Reduction Of Long-term Potentiation Research Articles

Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities

Dystrophic neurites are swollen dendrites or axons recognizable near amyloid plaques as a part of important pathological feature of Alzheimer's disease (AD). We report herein that reticulon 3 (RTN3) is accumulated in a distinct population of dystrophic neurites named as RTN3 immunoreactive dystrophic neurites (RIDNs). The occurrence of RIDNs is concomitant with the formation of high-molecular-weight RTN3 aggregates in brains of AD cases and mice expressing mutant APP. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. It appears that the protein level of RTN3 governs the formation of RIDNs because transgenic mice expressing RTN3 will develop RIDNs, initially in the hippocampal CA1 region, and later in other hippocampal and cortical regions. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Together, we demonstrate that aggregation of RTN3 contributes to AD pathogenesis by inducing neuritic dystrophy. Inhibition of RTN3 aggregation is likely a therapeutic approach for reducing neuritic dystrophy.

Mice Deficient in Collapsin Response Mediator Protein-1 Exhibit Impaired Long-Term Potentiation and Impaired Spatial Learning and Memory

Collapsing response mediator protein-1 (CRMP-1) was initially identified in brain and has been implicated in plexin-dependent neuronal function. The high amino acid sequence identity among the five CRMPs has hindered determination of the functions of each individual CRMP. We generated viable and fertile CRMP-1 knock-out (CRMP-1(-/-)) mice with no evidence of gross abnormality in the major organs. CRMP-1(-/-) mice exhibited intense microtubule-associated protein 2 (MAP2) staining in the proximal portion of the dendrites, but reduced and disorganized MAP2 staining in the distal dendrites of hippocampal CA1 pyramidal cells. Immunoreactivity to GAP-43 (growth-associated protein-43) and PSD95 (postsynaptic density-95) (a postsynaptic membrane adherent cytoskeletal protein) was also decreased in the CA1 region of the knock-out mice. These changes were consistent with the mutant mice showing a reduction in long-term potentiation (LTP) in the CA1 region and impaired performance in hippocampal-dependent spatial learning and memory tests. CRMP-1(-/-) mice showed a normal synapsin I labeling pattern in CA1 and normal paired-pulse facilitation. These findings provide the first evidence suggesting that CRMP-1 may be involved in proper neurite outgrowth in the adult hippocampus and that loss of CRMP-1 may affect LTP maintenance and spatial learning and memory.

Neonatal Exposure to Brominated Flame Retardant BDE-47 Reduces Long-Term Potentiation and Postsynaptic Protein Levels in Mouse Hippocampus

BackgroundIncreasing environmental levels of brominated flame retardants raise concern about possible adverse effects, particularly through early developmental exposure.ObjectiveThe objective of this research was to investigate neurodevelopmental mechanisms underlying previously observed behavioral impairments observed after neonatal exposure to polybrominated diphenyl ethers (PBDEs).MethodsC57Bl/6 mice received a single oral dose of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) on postnatal day (PND) 10 (i.e., during the brain growth spurt). On PND17–19, effects on synaptic plasticity, levels of postsynaptic proteins involved in long-term potentiation (LTP), and vesicular release mechanisms were studied ex vivo. We investigated possible acute in vitro effects of BDE-47 on vesicular catecholamine release and intracellular Ca2+ in rat pheochromocytoma (PC12) cells.ResultsField-excitatory postsynaptic potential (f-EPSP) recordings in the hippocampal CA1 area demonstrated reduced LTP after exposure to 6.8 mg (14 μmol)/kg body weight (bw) BDE-47, whereas paired-pulse facilitation was not affected. Western blotting of proteins in the postsynaptic, triton-insoluble fraction of hippocampal tissue revealed a reduction of glutamate receptor subunits NR2B and GluR1 and autophosphorylated-active Ca2+/calmodulin-dependent protein kinase II (αCaMKII), whereas other proteins tested appeared unaffected. Amperometric recordings in chromaffin cells from mice exposed to 68 mg (140 μmol)/kg bw BDE-47 did not reveal changes in catecholamine release parameters. Modest effects on vesicular release and intracellular Ca2+ in PC12 cells were seen following acute exposure to 20 μM BDE-47. The combined results suggest a post-synaptic mechanism in vivo.ConclusionEarly neonatal exposure to a single high dose of BDE-47 causes a reduction of LTP together with changes in postsynaptic proteins involved in synaptic plasticity in the mouse hippocampus.

Hippocampal Long-Term Potentiation Is Supported by Presynaptic and Postsynaptic Tyrosine Receptor Kinase B-Mediated Phospholipase Cγ Signaling

Neurotrophins have been shown to play a critical role in activity-dependent synaptic plasticity such as long-term potentiation (LTP) in the hippocampus. Although the role of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor [tyrosine receptor kinase B (TrkB)] is well documented, it still remains unresolved whether presynaptic or postsynaptic activation of TrkB is involved in the induction of LTP. To address this question, we locally and specifically interfered with a downstream target of the TrkB receptor, phospholipase Cgamma (PLCgamma). We prevented PLCgamma signaling by overexpression of the PLCgamma pleckstrin homology (PH) domain with a Sindbis virus vector. The isolated PH domain has an inhibitory effect and thereby blocks endogenous PLCgamma signaling and consequently also IP3 production. Surprisingly, concurrent presynaptic and postsynaptic blockade of PLCgamma signaling was required to reduce LTP to levels comparable with those in TrkB and BDNF knock-out mice. Blockade of presynaptic or postsynaptic signaling alone did not result in a significant reduction of LTP.

Blockade of nicotinic acetylcholine receptors suppresses hippocampal long‐term potentiation in wild‐type but not ApoE4 targeted replacement mice

Both impaired nicotinic neurotransmission and the inheritance of apoE4 are associated with increased risk for Alzheimer disease (AD) as well as other deficiencies in memory-related behavior. Long-term potentiation (LTP), a cellular model of memory, is known to be altered by nicotinic agents. Recent studies also support an emergent role for apoE in LTP. We compared the effects of mecamylamine, a nonspecific antagonist of nicotinic acetylcholine receptors (nAChRs), on basal synaptic transmission and LTP in hippocampal slices from wild-type (wt) mice and targeted replacement mice expressing human apoE4 (apoE4-TR). Field excitatory postsynaptic potentials (EPSPs) were recorded in the dentate gyrus (DG) in response to medial perforant path activation, and theta burst stimulation was used to induce LTP. Bath application of mecamylamine (3 microM) did not alter input-output relationships or paired pulse depression in either mouse strain. Under control conditions, apoE4-TR mice showed significantly less LTP than wt mice (17.5% +/- 3.2%, n = 9, vs. 30.1% +/- 3.9%, n = 11, P < 0.02). Mecamylamine reduced LTP in wt mice to a level that was similar to control levels for apoE4-TR mice (15.7% +/- 3.4%, n = 9), whereas apoE4-TR showed no further reduction of LTP (16.6% +/- 3.7%, n = 8) by mecamylamine. Thus mice expressing human apoE4 differ from wt mice both in their capacity for LTP and in the effect on LTP of nicotinic cholinergic blockade. It is possible that nicotinic neurotransmission is already compromised in apoE4-TR mice and, hence, that interference with the integrity of this cholinergic system represents a mechanism by which inheritance of the apoE4 allele contributes to cognitive risk.

Blood Lead and IQ in Older Children

In their article about blood lead and IQ in older children, Chen et al. (2005) made the very important observation that IQ (intelligence quotient) in older children correlates better with their current blood lead level than with levels determined at 2 years of age. This observation has enormous public health implications in terms of defining who is at risk of cognitive decrement upon exposure to lead, and challenges the widely held assumption that the effects of lead on neurobehavioral function are exclusively developmental. My colleagues and I (Carpenter et al. 2002) previously studied the effects of gestational and lactational exposure of rats to lead with measurement of long-term potentiation in hippocampal brain slices. Long-term potentiation is an electrophysiological measure of synaptic plasticity that is widely viewed as being at least one component of learning and memory, and it is reduced upon in vivo lead exposure. To our surprise we also found that acute perfusion of low concentrations of lead onto brain slices from control animals resulted in reduction of long-term potentiation, suggesting that the effect is more pharmacologic than developmental. The results of Chen et al. (2005) in humans and our studies in rats suggest that lead causes both developmental and pharmacologic impairment of cognitive function. If this is true, then steps should be taken to prevent exposure to lead and to reduce lead levels in individuals of any age, not just young children.

Agonists of peroxisome proliferator-activated receptor-γ attenuate the Aβ-mediated impairment of LTP in the hippocampus in vitro

The data we present here suggest that agonists of peroxisome proliferator-activated receptor-γ (PPARγ) can attenuate the effects of beta-amyloid peptide (Aβ). Alzheimer's disease is associated with elevated levels of Aβ, and enhanced expression of PPARγ. In this study, we determined that application of Aβ [1–40] could impair hippocampal post-tetanic potentiation (PTP) and long-term potentiation (LTP) in vitro. We investigated the effects of PPARγ agonists; troglitazone, ciglitazone and 15-deoxy-Δ 12,14 prostaglandin J 2 (PGJ 2) on synaptic transmission and plasticity in area CA1. Both ciglitazone and PGJ 2 increased baseline synaptic transmission significantly, without altering paired-pulse facilitation. PGJ 2 produced a significant reduction in LTP, whereas ciglitazone and troglitazone had no significant effect. In addition, prior application of each ligand attenuated the previously observed Aβ [1–40]-mediated impairment of LTP. The effect of troglitazone on the Aβ [1–40]-mediated impairment of LTP was not reversed by the PPARγ antagonist, GW-9662. These findings demonstrate that PPARγ agonists attenuate the effects of Aβ on LTP, and support the potential use of these agents to alleviate the symptoms of Alzheimer's disease. We also suggest that PPARγ agonists may regulate expression of hippocampal LTP in vitro.

A Non-sulfated Form of the HNK-1 Carbohydrate Is Expressed in Mouse Kidney

The HNK-1 carbohydrate, which is recognized by anti-HNK-1 antibody, is well known to be expressed predominantly in the nervous system. The characteristic structural feature of the HNK-1 carbohydrate is 3-sulfo-glucuronyl residues attached to lactosamine structures (Gal beta1-4GlcNAc) on glycoproteins and glycolipids. The biosynthesis of the HNK-1 carbohydrate is regulated mainly by two glucuronyltransferases (GlcAT-P and GlcAT-S) and a sulfotransferase. In this study, we found that GlcAT-S mRNA was expressed at higher levels in the kidney than in the brain, but that both GlcAT-P and HNK-1 sulfotransferase mRNAs, which were expressed at high levels in the brain, were not detected in the kidney. These results suggested that the HNK-1 carbohydrate without sulfate (non-sulfated HNK-1 carbohydrate) is expressed in the kidney. We substantiated this hypothesis using two different monoclonal antibodies: one (anti-HNK-1 antibody) requires sulfate on glucuronyl residues for its binding, and the other (antibody M6749) does not. Western blot analyses of mouse kidney revealed that two major bands (80 and 140 kDa) were detected with antibody M6749, but not with anti-HNK-1 antibody. The 80- and 140-kDa band materials were identified as meprin alpha and CD13/aminopeptidase N, respectively. We also confirmed the presence of the non-sulfated HNK-1 carbohydrate on N-linked oligosaccharides by multistage tandem mass spectrometry. Immunofluorescence staining with antibody M6749 revealed that the non-sulfated HNK-1 carbohydrate was expressed predominantly on the apical membranes of the proximal tubules in the cortex and was also detected in the thin ascending limb in the inner medulla. This is the first study indicating the presence of the non-sulfated HNK-1 carbohydrate being synthesized by GlcAT-S in the kidney. The results presented here constitute novel knowledge concerning the function of the HNK-1 carbohydrate.

Metabotropic glutamate receptors contribute to neocortical synaptic plasticity in vivo

Metabotropic glutamate receptors (mGluRs) have been shown to be important for hippocampus-dependent memory, as well as activity-dependent synaptic plasticity in the hippocampus. In this study, we examined the role of mGluRs in the induction of two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in the neocortex of awake, freely-moving rats. The mGluR antagonist AIDA was administered during the induction of LTP or LTD in the motor cortex. There was a 50% reduction of LTP induced in the early component of the evoked response, but there was no effect on the late component and no effect on the induction of LTD. Thus, mGluRs contribute to at least one form of activity dependent synaptic plasticity in the neocortex.

Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus.

NCAM, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation, axon outgrowth and fasciculation, and synaptic plasticity. To dissociate the functional roles of NCAM in the adult brain from developmental abnormalities, we generated a mutant in which the NCAM gene is inactivated by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMff+) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAM-/-) mice. However, similar to the NCAM-/- mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMff+ mice. The deficit in LTP could be rescued by elevation of extracellular Ca2+ concentrations from 1.5 or 2.0 to 2.5 mm, suggesting an involvement of NCAM in regulation of Ca2+-dependent signaling during LTP. Contrary to the NCAM-/- mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMff+ as opposed to abnormal lamination in NCAM-/- mice. NCAMff+ mutants did not show general deficits in short- and long-term memory in global landmark navigation in the water maze but were delayed in the acquisition of precise spatial orientation, a deficit that could be overcome by training. Thus, mice conditionally deficient in hippocampal NCAM expression in the adult share certain abnormalities characteristic of NCAM-/- mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.

Impaired Long-Term Memory and NR2A-Type NMDA Receptor-Dependent Synaptic Plasticity in Mice Lacking c-Fos in the CNS

The immediate early gene c-fos is part of the activator protein-1 transcription factor and has been postulated to participate in the molecular mechanisms of learning and memory. To test this hypothesis in vivo, we generated mice with a nervous system-specific c-fos knock-out using the Cre-loxP system. Adult mice lacking c-Fos in the CNS (c-fosDeltaCNS) showed normal general and emotional behavior but were specifically impaired in hippocampus-dependent spatial and associative learning tasks. These learning deficits correlated with a reduction of long-term potentiation (LTP) in hippocampal CA3-CA1 synapses. The magnitude of LTP was restored by a repeated tetanization procedure, suggesting impaired LTP induction in c-fosDeltaCNS mice. This rescue was blocked by a selective inhibitor of NR2B-type NMDA receptors. This blockade was compensated in wild-type mice by NR2A-type NMDA receptor-activated signaling pathways, thus indicating that these pathways are compromised in c-fosDeltaCNS mice. In summary, our data suggest a role for c-Fos in hippocampus-dependent learning and memory as well as in NMDA receptor-dependent LTP formation.

Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function.

DNA methylation-mediated epigenetic regulation plays critical roles in regulating mammalian gene expression, but its role in normal brain function is not clear. Methyl-CpG binding protein 1 (MBD1), a member of the methylated DNA-binding protein family, has been shown to bind methylated gene promoters and facilitate transcriptional repression in vitro. Here we report the generation and analysis of MBD1-/- mice. MBD1-/- mice had no detectable developmental defects and appeared healthy throughout life. However, we found that MBD1-/- neural stem cells exhibited reduced neuronal differentiation and increased genomic instability. Furthermore, adult MBD1-/- mice had decreased neurogenesis, impaired spatial learning, and a significant reduction in long-term potentiation in the dentate gyrus of the hippocampus. Our findings indicate that DNA methylation is important in maintaining cellular genomic stability and is crucial for normal neural stem cell and brain functions.

A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro

Long-term potentiation (LTP) and long-term depression (LTD) are two forms of activity-dependent synaptic plasticity that are thought to be involved in learning and memory. Evidence has shown that cyclooxygenase-2 (COX-2), an enzyme that converts arachidonic acid to prostaglandins, is expressed in postsynaptic dendritic spines and is regulated by synaptic activity. COX-2 inhibition has been shown to directly attenuate LTP in the dentate gyrus of the hippocampus. Also recently the p38 MAP kinase cascade, a pathway utilised by cells for COX-2 expression, has been implicated in LTD induction in the CA1 region of the hippocampus. Here we demonstrate for the first time a direct role for COX-2 and p38 MAP kinase in LTD and confirm the inhibitory role of COX-2 in LTP in the rat dentate gyrus. Perfusion of the COX-2 inhibitor NS-398 (1 μM) 60 min before tetanic stimulation resulted in an attenuation of LTD (84±5%, n=5 compared to controls of 57±7%, n=6, P<0.05). Prolonged exposure (2 h) to NS-398 (1 μM) resulted in a significant reduction in LTP (71±8%, n=5, P<0.01 compared to controls of 170±11%, n=5 at 60 min post HFS). The p38 MAPK inhibitor, SB220025 (250 nM) significantly attenuated LTD (88±5%, n=7; P<0.01 compared to vehicle controls at 60 min, 56±5%, n=6) but had no significant effect on LTP. Both NS-398 and SB220025 had no significant effect on the isolated NMDA-mediated EPSP. These data demonstrate a role for COX-2 and p38 MAPK in LTD in the dentate gyrus in vitro that is independent of NMDA receptor activation.

Sleep deprivation impairs long-term potentiation in rat hippocampal slices.

To determine if 12-h sleep deprivation disrupts neural plasticity, we compared long-term potentiation (LTP) in five sleep-deprived and five control rats. Thirty minutes after tetanus population spike amplitude increased 101 +/- 15% in 16 slices from sleep deprived rats and 139 +/- 14% in 14 slices from control rats. This significant (P < 0.05) reduction of LTP, the first demonstration that the sleep deprivation protocol impairs plasticity in adult rats, may be due to several factors. Reduced LTP may indicate that sleep provides a period of recuperation for cellular processes underlying neural plasticity. Alternatively, the stress of sleep deprivation, as indicated by elevated blood corticosterone levels, or other non-sleep-specific factors of deprivation may contribute to the LTP reduction.

Alpha3 integrin receptors contribute to the consolidation of long-term potentiation

Several lines of evidence suggest that integrin receptors play a pivotal role in consolidation of long-term potentiation (LTP), but which of the many integrin dimers are involved remains to be discovered. The present study used an LTP reversal paradigm to test if α3 integrins make an important contribution. Function blocking α3 monoclonal antibodies or vehicle were locally infused into recording sites in field CA1 of rat hippocampal slices and LTP induced with theta burst stimulation. Low frequency trains of pulses were applied 30 min after the theta bursts. Previous work indicates that low frequency stimulation reverses LTP when applied immediately after induction but is largely ineffective after 30–45-min delays. If the antibodies were to block consolidation, then they should extend the period over which potentiation is vulnerable to disruption. There was no detectable difference between the two groups in the initial degree of LTP or within slice decay of potentiation 1–10 min after induction; a small but reliable decay occurred from 10 to 30 min with antibody treatment ( P<0.01) but not in control slices. Percent potentiation was not statistically different for vehicle (55±19%, mean±S.D.) and anti-α3 (43±21%) slices at 30 min post-theta bursts. Five-Hz stimulation (‘theta pulse’ stimulation) 30 min after induction caused a reduction of LTP. The percent loss of potentiation after the 1-min trains was greater in the antibody-treated slices than in controls (98±4% vs. 62±28%, P<0.01, U-test) and correlated ( r=0.84, α3 slices) with the percent LTP present prior to low frequency stimulation, as expected if the stimulation reversed potentiation. Recovery occurred in both groups but percent LTP was significantly smaller in experimental slices at 10 min post-theta pulses (5±11% vs. 36±15%, P<0.01). Recovery continued for 20 min after theta pulses and, in accordance with earlier work, was nearly complete for the control slices (50±19% vs 55±15%, 40 min post- vs. immediately pre-theta pulses). LTP remained depressed after 40 min of recovery in the anti-α3 slices (23±19% vs. 43±21%) at which point it was substantially less than that found in controls ( P<0.01). Western blots with anti-α3 antibodies identified a polypeptide with the molecular mass (155 kDa) expected for the α3 subunit and further showed that it is broadly distributed in brain. Subcellular fractionation experiments demonstrated that α3 is concentrated in synaptic membranes over homogenates to about the same degree as the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptor. From these results we suggest that α3-containing integrins are localized to synapses and are needed to stabilize a slowly decaying form of LTP. The findings also show that vulnerability to reversal can be used in place of extended recording sessions in studying consolidation.

Different effects of anxiolytic agents, diazepam and 5-HT 1A agonist tandospirone, on hippocampal long-term potentiation in vivo

Benzodiazepines and 5-HT 1A agonists have been widely used as anxiolytic agents. Some clinical reports document that 5-HT 1A agonists induce memory impairment to a lesser degree than diazepam. In the present study, we compared the effects of diazepam and 5-HT 1A agonist, tandospirone, on hippocampal long-term potentiation (LTP) in Schaffer collateral-CA1, mossy fiber-CA3 and perforant path-dentate gyrus synapses. In the diazepam-injected group, the reduction in LTP was observed in all three types of synapses, although the effective dose differed among these. In the tandospirone-injected group, no reduction in LTP was observed except in Schaffer-CA1 synapses. In addition, population spike amplitude was potentiated by tandospirone in mossy fiber-CA3 synapses in a dose-dependent manner. Thus, there was a discrepancy in the effects on hippocampal LTP between diazepam and tandospirone, possibly reflecting the reported clinical properties of these drugs, in that 5-HT 1A partial agonists do not affect learning and memory, whereas diazepam impairs memory function.

Aminoguanidine prevented the impairment of learning behavior and hippocampal long-term potentiation following transient cerebral ischemia

The present study was performed to investigate whether increases in nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) were involved in impairment of learning behavior and hippocampal long-term potentiation (LTP) following transient ischemia. Rats with four-vessel occlusion (4-VO) were used as an ischemic model. One week after permanent occlusion of the vertebral arteries, the common carotid arteries were clamped for 10 min under halothane anesthesia. Aminoguanidine (10 mg/kg i.p.), a relatively selective iNOS inhibitor, or saline was administered 30 min before common carotid arteries occlusion, and every 24-h for 4 days. We investigated whether hippocampal NO production was increased by ischemic insult using microdialysis on days 1, 4 and 7 after 4-VO. On days 1 and 4 after 4-VO, increases in NO production were observed, and this effect was inhibited by aminoguanidine. Four days after 4-VO, rats were subjected to the Y-maze test and contextual fear conditioning. Ischemic insults impaired learning behavior, and aminoguanidine ameliorated the impairment induced by 4-VO. Four days after 4-VO, the changes in the population spike amplitude were recorded as an index of LTP in Schaffer collateral–CA1 (carotid artery 1), the mossy fiber–CA3 and the perforant path–dentate gyrus synapses. LTP was significantly inhibited by 4-VO, except in mossy fiber–CA3 synapses. Pretreatment with aminoguanidine prevented the reduction of LTP in perforant path–dentate gyrus, but not in Schaffer collateral–CA1 synapses. These results suggest that post-ischemic increase in NO production via iNOS impaired the learning behavior. There is an association between behavioral performance and LTP formation in perforant path–dentate gyrus synapses, but neither in Schaffer collateral–CA1 nor in mossy fiber–CA3 synapses.

SB203580, the p38 mitogen-activated protein kinase inhibitor blocks the inhibitory effect of β-amyloid on long-term potentiation in the rat hippocampus

The effect of the β-amyloid peptide (β-AP) 25–35 and SB203580, the p38 mitogen-activated protein (MAP) kinase inhibitor, were investigated on long term potentiation (LTP) in the dentate gyrus of the rat hippocampal slice. In the presence of 1 μM β-AP (25–35) basal synaptic transmission was reduced to 88.9±5.2% of control ( n=4, P<0.5). Tetanic stimulation of control slices gave rise to a robust LTP (139±4%, n=5, P<0.05). 1 μM β-AP (25–35) was found to inhibit this LTP (104.0±4.5% at 90 min; n=4, P<0.05). Perfusion of SB203580 alone (1 μM) had no significant effect on baseline synaptic transmission or LTP ( n=4). However, in the presence of SB203580, β-AP (25–35; 1 μM) did not give rise to a reduction in LTP (150±11.8%, n=4). These results suggest that high levels of β-AP (25–35) may inhibit LTP through a pathway involving the p38 MAP kinase.

Essential Role for TrkB Receptors in Hippocampus-Mediated Learning

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.

Relative Contribution of Endogenous Neurotrophins in Hippocampal Long-Term Potentiation

Recent evidence has shown that brain-derived neurotrophic factor (BDNF) is involved in hippocampal long-term potentiation (LTP). Because the reagents used in acute experiments react not only with BDNF but also with neurotrophin-4/5 (NT4/5) and neurotrophin-3 (NT3), we examined the involvement of these neurotrophins in LTP using two highly specific, function-blocking monoclonal antibodies against BDNF and NT3, as well as a TrkB-IgG fusion protein. Our results show that NT3 antibodies did not have any effects on LTP. However, both TrkB-IgG fusion proteins and BDNF antibody similarly reduced LTP, suggesting that only BDNF but no other ligands of the TrkB-receptor are likely to be involved in LTP induction. The reduction in LTP depended on the inducing stimuli and was only observed with theta-burst stimulation (TBS) but not with tetanic stimulation. We further observed that LTP was only reduced if BDNF was blocked before and during TBS stimulation, and BDNF antibodies did not affect early or late stages of LTP if they were applied 10, 30, or 60 min after TBS stimulation. These results point toward a specific and unique role of endogenous BDNF but not of other neurotrophins in the process of TBS-induced hippocampal LTP. Additionally, they suggest that endogenous BDNF is required for a limited time period only shortly before or around LTP induction but not during the whole process of LTP.