NMDAR-independent Long-term Potentiation Research Articles

Hyperoside improves learning and memory deficits by amyloid β1-42 in mice through regulating synaptic calcium-permeable AMPA receptors

Alzheimer's disease (AD) is the most common degenerative disease and is indicative of dementia. The cerebral accumulation of amyloid β (Aβ), a crucial factor in AD, initiates synaptic and cognitive dysfunction. Therefore, the elevation of synaptic and cognitive functions may help manage dementia in AD. In this study, we suggest hyperoside as a synaptic function- and memory-enhancing agent. Hyperoside enhanced learning and memory in passive avoidance and object recognition tasks. Hyperoside facilitated synaptic long-term potentiation (LTP) in acute hippocampal slices. IEM-1460, a calcium-permeable amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) antagonist, blocked the facilitation effect of hyperoside. Hyperoside also induced N-methyl-d-aspartate receptor (NMDAR)-independent LTP, which was blocked by IEM-1460, suggesting the involvement of CP-AMPARs in the synaptic effects of hyperoside-mediated LTP. PKI (a PKA inhibitor) or SQ22536 (adenylyl cyclase, an AC inhibitor) blocked hyperoside-facilitated LTP and hyperoside-induced NMDAR-independent LTP. Hyperoside-enhanced learning and memory were blocked by IEM-1460, suggesting the involvement of CP-AMPARs in the effect of hyperoside on learning and memory. Finally, hyperoside ameliorated Aβ-induced memory impairments in an AD mouse model. These results suggest that hyperoside enhances learning and memory, and this may be due to the effect of CP-AMPARs.

NMDA receptor-independent LTP in mammalian nervous system.

Long-term potentiation (LTP) of synaptic transmission is a form of activity-dependent synaptic plasticity that exists at most synapses in the nervous system. In the central nervous system (CNS), LTP has been recorded at numerous synapses and is a prime candidate mechanism associating activity-dependent plasticity with learning and memory. LTP involves long-lasting increase in synaptic strength with various underlying mechanisms. In the CNS, the predominant type of LTP is believed to be dependent on activation of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR), which is highly calcium-permeable. However, various forms of NMDAR-independent LTP have been identified in diverse areas of the nervous system. The NMDAR-independent LTP may require activation of glutamate metabotropic receptors (mGluR) or ionotropic receptors other than NMDAR such as nicotinic acetylcholine receptor (α7-nAChR), serotonin 5-HT3 receptor or calcium-permeable AMPA receptor (CP-AMPAR). In this review, NMDAR-independent LTP of various areas of the central and peripheral nervous systems are discussed.

Oleuropein promotes hippocampal LTP via intracellular calcium mobilization and Ca2+-permeable AMPA receptor surface recruitment

Oleuropein (OLE), a major phenolic compound in olive oil, has been demonstrated to possess several pharmacological properties, including neuroprotection. However, the cognitive effects of OLE and its action mechanism have remained unclear. Here, we examined the effect of OLE on long-term potentiation (LTP) using field excitatory postsynaptic potential recorded in the CA1 region of both wild-type and 5XFAD mouse hippocampal slice preparations. In initial experiments with wild-type mice, 100 μM/1 h of OLE produced significant enhancements in the LTPs of Schaffer collateral synapses in the CA1 regions of treated mice, as compared to the vehicle-treated controls. As assessed by surface biotinylation and Western blot analysis, OLE caused a significant increase in protein kinase A (PKA)-mediated phosphorylation and the surface expression of GluA1 containing calcium permeable- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) in the hippocampus. Furthermore, we found that OLE enhanced LTP induction, while GluA1 phosphorylation occurred in an N-methyl-d-aspartate receptors (NMDARs)-independent manner. The OLE-induced CP-AMPAR trafficking resulted from elevated intracellular Ca2+ levels via regulation of phospholipase C (PLC). Consistently, we also found involvement of NMDAR-independent LTP and GluA1 phosphorylation in 5XFAD transgenic mice hippocampal slices treated with OLE. Together, our findings indicate that OLE may regulate beneficial effects on memory through the facilitation of CP-AMPAR trafficking and synaptic transmission.

Noncanonical, Dopamine-Dependent Long-Term Potentiation at Hippocampal Output Synapses in a Rodent Model of First-Episode Psychosis.

Cognitive deficits and positive symptoms in schizophrenia have both been linked to hippocampal dysfunction. Recently, subregion-specific aberrant and maladaptive hippocampal synaptic plasticity has been suggested as one of the mechanistic underpinnings. The subiculum is the final output hub of the hippocampus and orchestrates hippocampal information transfer to other brain regions. While most CA1 pyramidal neurons show regular-spiking behavior, subicular output neurons comprise bursting and regular-firing pyramidal cells. These two cell types target different brain regions and express unique forms of synaptic plasticity. Here, we used a single systemic application of the noncompetitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 to model first-episode psychosis in rats and studied long-term potentiation (LTP) in subicular regular-firing cells in acute hippocampal slices. Previously, we have reported a facilitation of a presynaptic, late-onset LTP in subicular bursting pyramidal cells after systemic NMDAR antagonism. Here, we show that single systemic NMDAR antagonist application also facilitates the induction of a noncanonical, but postsynaptic NMDAR-independent LTP in ventral subicular but not in CA1 regular-firing pyramidal cells. This form of LTP was dependent on D1/D5 dopamine receptor activation. Activation of D1/D5 dopamine receptors by a specific agonist mimicked and occluded LTP induced by electrical high-frequency stimulation (HFS). Furthermore, our results indicate that this form of LTP relies on postsynaptic Ca2+ signaling and requires the activation of protein kinase A. Considering the pivotal role of the subiculum as information gatekeeper between the hippocampus and other brain regions, this aberrant LTP in ventral subicular regular-firing neurons is expected to interfere with physiological hippocampal output processing and might thereby contribute to hippocampal dysfunction in psychotic events.

Synaptic Plasticity at Inhibitory Synapses in the Ventral Tegmental Area Depends upon Stimulation Site.

Drug exposure induces cell and synaptic plasticity within the brain reward pathway that could be a catalyst for progression to addiction. Several cellular adaptations have been described in the ventral tegmental area (VTA), a central component of the reward pathway that is the major source of dopamine release. For example, administration of morphine induces long-term potentiation (LTP) of excitatory synapses on VTA dopamine cells and blocks LTP at inhibitory synapses. Drug-induced synaptic changes have a common endpoint of increasing dopamine cell firing and dopamine release. However, gaining a complete picture of synaptic plasticity in the VTA is hindered by its complex circuitry of efferents and afferents. Most studies of synaptic plasticity in the VTA activated a mixed population of afferents, potentially yielding an incomplete and perhaps misleading view of how drugs of abuse modify VTA synapses. Here, we use midbrain slices from mice and find that electrical stimulation in two different regions induces different forms of plasticity, including two new forms of LTP at inhibitory synapses. High-frequency stimulation (HFS) induces LTP independently of NMDA receptor (NMDAR) activation, and surprisingly, some inhibitory inputs to the VTA also undergo NMDAR-independent LTP after a low-frequency stimulation (LFS) pairing protocol.

Differentially Altered NMDAR Dependent and Independent Long-Term Potentiation in the CA3 Subfield in a Model of Anti-NMDAR Encephalitis.

Purpose: Autoantibodies against NMDA receptors (NMDAR) in the cerebrospinal fluid (CSF) from anti-NMDAR encephalitis patients have been suggested to be pathogenic since in previous studies using patient CSF, NMDAR-dependent processes such as long-term potentiation (LTP) were compromised. However, autoantibodies may represent a family of antibodies targeted against different epitopes, and CSF may contain further autoantibodies. Here, we tested the specificity of the autoantibody by comparing NMDAR-dependent and NMDAR-independent LTP within the same hippocampal subfield, CA3, using CSF samples from four anti-NMDAR encephalitis patients and three control patients.Methods: We performed a stereotactic injection of patient-derived cell-free CSF with proven presence or absence of NMDAR-antibodies into the rat hippocampus in vivo. Hippocampal brain slices were prepared 1–8 days after intrahippocampal injection, and NMDAR-dependent LTP at the associational-commissural (A/C) fiber-CA3 synapse was compared to NMDAR-independent LTP at the mossy fiber (MF)-CA3 synapse.Results: The LTP magnitude at A/C fiber-CA3 synapses in slices from control-CSF-treated animals (168 ± 8% n = 54) was significantly higher than LTP in slices from NMDAR-CSF-treated animals (139 ± 9%, n = 40; P = 0.015), although there was some variation between the individual CSF samples. We found residual LTP in NMDAR-CSF-treated tissue which could be abolished by the NMDAR inhibitor D-AP5. Moreover, the CA3 field excitatory postsynaptic potential (fEPSP) was followed by epileptiform afterpotentials in 5% of slices (4/78) from control-CSF-treated animals, but in 26% of slices (12/46) from NMDAR-CSF-treated animals (P = 0.002). Application of the LTP-inducing paradigm increased the proportion of slices with epileptiform afterpotentials, but D-AP5 significantly reduced the occurrence of epileptiform afterpotentials only in NMDAR-CSF-treated, but not in control tissue. At the MF synapse, no significant difference in LTP values of control-CSF and in NMDAR-CSF-treated tissue was observed indicating that NMDAR-independent MF-LTP is intact in NMDAR-CSF-treated tissue.Conclusion: These findings indicate that anti-NMDAR containing CSF impairs LTP at the A/C fiber-CA3 synapse, although there is substantial variation among CSF samples suggesting different epitopes among patient-derived antibodies. The differential inhibition of LTP at this synapse in contrast to the MF-CA3 synapse suggests the specificity and underlines the pathophysiological role of the NMDAR-antibody.

Nitric Oxide Is Required for L-Type Ca(2+) Channel-Dependent Long-Term Potentiation in the Hippocampus.

Nitric oxide (NO) has long been implicated in the generation of long-term potentiation (LTP) and other types of synaptic plasticity, a role for which the intimate coupling between NMDA receptors (NMDARs) and the neuronal isoform of NO synthase (nNOS) is likely to be instrumental in many instances. While several types of synaptic plasticity depend on NMDARs, others do not, an example of which is LTP triggered by opening of L-type voltage-gated Ca2+ channels (L-VGCCs) in postsynaptic neurons. In CA3-CA1 synapses in the hippocampus, NMDAR-dependent LTP (LTPNMDAR) appears to be primarily expressed postsynaptically whereas L-VGCC-dependent LTP (LTPL−VGCC), which often coexists with LTPNMDAR, appears mainly to reflect enhanced presynaptic transmitter release. Since NO is an excellent candidate as a retrograde messenger mediating post-to-presynaptic signaling, we sought to determine if NO functions in LTPL−VGCC in mouse CA3-CA1 synapses. When elicited by a burst type of stimulation with NMDARs and the associated NO release blocked, LTPL−VGCC was curtailed by inhibition of NO synthase or of the NO-receptor guanylyl cyclase to the same extent as occurred with inhibition of L-VGCCs. Unlike LTPNMDAR at these synapses, LTPL−VGCC was unaffected in mice lacking endothelial NO synthase, implying that the major source of the NO is neuronal. Transient delivery of exogenous NO paired with tetanic synaptic stimulation under conditions of NMDAR blockade resulted in a long-lasting potentiation that was sensitive to inhibition of NO-receptor guanylyl cyclase but was unaffected by inhibition of L-VGCCs. The results indicate that NO, acting through its second messenger cGMP, plays an unexpectedly important role in L-VGCC-dependent, NMDAR-independent LTP, possibly as a retrograde messenger generated in response to opening of postsynaptic L-VGCCs and/or as a signal acting postsynaptically, perhaps to facilitate changes in gene expression.

Editorial: Neuroplasticity and Extracellular Proteolysis.

Editorial: Neuroplasticity and Extracellular Proteolysis.

Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of α7 Nicotinic Acetylcholine Receptor.

Simvastatin (SV) has been reported to improve cognitive deficits in Alzheimer's disease. Here, we show that chronic administration of SV (20mg/kg) for 30days in adult mice (SVmice) enhanced spatial cognitive performance as assessed by Morris water maze and Y-maze. To explore mechanisms underlying SV-enhanced spatial cognition, we further examined synaptic properties and long-term potentiation (LTP) in hippocampal CA1, hippocampal α7nAChR expression, and Akt and ERK2 phosphorylation. In comparison with controls, the SV administration caused increase in presynaptic glutamate release and amplitude of NMDAr-dependent LTP (LTP-augmentation), and decrease in threshold of NMDAr-independent LTP induction (LTP-facilitation). The supplement of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the spatial cognitive potentiation, increased glutamate release, and LTP-augmentation/facilitation in SV mice. Expression of α7nAChR, but not α4β2nAChR, was increased in hippocampal pyramidal cells of SV mice with the reduction of transcription factor AP-2α, which were abolished by FOH. Levels of Akt and ERK2 phosphorylation in SVmice were elevated, which were suppressed by FOH or α7nAChR antagonist methyl-lycaconitine (MLA). In hippocampal slices obtained from SV mice, acute perfusion of MLA blocked the increased glutamate release, whereas FOH, PI3K inhibitor LY294002, or MEK inhibitor U0126 could not. In the slices of SV mice, the perfusion of MLA or U0126, but not FOH, abolished the LTP-augmentation and LTP-facilitation. By contrast, LY294002 prevented the LTP-facilitation but failed to affect the LTP-augmentation. The findings indicate that the administration of SV through reducing FPP increases α7nAChR expression and α7nAChR-related Akt and ERK2 phosphorylation, leading to LTP enhancement and spatial cognitive potentiation.

Chronic brain inflammation impairs two forms of long-term potentiation in the rat hippocampal CA1 area

Neuroinflammation plays an important role in the progression of Alzheimer's disease (AD) and is characterized by the presence of activated microglia. We investigated whether chronic neuroinflammation affects the induction of N-methyl- d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and NMDAR-independent LTP which is expressed by voltage-dependent calcium channel (VDCC). Chronic neuroinflammation was induced by administration of lipopolysaccharide (LPS) (28 days, 0.35 μg/h) to the fourth ventricle. The Morris water maze test was conducted to measure the memory impairment and then excitatory postsynaptic potentials were recorded extracelluarly from stratum radiatum in the rat hippocampal CA1 area to examine the changes in synaptic plasticity induced by LPS infusion. Chronic administration of LPS induced remarkable memory impairment. The field recording experiments revealed that the induction of both NMDAR-dependent LTP and NMDAR-independent LTP were impaired in the hippocampal Schaffer collateral-CA1 synapse in animals chronically infused with LPS. The present results show that chronic neuroinflammation can lead to the impaired spatial memory and attenuation of VDCC-dependent LTP as well as NMDAR-dependent LTP. The attenuation of synaptic plasticity may be caused by the impairment of both NMDAR and L-type Ca 2+ via elevated levels of inflammatory proteins, which may underlie aspects of dementia.

Potential Adaptive Function for Altered Long-Term Potentiation Mechanisms in Aging Hippocampus

Age-dependent alterations in the induction of long-term potentiation (LTP) are well documented, providing a likely neural basis for memory decline associated with aging. Studies of neural plasticity are also important to understand the neural basis of individual differences in aging, ranging from significant cognitive impairment to preservation of function on a par with younger adults. To examine the cellular mechanisms that distinguish such outcomes, we studied the induction of LTP in male outbred young and aged rats behaviorally characterized in hippocampal-dependent spatial learning. We evaluated, in vitro, the magnitude of NMDA receptor (NMDAR)-dependent and -independent forms of LTP induced in the Schaffer collateral to CA1 synapses. We found that age substantially reduces NMDAR-dependent LTP across the spectrum of cognitive outcomes, whereas increased NMDAR-independent LTP occurs distinctively in high-performing aged rats. Moreover, in young rats, behavioral performance correlates strongly with the magnitude of NMDAR-LTP, whereas NMDAR-independent LTP correlates with behavioral performance only in aged rats. Together with similar previous findings on the mechanisms for LTD in this model, these results support the notion that a shift from NMDAR-dependent to NMDAR-independent mechanisms for neural plasticity during aging is associated with better cognitive outcomes.

Emergence of NMDAR‐independent long‐term potentiation at hippocampal CA1 synapses following early adolescent exposure to chronic intermittent ethanol: Role for sigma‐receptors

Adolescent humans who abuse alcohol are more vulnerable than adults to the development of memory impairments. Memory impairments often involve modifications in the ability of hippocampal neurons to establish long-term potentiation (LTP) of excitatory neurotransmission; however, few studies have examined how chronic ethanol exposure during adolescence affects LTP mechanisms in hippocampus. We investigated changes in LTP mechanisms in hippocamal slices from rats exposed to intoxicating concentrations of chronic intermittent ethanol (CIE) vapors in their period of early-adolescent (i.e., prepubescent) or late-adolescent (i.e., postpubescent) development. LTP was evaluated at excitatory CA1 synapses in hippocampal slices at 24 h after the cessation of air (control) or CIE vapor treatments. CA1 synapses in control slices showed steady LTP following induction by high-frequency stimulation, which was fully dependent on NMDAR function. By contrast, slices from early-adolescent CIE exposed animals showed a compound form of LTP consisting of an NMDAR-dependent component and a slow-developing component independent of NMDARs. These components summated to yield LTP of robust magnitude above LTP levels in age-matched control slices. Bath-application of the sigma-receptor antagonist BD1047 and the neuroactive steroid pregnenolone sulfate, but not acute ethanol application, blocked NMDAR-independent LTP, while leaving NMDAR-dependent LTP intact. Analysis of presynaptic function during NMDAR-independent LTP induction demonstrated increased presynaptic function via a sigma-receptor-dependent mechanism in slices from early-adolescent CIE-exposed animals. By contrast, CIE exposure after puberty onset in late-adolescent animals produced decrements in LTP levels. The identification of a role for sigma-receptors and neuroactive steroids in the development of NMDAR-independent LTP suggests an important pathway by which hippocampal synaptic plasticity, and perhaps memory, may be uniquely altered by chronic ethanol exposure during the prepubescent phase of adolescent development.

D-serine relieves chronic lead exposure-impaired long-term potentiation in the CA1 region of the rat hippocampus in vitro

Chronic lead-exposure produces long-lasting astroglial morphological and functional changes, which disturb the neuronal functions in the hippocampus. It has been shown that glia-derived d-serine is an essential signal for N-methyl- d-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampal CA1 region. However, the relationship between d-serine and the chronic lead exposure-induced deficit of synaptic plasticity is not clear. In the present study, the properties of d-serine on the chronic lead exposure-impaired synaptic plasticity in the rat hippocampal CA1 region were investigated with electrophysiological recording techniques in vitro. We found that 50 μM d-serine rescued the chronic lead exposure-induced deficit of long-term potentiation (LTP). However, this effect could be abolished by 7-chlorokynurenic acid (7-ClKY), which is a specific antagonist of the glycine-binding site of NMDARs. In contrast, d-serine had no effect on the NMDAR-independent LTP, which was induced in the mossy-CA3 synapses. In addition, we found that d-serine rescued the acute Pb 2+-impaired NMDAR-mediated excitatory postsynaptic currents (EPSCs) partially. These findings demonstrate that d-serine relieves the chronic lead exposure-induced deficit of synaptic plasticity via NMDAR activation suggesting that administration of d-serine may be a potential therapeutic intervention to treat chronic lead exposure-impaired cognitive functions or affective disorders.

Role of Hippocampal Cav1.2 Ca2+Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Current knowledge about the molecular mechanisms of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in the hippocampus and its function for memory formation in the behaving animal is limited. NMDAR-independent LTP in the CA1 region is thought to require activity of postsynaptic L-type voltage-dependent Ca2+ channels (Cav1.x), but the underlying channel isoform remains unknown. We evaluated the function of the Cav1.2 L-type Ca2+ channel for spatial learning, synaptic plasticity, and triggering of learning-associated biochemical processes using a mouse line with an inactivation of the CACNA1C (Cav1.2) gene in the hippocampus and neocortex (Cav1.2(HCKO)). This model shows (1) a selective loss of protein synthesis-dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP (L-LTP), (2) a severe impairment of hippocampus-dependent spatial memory, and (3) decreased activation of the mitogen-activated protein kinase (MAPK) pathway and reduced cAMP response element (CRE)-dependent transcription in CA1 pyramidal neurons. Our results provide strong evidence for a role of L-type Ca2+ channel-dependent, NMDAR-independent hippocampal L-LTP in the formation of spatial memory in the behaving animal and for a function of the MAPK/CREB (CRE-binding protein) signaling cascade in linking Cav1.2 channel-mediated Ca2+ influx to either process.

Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide.

The mechanisms underlying the inhibition of long-term potentiation (LTP) induction by amyloidbeta-peptide (Abeta) were investigated in the medial perforant path of the rat and mouse dentate gyrus in vitro. Evidence is presented in this study that the Abeta-mediated inhibition of LTP induction involves activation of microglia and production of reactive oxygen and nitrogen species. In control slices, Abeta strongly inhibited induction of NMDA receptor-dependent (NMDAR-dependent) LTP, although not induction of NMDAR-independent LTP or long-term depression (LTD). The inhibition of NMDAR-dependent LTP was prevented by minocycline, an agent that prevents activation of microglia. The involvement of inducible nitric oxide synthase (iNOS) was shown by the inability of Abeta to inhibit LTP induction in iNOS knock-out mice and also by the ability of two iNOS inhibitors, aminoguanidine and 1400W, to prevent the Abeta-mediated inhibition of LTP induction. The Abeta-mediated inhibition of LTP induction also was prevented by the superoxide scavenger superoxide dismutase applied together with catalase. Evidence for involvement of superoxide in the action of Abeta on LTP induction was shown by the ability of an inhibitor of NADPH oxidase to prevent the Abeta-mediated inhibition of LTP induction. The study thus provides evidence that the Abeta-mediated inhibition of LTP induction involves an inflammatory-type reaction in which activation of microglia results in the production of nitric oxide and superoxide and thence possibly peroxynitrite, a highly reactive oxidant.

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

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

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

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

An NMDAR-independent LTP mediated by group II metabotropic glutamate receptors and p42/44 MAP kinase in the dentate gyrus in vitro

The induction of long-term potentiation (LTP) under conditions of blockade of the N-methyl- d-aspartate receptor (NMDAR) was studied in the medial perforant path to granule cell synapse in the dentate gyrus. A small amplitude NMDAR-independent potentiation was induced by a single brief high frequency stimulation (HFS), and a summated larger LTP was induced by repeated spaced HFS. The NMDAR-independent LTP was mediated by activation of group II mGluR as it was inhibited by the group II antagonists EGLU and also low concentrations of LY341495, but not the group I mGluR antagonist MPEP. Perfusion of the group II mGluR agonist DCG-IV induced NMDAR-independent LTP in media containing an NMDAR antagonist. The NMDAR-independent LTP induced by HFS was mediated via activation of p42/44 MAP kinase as it was blocked by the selective inhibitor PD98059.

Age and experience dependence of N-methyl- d-aspartate receptor-independent long-term potentiation in rat visual cortex

Dark rearing prolongs the critical period for experience-dependent modification of visual cortical functions. To test whether long-term potentiation (LTP) could potentially underlie this modification, we studied the age and experience dependence of LTP, induced in layer 2/3 cells by layer 4 stimulation continued for 15 min at 2 Hz, in rat visual cortical slices. This LTP was independent of N-methyl- d-aspartate receptor (NMDAR) activation, but it likely required Ni 2+-sensitive Ca 2+ channel activation for induction. LTP occurred frequently during development, but rarely in adulthood. Dark rearing prevented this developmental decline. These age- and experience-dependent changes were demonstrated in both excitatory postsynaptic potentials recorded from pyramidal cells under a local blockade of inhibition and extracellular field potentials. These results suggest the possible involvement of NMDAR-independent LTP in the experience-dependent development of visual cortex.

Facilitation of NMDAR-Independent LTP and Spatial Learning in Mutant Mice Lacking Ryanodine Receptor Type 3

To evaluate the role in synaptic plasticity of ryanodine receptor type 3 ( RyR3), which is normally enriched in hippocampal area CA1, we generated RyR3-deficient mice. Mutant mice exhibited facilitated CA1 long-term potentiation (LTP) induced by short tetanus (100 Hz, 100 ms) stimulation. Unlike LTP in wild-type mice, this LTP was not blocked by the NMDA receptor antagonist D-AP5 but was partially dependent on L-type voltage-dependent Ca 2+ channels (VDCCs) and metabotropic glutamate receptors (mGluRs). Long-term depression (LTD) was not induced in RyR3-deficient mice. RyR3-deficient mice also exhibited improved spatial learning on a Morris water maze task. These results suggest that in wild-type mice, in contrast to the excitatory role of Ca 2+ influx, RyR3-mediated intracellular Ca 2+ ([Ca 2+] i) release from endoplasmic reticulum (ER) may inhibit hippocampal LTP and spatial learning.