Expression Of Long-term Potentiation Research Articles

Activation of β‐adrenergic receptors facilitates heterosynaptic translation‐dependent long‐term potentiation

Noradrenaline critically modulates the ability of synapses to undergo long-term plasticity on time scales extending well beyond fast synaptic transmission. Noradrenergic signalling through β-adrenergic receptors (β-ARs) enhances memory consolidation and can boost the longevity of long-term potentiation (LTP). Previous research has shown that stimulation of one synaptic pathway with a protocol that induces persistent, translation-dependent LTP can enable the induction of LTP by subthreshold stimulation at a second, independent synaptic pathway. This heterosynaptic facilitation depends on the regulation and synthesis of proteins. Recordings taken from area CA1 in mouse hippocampal slices showed that induction of β-AR-dependent LTP at one synaptic pathway (S1) can facilitate LTP at a second, independent pathway (S2) when low-frequency, subthreshold stimulation is applied after a 30 min delay. β-AR-dependent heterosynaptic facilitation requires protein synthesis as inhibition of mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK), or translation, prevented homo- and heterosynaptic LTP. Shifting application of a translational repressor, emetine, to coincide with S2 stimulation did not block LTP. Heterosynaptic LTP was prevented in the presence of the cell-permeable cAMP-dependent protein kinase inhibitor, PKI. Conversely, the time window for inter-pathway transfer of heterosynaptic LTP was extended through inhibition of GluR2 endocytosis. Our data show that activation of β-ARs boosts the heterosynaptic expression of translation-dependent LTP. These results suggest that engagement of the noradrenergic system may extend the associative capacity of hippocampal synapses through facilitation of intersynaptic crosstalk.

Munc13-1 Is Required for Presynaptic Long-Term Potentiation

Long-lasting forms of synaptic plasticity involve modification of presynaptic strength in many brain regions. Although a presynaptic site for expression is well established, the detailed molecular mechanisms that lead to sustained changes in neurotransmitter release remain unclear. Here, we use acute in vivo genetic manipulation of synaptic proteins to investigate the molecular basis for presynaptic long-term potentiation (LTP) at hippocampal mossy fiber synapses. Munc13 proteins are active zone proteins that are essential for synaptic vesicle priming and neurotransmitter release. Munc13 proteins also interact with RIM1α, an active zone protein required for presynaptic long-term plasticity. By taking advantage of the observation that the RIM-binding domain of Munc13 is separable from the domain that is required for neurotransmitter release, we selectively tested whether Munc13-1 is an effector for RIM1α in presynaptic LTP. Our results provide the first evidence for the involvement of Munc13-1 in presynaptic long-term synaptic plasticity. We further demonstrate that the interaction between RIM1α and Munc13-1 is required for this plasticity. These results advance our understanding of the molecular mechanisms of presynaptic plasticity and suggest that modulation of vesicle priming may provide the cellular substrate for expression of LTP at mossy fiber synapses.

Erythropoietin decreases the excitatory neurotransmitter release probability and enhances synaptic plasticity in mice hippocampal slices

In order to examine the direct acute effect of erythropoietin (EPO) perfusion on synaptic plasticity and transmitter release probability in hippocampal slices, one month old mice were decapitated and hippocampal slices were prepared. The effect of EPO perfusion (50 U/ml) on the basic synaptic transmission of hippocampal slices was examined. In addition, paired-pulse facilitation (PPF with inter stimulus intervals ISI of 50, 100 and 200 ms), long term potentiation (LTP) and depression (LTD) were recorded using high (HFS) and low (LFS) frequency stimulations. EPO-perfusion depressed significantly the slope of the fEPSP. The PPF ratio was increased significantly when compared with pre-EPO-perfusion. Stimulation of the control slices with LFS (1 Hz) depressed significantly the slope of the fEPSP (77.7 ± 3.85% of the baseline responses). Intermediate stimulation frequency (10 Hz) produced no significant changes, while HFS (100 Hz) induced significant potentiation of the responses (142.38 ± 7.72%). In EPO-perfused slices significant bigger responses were obtained (1 Hz, 101.12 ± 5.69%, 10 Hz, 123.24 ± 2.68, and 100 Hz, 216.41 ± 20.1) when compared to the control slices. These results suggest that erythropoietin decreases the excitatory neurotransmitter release probability and may in this way protect the synapses from toxic levels of glutamate. Erythropoietin perfusion increased the expression of long-term potentiation in the hippocampus which is considered as basic cellular model for learning and memory.

Neuroprotection with a new kynurenic acid analog in the four-vessel occlusion model of ischemia

Global forebrain ischemia results in damage to the pyramids in the CA1 hippocampal subfield, which is particularly vulnerable to excitotoxic processes. Morphological and functional disintegration of this area leads to a cognitive dysfunction and neuropsychiatric disorders. Treatment with N-methyl- d-aspartate receptor antagonists is a widely accepted method with which to stop the advance of excitotoxic processes and concomitant neuronal death. From a clinical aspect, competitive glycine- and polyamine-site antagonists with relatively low affinity and moderate side-effects are taken into account. Endogenous kynurenic acid acts as an antagonist on the obligatory co-agonist glycine site, and has long been at the focus of neuroprotective trials. In the present study, we estimated the neuroprotective capability of a novel kynurenic acid analog in transient global forebrain ischemia, measuring the rate of hippocampal CA1 pyramidal cell loss and the preservation of long-term potentiation at Schaffer collateral-CA1 synapses. The neuroprotective potential was reflected by a significantly diminished hippocampal CA1 cell loss and preserved long-term potentiation expression. The neuroprotective effect was robust in the event of pretreatment, and also when the drug was administered at the time of reperfusion. This result is beneficial since a putative neuroprotectant proven to be effective as post-treatment is of much greater benefit.

Learning-facilitated synaptic plasticity at CA3 mossy fiber and commissural-associational synapses reveals different roles in information processing.

Subregion-dependent differences in the role of the hippocampus in information processing exist. Recently, it has emerged that a special relationship exists between the expression of persistent forms of synaptic plasticity in hippocampal subregions and the encoding of different types of spatial information. Little is known about this type of information processing at CA3 synapses. We report that in freely behaving rats, long-term potentiation (LTP) is facilitated at both mossy fiber (mf)–CA3 and commissural–associational (AC)–CA3 synapses by exploration of a novel (empty) environment. Exploration of large spatial landmarks facilitates long-term depression (LTD) at mf-CA3 synapses and impairs synaptic depression at AC-CA3 synapses. Novel exploration of small environmental features does not facilitate LTD at mf synapses but facilitates persistent LTD at AC synapses. Thus, depending on the quality of the information synaptic plasticity at AC-CA3 and mf-CA3 synapses is differentially modulated. These data suggest that expression of LTP as a result of environmental change is a common property of hippocampal synapses. However, LTD at mf synapses or AC synapses may subserve distinct and separate functions within the CA3 region.

The AAA + ATPase Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior

The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase Thorase, which regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP, and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. This study identifies an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory.

The expression mechanism of the residual LTP in the CA1 region of BDNF k.o. mice is insensitive to NO synthase inhibition

BDNF and nitric oxide signaling both contribute to long-term potentiation (LTP) at glutamatergic synapses, but to date, few studies analyzed the interaction of both signaling cascades in the same synaptic pathway. Here we addressed the question whether the residual LTP in the CA1 region of hippocampal slices from heterozygous BDNF knockout mice (BDNF +/−) is dependent on nitric oxide (NO) signaling. Extracellular recording of synaptic field potentials elicited by presynaptic Schaffer collateral stimulation was performed in the CA1 region of hippocampal slices of 4- to 6-week-old mice, and LTP was induced by a theta burst stimulation protocol. Application of the nitric oxide inhibitor L-NAME (200 μM) strongly inhibited LTP by 70% in wildtype animals. This inhibition of LTP was not a consequence of altered basal synaptic properties. In CA1 of BDNF +/− mice, stimulated with the same theta burst protocol, LTP was reduced by 50% as compared to wildtype animals. This impairment in the expression of LTP in BDNF +/− mice did not result from an increased synaptic fatigue. The residual LTP in BDNF +/− was not further reduced by preincubation of slices with L-NAME. These results suggest that BDNF and NO share overlapping intracellular signaling cascades to mediate LTP in CA1, and part of their signaling cascades are most likely arranged consecutively in the signaling pathway mediating LTP.

Dopaminergic Modulation of Cortical Inputs during Maturation of Adult-Born Dentate Granule Cells

Adult neurogenesis, a particular form of plasticity in the adult brain, is under dynamic control of neuronal activity mediated by various neurotransmitters. Despite accumulating evidence suggesting that the neurotransmitter dopamine (DA) regulates proliferation of neural precursor cells in the neurogenic zones, whether and how it acts on newly generated neurons that integrate into the established network remains unknown. Using patch-clamp recordings from retrovirus-labeled newborn hippocampal dentate granule cells (DGCs) in acute mouse brain slices, we found that DA not only caused a long-lasting attenuation of medial perforant path (MPP) inputs to the young DGCs, but also decreased their capacity to express long-term potentiation (LTP). In contrast, DA suppressed MPP transmission to mature DGCs to a similar extent but did not influence their LTP expression. This difference was linked to activation of distinct subtypes of DA receptors in DGCs at different developmental stages. Our observations suggest that DA is particularly effective in modulating the activities of hyperexcitable young neurons, which may have important implications for the dentate function as a filter for incoming information to the hippocampus.

Bidirectional synaptic plasticity induced by conditioned stimulations with different number of pulse at hippocampal CA1 synapses: Roles ofN‐methyl‐D‐aspartate and metabotropic glutamate receptors

In the mammalian brain, the hippocampus has been established as a principle structure for learning and memory processes, which involve synaptic plasticity. Although a relationship between synaptic plasticity and stimulation frequency has been reported in numerous studies, little is known about the importance of pulse number on synaptic plasticity. Here we investigated whether the pulse number can modulate bidirectional plasticity in hippocampal CA1 areas. When a CA1 area was induced by a paired-pulse (PP) with a 10-ms interval, the strength of the synapse was altered to form a long-term depression (LTD), with a 68 ± 4% decrease in expression. The PP-induced LTD (PP-LTD) was blocked by the metabotropic glutamate receptors subtype 5 (mGluR5) antagonist MPEP, suggesting that the PP-LTD relied on the activation of GluR5. In addition, this modulation of LTD was protein kinase C (PKC)- and Group II mGluR-independent. However, when increasing the pulse number to 4 and 6, potentiated synaptic strength was observed, which was N-methyl-D-aspartate receptor (NMDAR)-dependent but mGluR5-independent. Surprisingly, when blocking mGluR, the synaptic efficacy induced by triple-pulse stimulation was altered to form a long-term potentiation (LTP) with a 142 ± 7% enhancement, and was further blocked by NMDA antagonist APV. Following treatment with APV and PKC blocker chelerythrine, the LTP expression induced by 4- and 6-pulse stimulation was switched to LTD. We suggest that CA1 synaptic plasticity is regulated by the result of competition between NMDA and mGluR5 receptors. We suggest that the pulse number can bidirectionally modulate synaptic plasticity through the activation of NMDA and mGluR5 in hippocampal CA1 areas.

Role of inositol 1, 4, 5-trisphosphate receptors in the postsynaptic expression of guinea pig hippocampal mossy fiber depotentiation

Long-term potentiation (LTP) at hippocampal mossy fiber-CA3 pyramidal neuron synapses was induced in the field excitatory postsynaptic potential (EPSP) by the delivery of HFS (a tetanus of two trains of 100 pulses at 100 Hz with a 10 s interval) and was reversed (depotentiated) by a train of LFS of 1000 pulses at 2 Hz applied 60 min later. This depotentiation was triggered by activation of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) during HFS, which may increase the postsynaptic intracellular Ca 2+ concentration, leading to a cellular process responsible for modification of LTP expression at mossy fiber-CA3 synapses. Furthermore, we found that activation of IP3Rs or protein phosphatase during LFS was required for the reversal of LTP expressed at mossy fiber-CA3 synapses. These results suggest that, in hippocampal mossy fiber-CA3 neuron synapses, activation of IP3Rs by a preconditioning HFS results in modulation of IP3R activation and/or postsynaptic protein phosphorylation during a subsequent LFS, leading to a decrease in the field EPSP and the erasure of LTP.

Local infusion of ghrelin enhanced hippocampal synaptic plasticity and spatial memory through activation of phosphoinositide 3-kinase in the dentate gyrus of adult rats

Ghrelin, an orexigenic hormone, is mainly produced by the stomach and released into the circulation. Ghrelin receptors (growth hormone secretagogue receptors) are expressed throughout the brain, including the hippocampus. The activation of ghrelin receptors facilitates high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in vitro, and also improves learning and memory. Herein, we report that a single infusion of ghrelin into the hippocampus led to long-lasting potentiation of excitatory postsynaptic potentials (EPSPs) and population spikes (PSs) in the dentate gyrus of anesthetized rats. This potentiation was accompanied by a reduction in paired-pulse depression of the EPSP slope, an increase in paired-pulse facilitation of the PS amplitude, and an enhancement of EPSP-spike coupling, suggesting the involvement of both presynaptic and postsynaptic mechanisms. Meanwhile, ghrelin infusion time-dependently increased the phosphorylation of Akt-Ser473, a downstream molecule of phosphoinositide 3-kinase (PI3K). Interestingly, PI3K inhibitors, but not NMDA receptor antagonist, inhibited ghrelin-induced potentiation. Although ghrelin had no effect on the induction of HFS-induced LTP, it prolonged the expression of HFS-induced LTP through extracellular signal-regulated kinase (ERK)1/2. The Morris water maze test showed that ghrelin enhanced spatial memory, and that this was prevented by pretreatment with PI3K inhibitor. Taken together, the findings show that: (i) a single infusion of ghrelin induced a new form of synaptic plasticity by activating the PI3K signaling pathway, without HFS and NMDA receptor activation; (ii) a single infusion of ghrelin also enhanced the maintenance of HFS-induced LTP through ERK activation; and (iii) repetitive infusion of ghrelin enhanced spatial memory by activating the PI3K signaling pathway. Thus, we propose that the ghrelin signaling pathway could have therapeutic value in cognitive deficits.

Altered anxiety-like behavior and long-term potentiation in the bed nucleus of the stria terminalis in adult mice exposed to chronic social isolation, unpredictable stress, and ethanol beginning in adolescence

Alcohol and chronic stress exposure, especially during adolescence, can lead to an increased risk in adulthood of developing alcohol use disorders. To date, however, no study has assessed the potential long-term effects of chronic intermittent and unpredictable ethanol (EtOH) exposure in mice chronically stressed beginning in adolescence on brain function and anxiety-like behaviors in adulthood. In particular, alterations in function of the bed nucleus of the stria terminalis (BNST), a brain region heavily implicated in anxiety-related behaviors and altered plasticity following EtOH exposure, may play a key role in the pathological responses to chronic stress and EtOH. In the present study, adolescent and adult C57Bl/6J mice were exposed to a regimen of chronic social isolation and unpredictable stressors and EtOH (or air [sham]; CSI-CUS-EtOH and CSI-CUS-Sham, respectively) for 8–10 weeks. In adulthood, mice were tested for altered anxiety-like behavior (elevated plus maze [EPM] and modified social interaction [SI] test). Following behavioral testing, mice were reexposed to CSI-CUS-EtOH (and CSI-CUS-Sham for controls) for an additional 3 days. Four to six hours following the final EtOH (or air) exposure, field potential recordings of the dorsal-lateral (dl)BNST were performed. Mice first exposed during adolescence to CSI-CUS-EtOH displayed lower levels of anxiety-like behavior on the EPM compared with mice first exposed to CSI-CUS-EtOH during adulthood and control mice only exposed to CSI-CUS-Sham, regardless of age of first exposure. However, mice first exposed to CSI-CUS-EtOH during adulthood displayed lower levels of anxiety-like behavior on the SI test compared with mice first exposed during adolescence and control CSI-CUS-Sham mice. CSI-CUS-EtOH exposure, regardless of age, produced blunted expression of long-term potentiation (LTP) in the dlBNST compared with CSI-CUS-Sham mice. This study demonstrates age-dependent effects of chronic unpredictable ethanol exposure in chronically stressed mice on anxiety-like behaviors during adulthood. Further, CSI-CUS-EtOH exposure results in blunted LTP expression in the adult dlBNST.

Neurogranin phosphorylation fine-tunes long-term potentiation.

Learning-related potentiation of synaptic strength at Cornu ammonis subfield 1 (CA1) hippocampal excitatory synapses is dependent on neuronal activity and the activation of glutamate receptors. However, molecular mechanisms that regulate and fine-tune the expression of long-term potentiation (LTP) are not well understood. Recently it has been indicated that neurogranin (Ng), a neuron-specific, postsynaptic protein that is phosphorylated by protein kinase C, potentiates synaptic transmission in an LTP-like manner. Here, we report that a Ng mutant that is unable to be phosphorylated cannot potentiate synaptic transmission in rat CA1 hippocampal neurons and results in a submaximal expression of LTP. Our results provide the first evidence that the phosphorylation of Ng can regulate LTP expression.

Making memories last: the synaptic tagging and capture hypothesis

The synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation asserts that the induction of synaptic potentiation creates only the potential for a lasting change in synaptic efficacy, but not the commitment to such a change. Other neural activity, before or after induction, can also determine whether persistent change occurs. Recent findings, leading us to revise the original hypothesis, indicate that the induction of a local, synapse-specific 'tagged' state and the expression of long-term potentiation are dissociable. Additional observations suggest that there are major differences in the mechanisms of functional and structural plasticity. These advances call for a revised theory that incorporates the specific molecular and structural processes involved. Addressing the physiological relevance of previous in vitro findings, new behavioural studies have experimentally translated the hypothesis to learning and the consolidation of newly formed memories.

Synaptic Neurotransmission Depression in Ventral Tegmental Dopamine Neurons and Cannabinoid-Associated Addictive Learning

Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction.

Beta-adrenergic receptor activation induces long-lasting potentiation in burst-spiking but not regular-spiking cells at CA1-subiculum synapses

The hippocampus plays a central role in memory formation in the mammalian brain. The subiculum is the principal target of CA1 pyramidal cells and thus serves as the major relay station for the outgoing hippocampal information. Pyramidal cells in the subiculum have been classified as burst-spiking (BS) and regular-spiking (RS) cells. In this study we demonstrate that application of the β-adrenergic agonist isoproterenol (2 μM) induces a chemical form of long-term potentiation (LTP) of responses to alvear stimulation in (BS) but not in (RS) cells. This effect is prevented by the β-adrenergic receptor antagonist propranolol (2 μM). The isoproterenol-induced LTP in (BS) cells does not depend on postsynaptic Ca2+-signaling, as 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) does not prevent its induction. Furthermore, paired-pulse facilitation (PPF) and coefficient of variation (CV) analysis indicate the site of the LTP expression to be presynaptic. Our findings show that activation of β-adrenergic receptors (β-ARs) at CA1-subiculum synapses induces a cell-type-specific form of chemical LTP in subicular (BS) cells that may allow a target-specific trafficking of hippocampal output.

ELECTROACUPUNCTURE AT BAIHUI ACUPOINT (GV20) REVERSES BEHAVIOR DEFICIT AND LONG-TERM POTENTIATION THROUGH N-METHYL-D-ASPARTATE AND TRANSIENT RECEPTOR POTENTIAL VANILLOID SUBTYPE 1 RECEPTORS IN MIDDLE CEREBRAL ARTERY OCCLUSION RATS

Vascular dementia is one of the most important causes that account for 20-40% of all dementia cases. The aim of this study was to investigate whether electroacupuncture can reduce behavior deficit and long-term potentiation (LTP) in vascular dementia. Here we used a middle cerebral artery occlusion (MCAo) technique to induce a vascular dementia model with additional electroacupuncture (EA) manipulation. Behaviors were impaired in animals with MCAo, and similar results were observed with long-term potentiation induction. MCAo decreased the expression of LTP from 180.4±14.9% to 112.5±18.3%, suggesting that cerebral ischemia could impair the hippocampal LTP. In addition, immunostaining results showed that the expressions of N-methyl-D-aspartate receptor subtype 1 (NR1) and transient receptor potential vanilloid subtype 1 (TRPV1) receptors were significantly increased in the hippocampal CA1 areas. Noticeably, these phenomena can be reversed by 2 Hz EA at Baihui acupoint (GV20) for six consecutive days. Our results support a rescue role of 2 Hz EA for MCAo-induced behavior and LTP impairment. These results also suggest that NMDAR1 and TRPV1 may be involved in this pathway.

Orexin-1 receptor mediates long-term potentiation in the dentate gyrus area of freely moving rats

Orexin neurons, localized in the lateral hypothalamus area, synthesize two neuropeptides called orexin A and orexin B and send their axons to hippocampal formation including dentate gyrus (DG). Orexin A and orexin B act as endogenous ligands for two G-protein coupled receptors called orexin-1 and orexin-2 receptors (OX1R and OX2R). In the dentate gyrus (DG) region, OX1R, which has high affinity for orexin A, is expressed. Conflicting results have been reported regarding the effect of orexinergic system on synaptic plasticity. When given alone, SB-334867-A, a non-peptide OX1R antagonist, is a suitable drug to assess the natural and physiological significance of endogenous orexins. In the present research, we studied the effects of DG-OX1Rs antagonization on long-term potentiation (LTP) using two different high frequency stimulation (HFS) protocols i.e. 200 and 400 Hz in freely moving rats. The results showed that inactivation of DG-OX1Rs impair LTP induction in both HFS protocols which lasts beyond 24 h. This occurs with respect to both the population excitatory post-synaptic potential slope and population spike amplitude. Our findings suggest that endogenous orexins are involved in the expression of LTP, at least through DG-OX1Rs.

Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice.

Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice.

Disruption of the CaMKII/CREB Signaling is Associated with Zinc Deficiency-Induced Learning and Memory Impairments

Many studies have shown that zinc deficiency not only retards growth, but also affects several brain functions, including learning and memory. However, the underlying mechanism of impaired hippocampus-dependent learning and memory under zinc deficiency is poorly understood. In this study, young mice were fed a zinc-deficient diet (0.85ppm) for 5weeks. Morris water maze result showed that zinc deficiency results in spatial learning impairment. We then examined whether zinc depletion-induced learning and memory defects are associated with changes in signaling molecules essential for the expression of long-term potentiation. Immunoblot results showed that the protein levels of calmodulin (CaM), phosphorylated CaM-dependent protein kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (CREB) were significantly reduced, whereas the total protein levels of CaMKII and CREB did not change in the zinc-deficient hippocampus. Thus, we provide a previously unrecognized mechanism whereby zinc deficiency impairs hippocampal learning and memory, at least in part, through disruption of the CaM/CaMKII/CREB signaling pathway.