Long-term Potentiation In Wild-type Mice Research Articles

Tyrosine phosphatase PTP1B impairs presynaptic NMDA receptor-mediated plasticity in a mouse model of Alzheimer's disease

Mutations in the beta-amyloid protein (APP) cause familial Alzheimer's disease. In hAPP-J20 mice expressing mutant APP, pharmacological inhibition or genetic ablation of the tyrosine phosphatase PTP1B prevents CA3 hippocampus neuron loss and cognitive decline. However, how targeting PTP1B affects the cellular mechanisms underlying these cognitive deficits remains unknown. Changes in synaptic strength at the hippocampus can affect information processing for learning and memory. While prior studies have focused on post-synaptic mechanisms to account for synaptic deficits in Alzheimer's disease models, presynaptic mechanisms may also be affected. Here, using whole cell patch-clamp recording, coefficient of variation (CV) analysis suggested a profound presynaptic deficit in long-term potentiation (LTP) of CA3:CA1 synapses in hAPP-J20 mice. While the membrane-impermeable ionotropic NMDA receptor (NMDAR) blocker norketamine in the post-synaptic recording electrode had no effect on LTP, additional bath application of the ionotropic NMDAR blockers MK801 could replicate the deficit in LTP in wild type mice. In contrast to LTP, the paired-pulse ratio and short-term facilitation (STF) were aberrantly increased in hAPP-J20 mice. These synaptic deficits in hAPP-J20 mice were associated with reduced phosphorylation of NMDAR GluN2B and the synaptic vesicle recycling protein NSF (N-ethylmaleimide sensitive factor). Phosphorylation of both proteins, together with synaptic plasticity and cognitive function, were restored by PTP1B ablation or inhibition by the PTP1B-selective inhibitor Trodusquemine. Taken together, our results indicate that PTP1B impairs presynaptic NMDAR-mediated synaptic plasticity required for spatial learning in a mouse model of Alzheimer's disease. Since Trodusquemine has undergone phase 1/2 clinical trials to treat obesity, it could be repurposed to treat Alzheimer's disease.

Environmental Novelty Activates β2-Adrenergic Signaling to Prevent the Impairment of Hippocampal LTP by Aβ Oligomers

A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here, we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wild-type mice that promoted long-term potentiation. Akey feature of the EE effect was activation of β2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid β-protein (Aβ) isolated from AD cortex. Protection by EE occurred in both young and middle-aged wild-type mice. Exposure to novelty afforded greater protection than did aerobic exercise. Mice chronically fed a β-adrenergic agonist without EE were protected from hippocampal impairment by Aβ oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating β-adrenoceptor signaling and mitigating synaptotoxicity of human Aβ oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral β-adrenergic agonists to lessen the effects of Aβ accumulation during aging.

Increased astrocytic ATP release results in enhanced excitability of the hippocampus

Astrocytes, a major subtype of glia, interact with neurons as a supportive partner supplying energy sources and growth factors. Astrocytes regulate the activity of neighboring neurons by releasing chemical transmitters (gliotransmitters). However, the precise role of gilotransmitters in regulating neuronal activity is still under debate. Here, we report that a subtle enhancement in the release of one gliotransmitter, ATP, affects synaptic potentiation from an analysis of mice containing an astrocyte-selective (GFAP) mutation. We found that, relative to normal mice, weaker stimulation induced long-term potentiation (LTP) in mutant mice, indicating that the threshold to induce LTP was lowered in the mutant. While excitatory transmission was normal in the mutant, inhibitory GABAergic transmission was suppressed. We found that a low concentration of adenosine selectively attenuated inhibitory neuronal activity and lowered the threshold to induce LTP in wild type mice. In comparison, adenosine A(1) receptor antagonism reversed the lowered LTP threshold back to normal in the mutant mouse. We verified that adenosine levels in the cerebrospinal fluid of mutant mice were slightly elevated compared to wild type mice. This was apparently caused by an increase in ATP release from mutant astrocytes that could provide a source of augmented adenosine levels in the mutant. ATP is thought to suppress the excitability of neuronal circuits; however, a small increase in ATP release can result in a suppressed inhibitory tone and enhanced excitability of neuronal circuitry. These findings demonstrate that ATP released from astrocytes acts in a bidirectional fashion to regulate neuronal excitability depending on concentration.

The Inflammatory Chemokine CXCL10 Modulates Synaptic Plasticity and Neuronal Activity in the Hippocampus

Chemokines, a family member of cytokines, have been shown to play a major role in central nervous system inflammation. Among other chemokines, CXCR3 and its ligand CXCL10 are involved in the pathophysiology of several neuroinflammatory conditions. Most of these conditions are also associated with an increased incidence of seizure or epilepsy. Using age-matched wild-type (WT), as well as CXCR3-receptor-deficient (CXCR3-KO) mice, the present study aimed to investigate the effect of the chemokine CXCL10 and its receptor CXCR3 on synaptic plasticity as well as neuronal activities in hippocampal brain slices. Using field potential and intracellular recordings, the effect of exogenous CXCL10 on tetanus-induced long-term potentiation (LTP) as well as the neuronal spike activity was evaluated in hippocampal CA1 area. Exogenous application of CXCL10 enhanced LTP in WT mice, whereas it exerted no significant effect on CXCR3-KO mice. During intracellular recordings of spontaneous spike activity, exogenous application of CXCL10 significantly enhanced the amplitude, duration, and after-hyperpolarization of action potentials in slices obtained from WT mice compared to CXCR3-KO mice. In addition, CXCR3-KO mice exhibited a lower GABAA-mediated excitation in hippocampal CA1 neurons compared to WT mice. These data show that the inflammatory chemokine CXCL10, probably via its receptor CXCR3, modulates neuronal activity and synaptic plasticity in the hippocampus. CXCL10 may be involved in seizures observed during neuroinflammatory diseases such as meningitis and encephalitis.

Postsynaptic BDNF signalling regulates long‐term potentiation at thalamo‐amygdala afferents

The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in the hippocampus and the neocortex of the mammalian brain. In contrast, a role of BDNF in mediating synaptic plasticity and fear learning in the amygdala is just beginning to evolve. Using patch clamp recordings from projection neurons of the dorsal lateral amygdala (LA) in acute slices of mice, we now investigated the cellular mechanism of BDNF-mediated long-term potentiation (LTP) of excitatory postsynaptic currents (EPSCs) in the amygdala. LTP was elicited in cortical and thalamic synaptic inputs by pairing postsynaptic depolarisation with presynaptic stimulation. LTP in the cortico-amygdala pathway was not changed in heterozygous BDNF-knockout (BDNF(+/-)) mice. In contrast, pairing induced LTP in the thalamic input was abolished in BDNF(+/-) mice (BDNF(+/-): 104.0 ± 5.7% of initial EPSC values; WT: 132.5 ± 7.3%). Likewise, inhibition of BDNF/TrkB signalling with TrkB-IgGs as scavenger molecules for endogenous BDNF blocked LTP in wild-type mice in this pathway (TrkB-IgG: 102.7 ± 6.9% of initial EPSC values; control: 132.5 ± 8.7%). Inclusion of the tyrosine kinase inhibitor K252a in the pipette solution also prevented the induction of LTP in the thalamic pathway, indicating a postsynaptic site of action of BDNF in regulating LTP. Reduced BDNF levels in BDNF(+/-) mice did not affect intrinsic membrane properties of LA projection neurons. Likewise, presynaptic glutamate release, and postsynaptic membrane properties also remained unaffected in BDNF(+/-) mice. These data suggest a postsynaptic site of action of BDNF in mediating LTP selectively in the thalamic fear conditioning pathway.

Long Term Potentiation Is Impaired in Membrane Glycoprotein CD200-deficient Mice: A ROLE FOR Toll-LIKE RECEPTOR ACTIVATION

The membrane glycoprotein CD200 is expressed on several cell types, including neurons, whereas expression of its receptor, CD200R, is restricted principally to cells of the myeloid lineage, including microglia. The interaction between CD200 and CD200R maintains microglia and macrophages in a quiescent state; therefore, CD200-deficient mice express an inflammatory phenotype exhibiting increased macrophage or microglial activation in models of arthritis, encephalitis, and uveoretinitis. Here, we report that lipopolysaccharide (LPS) and Pam(3)CysSerLys(4) exerted more profound effects on release of the proinflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα), in glia prepared from CD200(-/-) mice compared with wild type mice. This effect is explained by the loss of CD200 on astrocytes, which modulates microglial activation. Expression of Toll-like receptors 4 and 2 (TLR4 and -2) was increased in glia prepared from CD200(-/-) mice, and the evidence indicates that microglial activation, assessed by the increased numbers of CD11b(+) cells that stained positively for both MHCII and CD40, was enhanced in CD200(-/-) mice compared with wild type mice. These neuroinflammatory changes were associated with impaired long term potentiation (LTP) in CA1 of hippocampal slices prepared from CD200(-/-) mice. One possible explanation for this is the increase in TNFα in hippocampal tissue prepared from CD200(-/-) mice because TNFα application inhibited LTP in CA1. Significantly, LPS and Pam(3)CysSerLys(4), at concentrations that did not affect LTP in wild type mice, inhibited LTP in slices prepared from CD200(-/-) mice, probably due to the accompanying increase in TLR2 and TLR4. Thus, the neuroinflammatory changes that result from CD200 deficiency have a negative impact on synaptic plasticity.

Tau Protein Is Required for Amyloid β-Induced Impairment of Hippocampal Long-Term Potentiation

Amyloid β (Aβ) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimer's disease (AD), but whether and how they interact is unknown. Consequently, we asked whether tau protein is required for the robust phenomenon of Aβ-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aβ and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.

Activation of nicotinic alpha 7 acetylcholine receptor enhances long-term potentiation in wild-type mice, but not APPswe/PS1deltaE9 mice

Activation of nicotinic alpha 7 acetylcholine receptor enhances long-term potentiation in wild-type mice, but not APPswe/PS1deltaE9 mice

Induction and expression of GluA1 (GluR‐A)‐independent LTP in the hippocampus

Long-term potentiation (LTP) at hippocampal CA3–CA1 synapses is thought to be mediated, at least in part, by an increase in the postsynaptic surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors induced by N-methyl-d-aspartate (NMDA) receptor activation. While this process was originally attributed to the regulated synaptic insertion of GluA1 (GluR-A) subunit-containing AMPA receptors, recent evidence suggests that regulated synaptic trafficking of GluA2 subunits might also contribute to one or several phases of potentiation. However, it has so far been difficult to separate these two mechanisms experimentally. Here we used genetically modified mice lacking the GluA1 subunit (Gria1−/− mice) to investigate GluA1-independent mechanisms of LTP at CA3–CA1 synapses in transverse hippocampal slices. An extracellular, paired theta-burst stimulation paradigm induced a robust GluA1-independent form of LTP lacking the early, rapidly decaying component characteristic of LTP in wild-type mice. This GluA1-independent form of LTP was attenuated by inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC), two enzymes known to regulate GluA2 surface expression. Furthermore, the induction of GluA1-independent potentiation required the activation of GluN2B (NR2B) subunit-containing NMDA receptors. Our findings support and extend the evidence that LTP at hippocampal CA3–CA1 synapses comprises a rapidly decaying, GluA1-dependent component and a more sustained, GluA1-independent component, induced and expressed via a separate mechanism involving GluN2B-containing NMDA receptors, neuronal nitric oxide synthase and PKC.

Altered Hippocampal Synaptic Potentiation in P2X4Knock-Out Mice

P2X4 purinergic receptors are calcium-permeable, ATP-activated ion channels. In the CA1 area of the hippocampus, they are located at the subsynaptic membrane somewhat peripherally to AMPA receptors. The possible role of P2X4 receptors has been difficult to elucidate because of the lack of selective antagonists. Here we report the generation of a P2X4 receptor knock-out mouse and show that long-term potentiation (LTP) at Schaffer collateral synapses is reduced relative to that in wild-type mice. Ivermectin, which selectively potentiates currents at P2X4, was found to increase LTP in wild-type mice but had no effect in P2X4 knock-out mice. We suggest that calcium entry through subsynaptic P2X4 receptors during high-frequency stimulation contributes to synaptic strengthening.

Modulation of Synaptic Plasticity by Physiological Activation of M1Muscarinic Acetylcholine Receptors in the Mouse Hippocampus

The muscarinic acetylcholine receptor (mAChR) has been considered one of the neurotransmitter receptors regulating hippocampal synaptic plasticity, which likely plays a critical role in learning and memory. In previous studies, however, muscarinic agonists were used at relatively high concentrations, and the subtype selectivity of muscarinic antagonists was not satisfactory. Thus, it remains to be answered whether physiological levels of ACh are involved in the regulation of synaptic plasticity and which mAChR subtypes are responsible for such effects. We found in this study that a low concentration (50 nM) of carbachol enhanced long-term potentiation (LTP) of excitatory synaptic transmission in mouse hippocampal slices. Notably, this enhancing effect was abolished in M1 mAChR knock-out (KO) but not in M3 mAChR KO mice, although LTP itself was intact in both mutant mice. Furthermore, we found that repetitive stimulation in the stratum oriens, which presumably triggered the release of endogenous ACh from cholinergic terminals, could enhance LTP in wild-type mice but not in M1 mAChR KO mice. These results suggest that physiologically released ACh from cholinergic fibers modulates hippocampal synaptic plasticity through the postsynaptic M1 mAChR activation.

Group I Metabotropic Glutamate Receptor Signaling via Gαq/Gα11 Secures the Induction of Long-Term Potentiation in the Hippocampal Area CA1

Heterotromeric G-proteins of the Gq family are thought to transduce signals from group I metabotropic glutamate receptors (mGluRs) in central neurons. We investigated roles of this cascade in hippocampal long-term potentiation (LTP) by using null-mutant mice lacking the alpha subunit of Gq (Galphaq) or G11 (Galpha11). We found no obvious abnormalities in the morphology, layer structure, expression of NMDA receptors, and basic parameters of excitatory synaptic transmission in the hippocampus of Galphaq mutant mice. We used theta burst stimulation (TBS) (3-10 burst trains at 5 Hz; each train consisted of five stimuli at 100 Hz) to induce LTP at Schaffer collateral to CA1 pyramidal cell synapses. Conventional TBS with 10 burst trains induced robust LTP in wild-type, Galphaq mutant, and Galpha11 mutant mice. Weak TBS with three burst trains consistently induced LTP in wild-type mice. In contrast, the same weak TBS was insufficient to induce LTP in Galphaq and Galpha11 mutant mice. In wild-type mice, the LTP by weak TBS was abolished by inhibiting group I mGluR or protein kinase C (PKC) but not by blocking muscarinic acetylcholine receptors. Prior activation of group I mGluR by an agonist significantly enhanced the LTP by weak TBS in wild-type mice. However, this priming effect was absent in Galphaq mutant mice. These results indicate that the signaling from group I mGluR to PKC involving Galphaq/Galpha11 does not constitute the main pathway for LTP, but it secures LTP induction by lowering its threshold in the hippocampal area CA1.

Impairment of L-type Ca2+ channel-dependent forms of hippocampal synaptic plasticity in mice deficient in the extracellular matrix glycoprotein tenascin-C.

The extracellular matrix glycoprotein tenascin-C (TN-C) has been suggested to play important functional roles during neural development, axonal regeneration, and synaptic plasticity. We generated a constitutively TN-C-deficient mouse mutant from embryonic stem cells with a floxed tn-C allele, representing a standard for future analysis of conditionally targeted mice. The gross morphology of the CNS was not detectably affected, including no evidence for perturbed nerve cell migration, abnormal oligodendrocyte distribution, or defective myelination. Despite the apparent normal histology of the hippocampus and normal performance in the water maze, theta-burst stimulation (TBS) of Schaffer collaterals elicited reduced long-term potentiation (LTP) in the CA1 region of TN-C-deficient mutants, as compared with wild-type littermates. However, high-frequency stimulation evoked normal LTP not only in CA1, but also at mossy fiber-CA3 and medial and lateral perforant path-granule cell synapses in the dentate gyrus. Low-frequency stimulation failed to induce long-term depression in the CA1 region of TN-C-deficient animals. Recordings of TBS-induced LTP in the presence of nifedipine, an antagonist of L-type voltage-dependent Ca2+ channels (VDCCs), did not affect LTP in TN-C-deficient mice, but reduced LTP in wild-type mice to the levels seen in mutants. Furthermore, chemical induction of a L-type VDCC-dependent LTP in the CA1 region by application of the K+ channel blocker tetraethylammonium resulted in impaired LTP in TN-C mutants. Thus, reduction in L-type VDCC-mediated signaling appears to mediate the deficits in certain forms of synaptic plasticity in constitutively TN-C-deficient mice.

Impairment of L-type Ca2+Channel-Dependent Forms of Hippocampal Synaptic Plasticity in Mice Deficient in the Extracellular Matrix Glycoprotein Tenascin-C

The extracellular matrix glycoprotein tenascin-C (TN-C) has been suggested to play important functional roles during neural development, axonal regeneration, and synaptic plasticity. We generated a constitutively TN-C-deficient mouse mutant from embryonic stem cells with a floxed tn-C allele, representing a standard for future analysis of conditionally targeted mice. The gross morphology of the CNS was not detectably affected, including no evidence for perturbed nerve cell migration, abnormal oligodendrocyte distribution, or defective myelination. Despite the apparent normal histology of the hippocampus and normal performance in the water maze, theta-burst stimulation (TBS) of Schaffer collaterals elicited reduced long-term potentiation (LTP) in the CA1 region of TN-C-deficient mutants, as compared with wild-type littermates. However, high-frequency stimulation evoked normal LTP not only in CA1, but also at mossy fiber-CA3 and medial and lateral perforant path-granule cell synapses in the dentate gyrus. Low-frequency stimulation failed to induce long-term depression in the CA1 region of TN-C-deficient animals. Recordings of TBS-induced LTP in the presence of nifedipine, an antagonist of L-type voltage-dependent Ca2+ channels (VDCCs), did not affect LTP in TN-C-deficient mice, but reduced LTP in wild-type mice to the levels seen in mutants. Furthermore, chemical induction of a L-type VDCC-dependent LTP in the CA1 region by application of the K+ channel blocker tetraethylammonium resulted in impaired LTP in TN-C mutants. Thus, reduction in L-type VDCC-mediated signaling appears to mediate the deficits in certain forms of synaptic plasticity in constitutively TN-C-deficient mice.

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.

Plasma uric acid levels in children.

Heterotromeric G-proteins of the Gq family are thought to transduce signals from group I metabotropic glutamate receptors (mGluRs) in central neurons. We investigated roles of this cascade in hippocampal long-term potentiation (LTP) by using null-mutant mice lacking the α subunit of Gq (Gαq) or G11 (Gα11). We found no obvious abnormalities in the morphology, layer structure, expression of NMDA receptors, and basic parameters of excitatory synaptic transmission in the hippocampus of Gαq mutant mice. We used theta burst stimulation (TBS) (3–10 burst trains at 5 Hz; each train consisted of five stimuli at 100 Hz) to induce LTP at Schaffer collateral to CA1 pyramidal cell synapses. Conventional TBS with 10 burst trains induced robust LTP in wild-type, Gαq mutant, and Gα11 mutant mice. Weak TBS with three burst trains consistently induced LTP in wild-type mice. In contrast, the same weak TBS was insufficient to induce LTP in Gαq and Gα11 mutant mice. In wild-type mice, the LTP by weak TBS was abolished by inhibiting group I mGluR or protein kinase C (PKC) but not by blocking muscarinic acetylcholine receptors. Prior activation of group I mGluR by an agonist significantly enhanced the LTP by weak TBS in wild-type mice. However, this priming effect was absent in Gαq mutant mice. These results indicate that the signaling from group I mGluR to PKC involving Gαq/Gα11 does not constitute the main pathway for LTP, but it secures LTP induction by lowering its threshold in the hippocampal area CA1.

Radiography in Determining the Placental Site

The extracellular matrix glycoprotein tenascin-C (TN-C) has been suggested to play important functional roles during neural development, axonal regeneration, and synaptic plasticity. We generated a constitutively TN-C-deficient mouse mutant from embryonic stem cells with a floxed <i>tn-C</i> allele, representing a standard for future analysis of conditionally targeted mice. The gross morphology of the CNS was not detectably affected, including no evidence for perturbed nerve cell migration, abnormal oligodendrocyte distribution, or defective myelination. Despite the apparent normal histology of the hippocampus and normal performance in the water maze, theta-burst stimulation (TBS) of Schaffer collaterals elicited reduced long-term potentiation (LTP) in the CA1 region of TN-C-deficient mutants, as compared with wild-type littermates. However, high-frequency stimulation evoked normal LTP not only in CA1, but also at mossy fiber–CA3 and medial and lateral perforant path–granule cell synapses in the dentate gyrus. Low-frequency stimulation failed to induce long-term depression in the CA1 region of TN-C-deficient animals. Recordings of TBS-induced LTP in the presence of nifedipine, an antagonist of L-type voltage-dependent Ca²⁺ channels (VDCCs), did not affect LTP in TN-C-deficient mice, but reduced LTP in wild-type mice to the levels seen in mutants. Furthermore, chemical induction of a L-type VDCC-dependent LTP in the CA1 region by application of the K⁺ channel blocker tetraethylammonium resulted in impaired LTP in TN-C mutants. Thus, reduction in L-type VDCC-mediated signaling appears to mediate the deficits in certain forms of synaptic plasticity in constitutively TN-C-deficient mice.

Ocular tension in glaucoma simplex.

Heterotromeric G-proteins of the Gq family are thought to transduce signals from group I metabotropic glutamate receptors (mGluRs) in central neurons. We investigated roles of this cascade in hippocampal long-term potentiation (LTP) by using null-mutant mice lacking the α subunit of Gq (Gαq) or G11 (Gα11). We found no obvious abnormalities in the morphology, layer structure, expression of NMDA receptors, and basic parameters of excitatory synaptic transmission in the hippocampus of Gαq mutant mice. We used theta burst stimulation (TBS) (3–10 burst trains at 5 Hz; each train consisted of five stimuli at 100 Hz) to induce LTP at Schaffer collateral to CA1 pyramidal cell synapses. Conventional TBS with 10 burst trains induced robust LTP in wild-type, Gαq mutant, and Gα11 mutant mice. Weak TBS with three burst trains consistently induced LTP in wild-type mice. In contrast, the same weak TBS was insufficient to induce LTP in Gαq and Gα11 mutant mice. In wild-type mice, the LTP by weak TBS was abolished by inhibiting group I mGluR or protein kinase C (PKC) but not by blocking muscarinic acetylcholine receptors. Prior activation of group I mGluR by an agonist significantly enhanced the LTP by weak TBS in wild-type mice. However, this priming effect was absent in Gαq mutant mice. These results indicate that the signaling from group I mGluR to PKC involving Gαq/Gα11 does not constitute the main pathway for LTP, but it secures LTP induction by lowering its threshold in the hippocampal area CA1.