Differential Effect of TEA on Long-Term Synaptic Modification in Hippocampal CA1 and Dentate Gyrus in vitro

The effectiveness of tetraethylammonium (TEA) and high-frequency stimulation (HFS) in inducing long-term synaptic modification is compared in CA1 and dentate gyrus (DG) in vitro. High-frequency stimulation induces long-term potentiation (LTP) at synapses of both perforant path-DG granule cell and Schaffer collateral-CA1 pyramidal cell pathways. By contrast, TEA (25 mM) induces long-term depression in DG while inducing LTP in CA1. The mechanisms underlying the differential effect of TEA in CA1 and DG were investigated. It was observed that T-type voltage-dependent calcium channel (VDCC) blocker, Ni²⁺ (50 μM), partially blocked TEA-induced LTP in CA1. A complete blockade of the TEA-induced LTP occurred when Ni²⁺ was applied together with the NMDA receptor antagonist, D-APV. The L-type VDCC blocker, nifidipine (20 μM), had no effect on CA1 TEA-induced LTP. In DG of the same slice, TEA actually induced long-term depression (LTD) instead of LTP, an effect that was blocked by D-APV. Neither T-type nor L-type VDCC blockade could prevent this LTD. When the calcium concentration in the perfusion medium was increased, TEA induced a weak LTP in DG that was blocked by Ni²⁺. During exposure to TEA, the magnitude of field EPSPs was increased in both CA1 and DG, but the increase was substantially greater in CA1. Tetraethylammonium application also was associated with a large, late EPSP component in CA1 that persisted even after severing the connections between CA3 and CA1. All of the TEA effects in CA1, however, were dramatically reduced by Ni²⁺. The results of this study indicate that TEA indirectly acts via both T-type VDCCs and NMDA receptors in CA1 and, as a consequence, induces LTP. By contrast, TEA indirectly acts via only NMDA receptors in DG and results in LTD. The results raise the possibility of a major synaptic difference in the density and/or distribution of T-type VDCCs and NMDA receptors in CA1 and DG of the rat hippocampus.     

Co-induction of long-term potentiation and long-term depression at a central synapse in the leech

Most studies of long-term potentiation (LTP) have focused on potentiation induced by the activation of postsynaptic NMDA receptors (NMDARs). However, it is now apparent that NMDAR-dependent signaling processes are not the only form of LTP operating in the brain [Malenka, R. C., & Bear, M. F. (2004). LTP and LTD: An embarrassment of riches. Neuron, 44, 5–21]. Previously, we have observed that LTP in leech central synapses made by the touch mechanosensory neurons onto the S interneuron was NMDAR-independent [Burrell, B. D., & Sahley, C. L. (2004). Multiple forms of long-term potentiation and long-term depression converge on a single interneuron in the leech CNS. Journal of Neuroscience, 24, 4011–4019]. Here we examine the cellular mechanisms mediating T-to-S (T → S) LTP and find that its induction requires activation of metabotropic glutamate receptors (mGluRs), voltage-dependent Ca²⁺ channels (VDCCs) and protein kinase C (PKC). Surprisingly, whenever LTP was pharmacologically inhibited, long-term depression (LTD) was observed at the tetanized synapse, indicating that LTP and LTD were activated at the same time in the same synaptic pathway. This co-induction of LTP and LTD likely plays an important role in activity-dependent regulation of synaptic transmission.     

Synaptic plasticity in hippocampal CA1 neurons of mice lacking type 1 inositol-1,4,5-trisphosphate receptors

In hippocampal CA1 neurons of wild-type mice, delivery of a standard tetanus (100 pulses at 100 Hz) or a train of low-frequency stimuli (LFS; 1000 pulses at 1 Hz) to a naive input pathway induces, respectively, long-term potentiation (LTP) or long-term depression (LTD) of responses, and delivery of LFS 60 min after tetanus results in reversal of LTP (depotentiation, DP), while LFS applied 60 min before tetanus suppresses LTP induction (LTP suppression). To evaluate the role of the type 1 inositol-1,4,5-trisphosphate receptor (IP3R1) in hippocampal synaptic plasticity, we studied LTP, LTD, DP, and LTP suppression of the field excitatory postsynaptic potentials (EPSPs) in the CA1 neurons of mice lacking the IP3R1. No differences were seen between mutant and wild-type mice in terms of the mean magnitude of the LTP or LTD induced by a standard tetanus or LFS. However, the mean magnitude of the LTP induced by a short tetanus (10 pulses at 100 Hz) was significantly greater in mutant mice than in wild-type mice. In addition, DP or LTP suppression was attenuated in the mutant mice, the mean magnitude of the responses after delivery of LFS or tetanus being significantly greater than in wild-type mice. These results suggest that, in hippocampal CA1 neurons, the IP3R1 is involved in LTP, DP, and LTP suppression but is not essential for LTD. The facilitation of LTP induction and attenuation of DP and LTP suppression seen in mice lacking the IP3R1 indicates that this receptor plays an important role in blocking synaptic potentiation in hippocampal CA1 neurons.     

Dopamine induces LTP differentially in apical and basal dendrites through BDNF and voltage-dependent calcium channels

The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC). Activation via NMDAR is critical for the induction of DA-LTP in both apical and basal dendrites, but only BDNF is required for the induction and maintenance of DA-LTP in apical dendrites. We report that dopaminergic modulation of LTP is lamina-specific at the Schaffer collateral/commissural synapses in the CA1 region.     

The Specific Role of cGMP in Hippocampal LTP

Previous results have suggested that cGMP is involved in hippocampal long-term potentiation (LTP), perhaps as the presynaptic effector of a retrograde messenger. However, other studies have failed to replicate some of those results, making the role of cGMP uncertain. We therefore reexamined this question and identified several variables that can affect the contribution of cGMP. First, brief perfusion with 8-Br–cGMP before weak tetanic stimulation produced long-lasting potentiation in the CA1 region of hippocampal slices, but more prolonged perfusion with 8-Br–cGMP before the tetanus did not produce long-lasting potentiation. Second, the activity-dependent long-lasting potentiation by cGMP analogs was reduced when NMDA receptors were completely blocked, indicating that NMDA receptor activation contributes to, but is not required for, the potentiation. The amount of reduction of the potentiation differed with different protocols, and in some cases could be complete. Third, LTP produced by strong tetanic stimulation in the stratum radiatum of CA1 (which expresses eNOS) was blocked by inhibitors of soluble guanylyl cyclase or cGMP-dependent protein kinase, but LTP in the stratum oriens (which does not express eNOS) was not. The results of these experiments should help to explain some of the discrepant findings from previous studies, and, in addition, may provide insights into the mechanisms and functional role of the cGMP-dependent component of LTP.     

Involvement of IP3 receptors in LTP and LTD induction in guinea pig hippocampal CA1 neurons

The role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) in long-term potentiation (LTP) and long-term depression (LTD) was studied in CA1 neurons in guinea pig hippocampal slices. In standard solution, short tetanic stimulation consisting of 15 pulses at 100 Hz induced LTP, while three short trains of low-frequency stimulation (LFS; 200 pulses at 1 Hz) at 18-min intervals or one long train of LFS (1000 pulses at 1 Hz) induced stable LTD in both the slope of the field EPSP (S-EPSP) and the amplitude of the population spike (A-PS). Bath application of 2-aminoethoxydiphenyl borate (2-APB), an IP3R antagonist, or of alpha-methyl-4-carboxyphenylglycine (MCPG), a wide-spectrum metabotropic glutamate receptor antagonist, during weak tetanic stimulation significantly increased the magnitude of the LTP in both the S-EPSP and A-PS. Three short trains of LFS or one long train of LFS delivered in the presence of 2-APB or MCPG did not induce LTD, but elicited LTP. Based on these results, we conclude that, in hippocampal CA1 neurons, IP3Rs play an important role in synaptic plasticity by attenuating LTP and facilitating LTD.     

Ovariectomy-induced disruption of long-term synaptic depression in the hippocampal CA1 region in vivo is attenuated with chronic estrogen replacement

Endogenous cyclical changes in the levels of estrogen can have marked effects on hippocampal synaptic plasticity. In two experiments, we examined the effect of chronic estrogen loss and replacement following ovariectomy on the induction of bidirectional changes in synaptic plasticity in the CA1 region in vivo. In Experiment 1, ovariectomy carried out either 5 days or 5 weeks before testing impaired the induction of long-term depression (LTD) and but not long-term potentiation (LTP). In Experiment 2, chronic estrogen replacement (0.2 ml of 10 microg injection of 17beta-estradiol every 48 h) over the course of 5 weeks enhanced the magnitude of paired-pulse-induced LTD in the CA1 region but had no effect on the induction of LTP. The results demonstrate that acute and chronic estrogen deprivation disrupted dynamic synaptic plasticity processes in the hippocampal CA1 region and that this disruption was ameliorated by chronic estrogen replacement. The findings are discussed with reference to: (1) the contribution of Ca(2+) regulated synaptic signalling pathways in the CA1 region to estradiol modulation of LTP and LTD and (2) the potential functional significance of ovariectomy-induced changes in synaptic plasticity for learning and memory processes.     

A nitric oxide-independent and beta-adrenergic receptor-sensitive form of metaplasticity limits theta-frequency stimulation-induced LTP in the hippocampal CA1 region

The induction of long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses in the hippocampus can be strongly modulated by patterns of synaptic stimulation that otherwise have no direct effect on synaptic strength. Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify synaptic strength but can also induce lasting changes that regulate how synapses will respond to subsequent trains of stimulation. Collectively known as metaplasticity, these activity-dependent processes that regulate LTP and LTD induction allow the recent history of synaptic activity to influence the induction of activity-dependent changes in synaptic strength and may thus have an important role in information storage during memory formation. To explore the cellular and molecular mechanisms underlying metaplasticity, we investigated the role of metaplasticity in the induction of LTP by υ-frequency (5-Hz) synaptic stimulation in the hippocampal CA1 region. Our results show that brief trains of υ-frequency stimulation not only induce LTP but also activate a process that inhibits the induction of additional LTP at potentiated synapses. Unlike other forms of metaplasticity, the inhibition of LTP induction at potentiated synapses does not appear to arise from activity-dependent changes in NMDA receptor function, does not require nitric oxide signaling, and is strongly modulated by β-adrenergic receptor activation. Together with previous findings, our results indicate that mechanistically distinct forms of metaplasticity regulate LTP induction and suggest that one way modulatory transmitters may act to regulate synaptic plasticity is by modulating metaplasticity.     

Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus

The dentate gyrus (DG) is among the few areas in the mammalian brain where production of new neurons continues in the adulthood. Although its functional significance is not completely understood, several lines of evidence suggest the role of DG neurogenesis in learning and memory. Considering that long-term potentiation (LTP) is a prime candidate for the process underlying hippocampal learning and memory, these results raise the possibility that LTP and neurogenesis are closely related. Here, we investigated whether or not LTP induction in the afferent pathway triggers enhanced proliferation of progenitor cells in the DG. LTP was induced by tetanic stimulation in perforant path-DG synapses in one hemisphere, and the number of newly generated progenitor (BrdU-labeled) cells in the DG was quantified. Compared with the control hemisphere (stimulated with low-frequency pulses), the LTP-induced hemisphere contained a significantly higher number of newly generated progenitor cells in the dorsal as well as ventral DG. When CPP, an NMDA receptor antagonist, was administered, tetanic stimulation neither induced LTP nor enhanced progenitor cell proliferation, indicating that NMDA receptor activation, rather than tetanic stimulation per se, is responsible for enhanced progenitor proliferation in the control animal. Our results show that tetanic stimulation of perforant path sufficient to induce LTP increases progenitor proliferation in adult DG in an NMDA receptor-dependent manner.     

Selective Abolition of the NMDA Component of Long-Term Potentiation in Mice Lacking mGluR5

The mechanisms underlying the differential expression of long-term potentiation (LTP) by AMPA and NMDA receptors, are unknown, but could involve G-protein-linked metabotropic glutamate receptors. To investigate this hypothesis we created mutant mice that expressed no metabotropic glutamate receptor 5 (mGluR5), but showed normal development. In an earlier study of these mice we analyzed field-excitatory postsynaptic potential (fEPSPs) in CA1 region of the hippocampus and found a small decrease; possibly arising from changes in the NMDAR-mediated component of synaptic transmission. In the present study we used whole-cell patch clamp recordings of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons to identify the AMPAR- and NMDAR-mediated components of LTP. Recordings from control mice following tetanus, or agonist application (IS, 3R-1-amino-cyclopentane 1,3-dicarboxylic acid) (ACPD), revealed equal enhancement of the AMPA and NMDA receptor-mediated components. In contrast, CA1 neurons from mGluR5-deficient mice showed a complete loss of the NMDA-receptor-mediated component of LTP (LTP_NMDA), but normal LTP of the AMPA-receptor-mediated component (LTP_AMPA). This selective loss of LTP_NMDA was seen in three different genotypic backgrounds and was apparent at all holding potentials (−70 mV to +20 mV). Furthermore, the LTP_NMDA deficit in mGluR5 mutant mice could be rescued by stimulating protein kinase C (PKC) with 4β-phorbol-12,13-dibutyrate (PDBu). These results suggest that PKC may couple the postsynaptic mGluR5 to the NMDA-receptor potentiation during LTP, and that this signaling mechanism is distinct from LTP_AMPA. Differential enhancement of AMPAR and NMDA receptors by mGluR5 also supports a postsynaptic locus for LTP.     

Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus

Silencing of a single gene, FMR1, is linked to a highly prevalent form of mental retardation, characterized by social and cognitive impairments, known as fragile X syndrome (FXS). The FMR1 gene encodes fragile X mental retardation protein (FMRP), which negatively regulates translation. Knockout of Fmr1 in mice results in enhanced long-term depression (LTD) induced by metabotropic glutamate receptor (mGluR) activation. Despite the evidence implicating FMRP in LTD, the role of FMRP in long-term potentiation (LTP) is less clear. Synaptic strength can be augmented heterosynaptically through the generation and sequestration of plasticity-related proteins, in a cell-wide manner. If heterosynaptic plasticity is altered in Fmr1 knockout (KO) mice, this may explain the cognitive deficits associated with FXS. We induced homosynaptic plasticity using the β-adrenergic receptor (β-AR) agonist, isoproterenol (ISO), which facilitated heterosynaptic LTP that was enhanced in Fmr1 KO mice relative to wild-type (WT) controls. To determine if enhanced heterosynaptic LTP in Fmr1 KO mouse hippocampus requires protein synthesis, we applied a translation inhibitor, emetine (EME). EME blocked homo- and heterosynaptic LTP in both genotypes. We also probed the roles of mTOR and ERK in boosting heterosynaptic LTP in Fmr1 KO mice. Although heterosynaptic LTP was blocked in both WT and KOs by inhibitors of mTOR and ERK, homosynaptic LTP was still enhanced following mTOR inhibition in slices from Fmr1 KO mice. Because mTOR will normally stimulate translation initiation, our results suggest that β-AR stimulation paired with derepression of translation results in enhanced heterosynaptic plasticity.     

'Silent' priming of translation-dependent LTP by ß-adrenergic receptors involves phosphorylation and recruitment of AMPA receptors

The capacity for long-term changes in synaptic efficacy can be altered by prior synaptic activity, a process known as "metaplasticity." Activation of receptors for modulatory neurotransmitters can trigger downstream signaling cascades that persist beyond initial receptor activation and may thus have metaplastic effects. Because activation of β-adrenergic receptors (β-ARs) strongly enhances the induction of long-term potentiation (LTP) in the hippocampal CA1 region, we examined whether activation of these receptors also had metaplastic effects on LTP induction. Our results show that activation of β-ARs induces a protein synthesis-dependent form of metaplasticity that primes the future induction of late-phase LTP by a subthreshold stimulus. β-AR activation also induced a long-lasting increase in phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluA1 subunits at a protein kinase A (PKA) site (S845) and transiently activated extracellular signal-regulated kinase (ERK). Consistent with this, inhibitors of PKA and ERK blocked the metaplastic effects of β-AR activation. β-AR activation also induced a prolonged, translation-dependent increase in cell surface levels of GluA1 subunit-containing AMPA receptors. Our results indicate that β-ARs can modulate hippocampal synaptic plasticity by priming synapses for the future induction of late-phase LTP through up-regulation of translational processes, one consequence of which is the trafficking of AMPARs to the cell surface.     

Dopamine transporter blockade increases LTP in the CA1 region of the rat hippocampus via activation of the D3 dopamine receptor

Dopamine has been demonstrated to be involved in the modulation of long-term potentiation (LTP) in the CA1 region of the hippocampus. As monoamine transporter blockade will increase the actions of endogenous monoamine neurotransmitters, the effect of a dopamine transporter (DAT) antagonist on LTP was assessed using field excitatory postsynaptic potentials recorded in the CA1 region of the rat hippocampal slice preparation. Application of the DAT-specific blocker GBR 12,935 produced a significant enhancement in LTP of Schaffer collateral synapses in the CA1 at concentrations as low as 100 nM. A selective D1/D5 dopamine receptor antagonist (SCH 23,390, 1 microM) did not affect the ability of GBR 12,935 to enhance LTP, whereas application of the D3 dopamine receptor antagonist U 99,194 (1 microM) blocked the GBR 12,935-induced enhancement in LTP. In addition, a D3 dopamine receptor agonist (7-OH-DPAT, 1 microM) caused a significant increase in LTP, an effect that was also blocked by U 99,194 (3 microM). These results suggest that either endogenously released dopamine (facilitated by DAT blockade) or exogenously applied dopamine agonist can act to increase LTP in the CA1 of the hippocampus via activation of the D3 subtype of dopamine receptor.     

Age-related enhancement of a protein synthesis-dependent late phase of LTP induced by low frequency paired-pulse stimulation in hippocampus

Protein synthesis-dependent late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation (HFS). This form of L-LTP is reduced in the aged animal and is positively correlated with age-related memory loss. Here we report a novel form of protein synthesis-dependent late phase of LTP in the CA1 region of hippocampus induced by a brief 1-Hz paired-pulse stimulation (PP-1 Hz, 1 min). In contrast to L-LTP induced by HFS, the late phase of PP-1 Hz LTP does not exist in young adult animals. Rather, it emerges and becomes enhanced in an age-related way. Thus, in 1.5- to 2-mo-old mice, a brief PP-1 Hz stimulation induces only a short lasting LTP, decaying to baseline in about 90 min. By contrast, PP-1 Hz stimulation induces an enduring and protein synthesis dependent LTP in 12- to 18-mo-old mice. The PP-1 Hz-induced L-LTP is dependent on NMDA receptor activation, requires voltage-dependent calcium channels, and is modulated by dopamine D1/D5 receptors. Because memory ability declines with aging, the age-related enhancement of L-LTP induced by PP-1 Hz stimulation indicates that this form of L-LTP appears to be inversely correlated with memory ability.     

A model of bidirectional synaptic plasticity: from signaling network to channel conductance

In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of sites on the alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit protein GluR1. Bidirectional synaptic plasticity can be induced by different frequencies of presynaptic stimulation, but there is considerable evidence indicating that the key variable is calcium influx through postsynaptic N-methyl-d-aspartate (NMDA) receptors. Here, we present a biophysical model of bidirectional synaptic plasticity based on [Ca2+]-dependent phospho/dephosphorylation of the GluR1 subunit of the AMPA receptor. The primary assumption of the model, for which there is wide experimental support, is that the postsynaptic calcium concentration, and consequent activation of calcium-dependent protein kinases and phosphatases, is the trigger for phosphorylation/dephosphorylation at GluR1 and consequent induction of LTP/LTD. We explore several different mathematical approaches, all of them based on mass-action assumptions. First, we use a first order approach, in which transition rates are functions of an activator, in this case calcium. Second, we adopt the Michaelis-Menten approach with different assumptions about the signal transduction cascades, ranging from abstract to more detailed and biologically plausible models. Despite the different assumptions made in each model, in each case, LTD is induced by a moderate increase in postsynaptic calcium and LTP is induced by high Ca2+ concentration.     

Differential effects of PACAP-38 on synaptic responses in rat hippocampal CA1 region

Pituitary adenylate cyclase-activating polypeptide (PACAP-38) is a member of the vasointestinal polypeptide (VIP)/secretin/glucagon family of neuropeptides for which neuroregulatory functions have been postulated. PACAP-38 receptors are expressed in different brain regions, including hippocampus. In this study, we examined the dose-dependent effects of PACAP-38 on the excitatory postsynaptic field potential (fEPSP) evoked at the Schaffer collateral-CA1 synapse in rat hippocampal slices. Bath application of low dose (0.05 nM) of PACAP-38 induced long-lasting facilitation of the fEPSP. This enhancement was blocked by the cholinergic receptor antagonist atropine and partially by the NMDA receptor antagonist 2-amino-5-phosphonovalerate (APV) and therefore, shares a common mechanism with LTP. In contrast, a high dose (1 μM) of PACAP-38 induced a persistent depression of the fEPSP that was not blocked by antagonists of cholinergic receptors (i.e., atropine and mecamylamine), adenosine receptors (i.e., DCPCX), or glutamatergic NMDA receptors (APV). Intermediate doses (0.1–0.5 μM) of PACAP-38 produced an initial decrease of the fEPSP followed by an enhancement. This decrease was not blocked by atropine whereas the facilitation was. These results show that PACAP-38 modulates CA1 synaptic transmission in a dose-dependent manner and that the peptide interacts with cholinergic and glutamatergic systems.     

Associative, bidirectional changes in neural signaling utilizing NMDA receptor- and endocannabinoid-dependent mechanisms

Persistent, bidirectional changes in synaptic signaling (that is, potentiation and depression of the synapse) can be induced by the precise timing of individual pre- and postsynaptic action potentials. However, far less attention has been paid to the ability of paired trains of action potentials to elicit persistent potentiation or depression. We examined plasticity following the pairing of spike trains in the touch mechanosensory neuron (T cell) and S interneuron (S cell) in the medicinal leech. Long-term potentiation (LTP) of T to S signaling was elicited when the T-cell spike train preceded the S-cell train. An interval 0 to +1 sec between the T- and S-cell spike trains was required to elicit long-term potentiation (LTP), and this potentiation was NMDA receptor (NMDAR)-dependent. Long-term depression (LTD) was elicited when S-cell activity preceded T-cell activity and the interval between the two spike trains was -0.2 sec to -10 sec. This surprisingly broad temporal window involved two distinct cellular mechanisms; an NMDAR-mediated LTD (NMDAR-LTD) when the pairing interval was relatively brief (<-1 sec) and an endocannabinoid-mediated LTD (eCB-LTD) when longer pairing intervals were used (-1 to -10 sec). This eCB-LTD also required activation of a presynaptic transient receptor potential vanilloid (TRPV)-like receptor, presynaptic Ca(2+) release from intracellular stores and activation of voltage-gated Ca(2+) channels (VGCCs). These findings demonstrate that the pairing of spike trains elicits timing-dependent forms of LTP and LTD that are supported by a complex set of cellular mechanisms involving NMDARs and endocannabinoid activation of TRPV-like receptors.     

Endogenous opioid peptides contribute to associative LTP in the hippocampal CA3 region

The medial and lateral perforant path projections to the hippocampal CA3 region display distinct mechanisms of long-term potentiation (LTP) induction, N-methyl-d-aspartate (NMDA) and opioid receptor dependent, respectively. However, medial and lateral perforant path projections to the CA3 region display associative LTP with coactivation, suggesting that while they differ in receptors involved in LTP induction they may share common downstream mechanisms of LTP induction. Here we address this interaction of LTP induction mechanisms by evaluating the contribution of opioid receptors to the induction of associative LTP among the medial and lateral perforant path projections to the CA3 region in vivo. Local application of the opioid receptor antagonists naloxone or Cys2-Tyr3-Orn5-Pen7-amide (CTOP) normally block induction of lateral perforant path-CA3 LTP. However, these opioid receptor antagonists failed to block associative LTP in lateral perforant path-CA3 synapses when it was induced by strong coactivation of the medial perforant pathway which displays NMDAR-dependent LTP. Thus strong activation of non-opioidergic afferents can substitute for the opioid receptor activation required for lateral perforant path LTP induction. Conversely, medial perforant path-CA3 associative LTP was blocked by opioid receptor antagonists when induced by strong coactivation of the opioidergic lateral perforant path. These data indicate endogenous opioid peptides contribute to associative LTP at coactive synapses when induced by strong coactivation of an opioidergic afferent system. These data further suggest that associative LTP induction is regulated by the receptor mechanisms of the strongly stimulated pathway. Thus, while medial and lateral perforant path synapses differ in their mechanisms of LTP induction, associative LTP at these synapses share common downstream mechanisms of induction.     

Bidirectional plasticity in striatonigral synapses: a switch to balance direct and indirect basal ganglia pathways

There is no hypothesis to explain how direct and indirect basal ganglia (BG) pathways interact to reach a balance during the learning of motor procedures. Both pathways converge in the substantia nigra pars reticulata (SNr) carrying the result of striatal processing. Unfortunately, the mechanisms that regulate synaptic plasticity in striatonigral (direct pathway) synapses are not known. Here, we used electrophysiological techniques to describe dopamine D(1)-receptor-mediated facilitation in striatonigral synapses in the context of its interaction with glutamatergic inputs, probably coming from the subthalamic nucleus (STN) (indirect pathway) and describe a striatonigral cannabinoid-dependent long-term synaptic depression (LTD). It is shown that striatonigral afferents exhibit D(1)-receptor-mediated facilitation of synaptic transmission when NMDA receptors are inactive, a phenomenon that changes to cannabinoid-dependent LTD when NMDA receptors are active. This interaction makes SNr neurons become coincidence-detector switching ports: When inactive, NMDA receptors lead to a dopamine-dependent enhancement of direct pathway output, theoretically facilitating movement. When active, NMDA receptors result in LTD of the same synapses, thus decreasing movement. We propose that SNr neurons, working as logical gates, tune the motor system to establish a balance between both BG pathways, enabling the system to choose appropriate synergies for movement learning and postural support.     

Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala

Stress can profoundly affect memory and alter the functioning of the hippocampus and amygdala. Studies have also shown that the antidepressant tianeptine can block the effects of stress on hippocampal and amygdala morphology and synaptic plasticity. We examined the effects of acute predator stress and tianeptine on long-term potentiation (LTP; induced by 100 pulses in 1 s) and primed burst potentiation (PB; a low threshold form of LTP induced by only five physiologically patterned pulses) in CA1 and in the basolateral nucleus (BLA) of the amygdala in anesthetized rats. Predator stress blocked the induction of PB potentiation in CA1 and enhanced LTP in BLA. Tianeptine blocked the stress-induced suppression of PB potentiation in CA1 without affecting the stress-induced enhancement of LTP in BLA. In addition, tianeptine administered under non-stress conditions enhanced PB potentiation in the hippocampus and LTP in the amygdala. These findings support the hypothesis that acute stress impairs hippocampal functioning and enhances amygdaloid functioning. The work also provides insight into the actions of tianeptine with the finding that it enhanced electrophysiological measures of plasticity in the hippocampus and amygdala under stress, as well as non-stress, conditions.