficacy (LTD) in vitro (Ahmadian et al. (2004) EMBO J 23:1040-1050). In the present study, we sought to determine whether similar mechanisms are involved in vivo, where different stimulation parameters are required for the induction of LTD. We initially used a paired-burst (PB) paradigm that reliably induces LTD in vivo. In these animals we were able to prevent the induction and expression of PB-LTD by administering a peptide (GluR-3Y) that acted as a competitive inhibitor of tyrosine phosphorylation. In a separate set of animals, we exposed animals to brief periods of stress (S) before using low-frequency stimuli to induce LTD (S-LTD). Again, GluR2-3Y blocked both the induction and expression of S-LTD. In contrast, an inert version of the peptide, with alanine replacing the three tyrosine residues, did not inhibit LTD induction. In addition, we demonstrated that GluR2-3Y did not affect the induction of long-term potentiation in vivo. These findings support the hypothesis that tyrosine phosphorylation and AMPA receptor endocytosis are necessary steps for the induction and maintenance of two forms of LTD in the CA1 region.     

Activation of the glycine site associated with the NMDA receptor is required for induction of LTP in neonatal hippocampus

The role played by the glycine site associated with the NMDA receptor in inducing long-term potentiation (LTP) in neonatal hippocampus was examined. An antagonist of the glycine site, 7-chlorokynurenic acid (Cl-Kyn), completely blocked both the short-term and the long-term potentiation associated with theta burst stimulation (TBS) linked to NMDA receptor activation in slices from hippocampus at postnatal days 10-16; this effect was reversed by the glycine agonist, D-serine. Analysis of the TBS-evoked responses showed: (1) a developmental alteration in the burst response morphology that may be related to maturation of GABA-mediated inhibition; and (2) that, unlike 2-amino-5-phosphonovalerate (AP5), Cl-Kyn did not reduce any portion of the burst response. These results suggest that stimulation of the glycine site coupled to the NMDA receptor complex is necessary to induce LTP in neonatal tissue and that two NMDA receptor types may be present in the hippocampus.     

Metaplastic Reinforcement of Long-Term Potentiation in Hippocampal Area CA2 by Cholinergic Receptor Activation

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years because of its role in social memory formation. However, the role of cholinergic inputs to the CA2 area for the regulation of synaptic plasticity remains to be fully understood. We show that cholinergic receptor activation with the nonselective cholinergic agonist, carbachol (CCh), triggers a protein synthesis-dependent and NMDAR-independent long-term synaptic depression (CCh-LTD) at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses in the hippocampus of adult male Wistar rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of CCh-LTD with the results suggesting an involvement of M3 and M1 mAChRs in the early facilitation of CCh-LTD, while nicotinic AChR activation plays a role in the late maintenance of CCh-LTD at CA2 synapses. Remarkably, we find that CCh priming lowers the threshold for the subsequent induction of persistent long-term potentiation (LTP) of synaptic transmission at EC-CA2 and the plasticity-resistant SC-CA2 pathways. The effects of such a cholinergic-dependent synaptic depression on subsequent LTP at EC-CA2 and SC-CA2 synapses have not been previously explored. Collectively, the results demonstrate that CA2 synaptic learning rules are regulated in a metaplastic manner, whereby modifications triggered by prior cholinergic stimulation can dictate the outcome of future plasticity events. Moreover, the reinforcement of LTP at EC inputs to CA2 following the priming stimulus coexists with concurrent sustained CCh-LTD at the SC-CA2 pathway and is dynamically scaled by modulation of SC-CA2 synaptic transmission.SIGNIFICANCE STATEMENT The release of the neuromodulator acetylcholine is critically involved in processes of hippocampus-dependent memory formation. Cholinergic afferents originating in the medial septum and diagonal bands of Broca terminating in the hippocampal area CA2 might play an important role in the modulation of area-specific synaptic plasticity. Our findings demonstrate that cholinergic receptor activation induces an LTD of synaptic transmission at entorhinal cortical- and Schaffer collateral-CA2 synapses. This cholinergic activation-mediated LTD displays a bidirectional metaplastic switch to LTP on a future timescale. This suggests that such bidirectional synaptic modifications triggered by the dynamic modulation of tonic cholinergic receptor activation may support the formation of CA2-dependent memories given the increased hippocampal cholinergic tone during active wakefulness observed in exploratory behavior.     

EPO induces changes in synaptic transmission and plasticity in the dentate gyrus of rats

Erythropoietin has shown wide physiological effects on the central nervous system in animal models of disease, and in healthy animals. We have recently shown that systemic EPO administration 15 min, but not 5 h, after daily training in a water maze is able to induce the recovery of spatial memory in fimbria‐fornix chronic‐lesioned animals, suggesting that acute EPO triggers mechanisms which can modulate the active neural plasticity mechanism involved in spatial memory acquisition in lesioned animals. Additionally, this EPO effect is accompanied by the up‐regulation of plasticity‐related early genes. More remarkably, this time‐dependent effects on learning recovery could signify that EPO in nerve system modulate specific living‐cellular processes. In the present article, we focus on the question if EPO could modulate the induction of long‐term synaptic plasticity like LTP and LTD, which presumably could support our previous published data. Our results show that acute EPO peripheral administration 15 min before the induction of synaptic plasticity is able to increase the magnitude of the LTP (more prominent in PSA than fEPSP‐Slope) to facilitate the induction of LTD, and to protect LTP from depotentiation. These findings showing that EPO modulates in vivo synaptic plasticity sustain the assumption that EPO can act not only as a neuroprotective substance, but is also able to modulate transient neural plasticity mechanisms and therefore to promote the recovery of nerve function after an established chronic brain lesion. According to these results, EPO could be use as a molecular tool for neurorestaurative treatments. Synapse 70:240–252, 2016 . © 2016 Wiley Periodicals, Inc.