Blockade of BDNF signaling turns chemically‐induced long‐term potentiation into long‐term depression

Long‐term potentiation (LTP) is accompanied by increased spine density and dimensions triggered by signaling cascades involving activation of the neurotrophin brain‐derived neurotrophic factor (BDNF) and cytoskeleton remodeling. Chemically‐induced long‐term potentiation (c‐LTP) is a widely used cellular model of plasticity, whose effects on spines have been poorly investigated. We induced c‐LTP by bath‐application of the N‐methyl‐d ‐aspartate receptor (NMDAR) coagonist glycine or by the K⁺ channel blocker tetraethylammonium (TEA) chloride in cultured hippocampal neurons and compared the changes in dendritic spines induced by the two models of c‐LTP and determined if they depend on BDNF/TrkB signaling. We found that both TEA and glycine induced a significant increase in stubby spine density in primary and secondary apical dendrites, whereas a specific increase in mushroom spine density was observed upon TEA application only in primary dendrites. Both TEA and glycine increased BDNF levels and the blockade of tropomyosin‐receptor‐kinase receptors (TrkRs) by the nonselective tyrosine kinase inhibitor K‐252a or the selective allosteric TrkB receptor (TrkBR) inhibitor ANA‐12, abolished the c‐LTP‐induced increase in spine density. Surprisingly, a blockade of TrkBRs did not change basal spontaneous glutamatergic transmission but completely changed the synaptic plasticity induced by c‐LTP, provoking a shift from a long‐term increase to a long‐term depression (LTD) in miniature excitatory postsynaptic current (mEPSC) frequency. In conclusion, these results suggest that BDNF/TrkB signaling is necessary for c‐LTP‐induced plasticity in hippocampal neurons and its blockade leads to a switch of c‐LTP into chemical‐LTD (c‐LTD). © 2013 Wiley Periodicals, Inc.     

Shifting patterns of polyribosome accumulation at synapses over the course of hippocampal long‐term potentiation

Hippocampal long‐term potentiation (LTP) is a cellular memory mechanism. For LTP to endure, new protein synthesis is required immediately after induction and some of these proteins must be delivered to specific, presumably potentiated, synapses. Local synthesis in dendrites could rapidly provide new proteins to synapses, but the spatial distribution of translation following induction of LTP is not known. Here, we quantified polyribosomes, the sites of local protein synthesis, in CA1 stratum radiatum dendrites and spines from postnatal day 15 rats. Hippocampal slices were rapidly fixed at 5, 30, or 120 min after LTP induction by theta‐burst stimulation (TBS). Dendrites were reconstructed through serial section electron microscopy from comparable regions near the TBS or control electrodes in the same slice, and in unstimulated hippocampus that was perfusion‐fixed in vivo. At 5 min after induction of LTP, polyribosomes were elevated in dendritic shafts and spines, especially near spine bases and in spine heads. At 30 min, polyribosomes remained elevated only in spine bases. At 120 min, both spine bases and spine necks had elevated polyribosomes. Polyribosomes accumulated in spines with larger synapses at 5 and 30 min, but not at 120 min. Small spines, meanwhile, proliferated dramatically by 120 min, but these largely lacked polyribosomes. The number of ribosomes per polyribosome is variable and may reflect differences in translation regulation. In dendritic spines, but not shafts, there were fewer ribosomes per polyribosome in the slice conditions relative to in vivo, but this recovered transiently in the 5 min LTP condition. Overall, our data show that LTP induces a rapid, transient upregulation of large polyribosomes in larger spines, and a persistent upregulation of small polyribosomes in the bases and necks of small spines. This is consistent with local translation supporting enlargement of potentiated synapses within minutes of LTP induction.     

Effect of chloramine-T on long-term potentiation at synapses between perforant path and dentate gyrus in hippocampus of rats in vivo

Reactive oxygen species (ROS), including superoxide, are generally considered as neurotoxic molecules whose effects can be alleviated by antioxidant enzymes. However, ROS also are known to be necessary components of the signal transduction cascades underlying normal synaptic plasticity. The oxidant chloramine-T (Ch-T), a specific oxidant to sulphur-containing residues, can oxidize methionine (Met) residues in proteins to alter protein function. To investigate the effect of Ch-T on the induction of hippocampal long-term potentiation (LTP) in dentate gyrus (DG), in vivo electrophysiological recording was employed. It was found that intracerebroventricular (ICV) injection of 0.1 μM Ch-T in 5 μL enhanced hippocampal LTP of rats slightly, whereas, 20 mM Ch-T in 5 μL greatly attenuated LTP. These effects can be reversed by pretreatment with 0.1 mM dithiothretol (DTT), a special thiol reductant. In addition, 0.1 μM Ch-T elevated LTP-induced increase in phosphorylation of Ca2+/calmodulin (CaM)-dependent protein kinase (CaMKII) and neurogranin (Ng), whereas 2 μM and 20 mM Ch-T reduced LTP-induced increase in phosphorylation status of the two key proteins, especially for 20 mM Ch-T. Pretreatment with DTT significantly prevented these effects. Taken together, these findings demonstrated that Ch-T has concentration-dependent effects on the induction of hippocampal LTP in vivo. In brief, low concentration of Ch-T facilitated hippocampal LTP by enhancing LTP-induced increase in p-CaMKII and p-Ng compared to controls, whereas high concentration of Ch-T obviously attenuated LTP accompanied by a decrease in the phosphorylated proteins, and both of these effects can be prevented by DTT. These results indicate that Ch-T modulates hippocampal LTP through regulating phosphorylation status of CaMKII and Ng.     

Activation of dopamine D1/D5 receptors facilitates the induction of presynaptic long‐term potentiation at hippocampal output synapses

Encoding of novel information has been proposed to rely on the time‐locked release of dopamine in the hippocampal formation during novelty detection. However, the site of novelty detection in the hippocampus remains a matter of debate. According to current models, the CA1 and the subiculum act as detectors and distributors of novel sensory information. Although most CA1 pyramidal neurons exhibit regular‐spiking behavior, the majority of subicular pyramidal neurons fire high‐frequency bursts of action potentials. The present study investigates the efficacy of dopamine D1/D5 receptor activation to facilitate the induction of activity‐dependent long‐term potentiation (LTP) in rat CA1 regular‐spiking and subicular burst‐spiking pyramidal cells. Using a weak stimulation protocol, set at a level subthreshold for the induction of LTP, we show that activation of D1/D5 receptors for 5–10 min facilitates LTP in subicular burst‐spiking neurons but not in CA1 neurons. The results demonstrate that D1/D5 receptor‐facilitated LTP is NMDA receptor‐dependent, and requires the activation of protein kinase A. In addition, the D1/D5 receptor‐facilitated LTP is shown to be presynaptically expressed and relies on presynaptic Ca²⁺ signaling. The phenomenon of dopamine‐induced facilitation of presynaptic NMDA receptor‐dependent LTP in subicular burst‐spiking pyramidal cells is in accordance with observations of the time‐locked release of dopamine during novelty detection in this brain region, and reveals an intriguing mechanism for the encoding of hippocampal output information.     

Plasticity of synaptic glun receptors is required for the Src‐dependent induction of long‐term potentiation at CA3‐CA1 synapses

The induction of long‐term potentiation (LTP) of CA3‐CA1 synapses requires activation of postsynaptic N‐methyl‐D ‐aspartate receptors (GluNRs). At resting potential, the contribution of GluNRs is limited by their voltage‐dependent block by extracellular Mg²⁺. High‐frequency afferent stimulation is required to cause sufficient summation of excitatory synaptic potentials (EPSPs) to relieve this block and to permit an influx of Ca²⁺. It has been assumed that this relief of Mg²⁺ block is sufficient for induction. We postulated that the induction of LTP also requires a Src‐dependent plasticity of GluNRs. Using whole‐cell recordings, LTP (GluARs) of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors‐EPSCS was induced by pairing postsynaptic depolarization with presynaptic stimulation. This LTP was both GluNR and Src‐dependent, being sensitive to AP‐5, a GluNR selective antagonist, or to SU6656, a Src‐selective inhibitor. When CNQX was used to block all GluARs, we observed a long‐lasting potentiation of GluNR‐mediated EPSCs. This plasticity was prevented by transiently blocking GluNRs during the induction protocol or by chelating intracellular Ca²⁺. GluNRs plasticity was also prevented by bath applications of SU6656 or intracellular applications of the Src‐selective inhibitory peptide, Src(40–58). It was also blocked by preventing activation of protein kinase C, a kinase that is upstream of Src‐kinase‐dependent regulation of GluNRs. Both GluN2A and GluN2B receptors were found to contribute to the plasticity of GluNRs. The contribution of GluNRs and, in particular, their plasticity to the maintenance of LTP was explored using AP5 and SU6656, respectively. When applied >20 min after induction neither drug influenced the magnitude of LTP. However, when applied immediately after induction, treatment with either drug caused the initial magnitude of LTP to progressively decrease to a sustained phase of reduced amplitude. Collectively, our findings suggest that GluNR plasticity, although not strictly required for induction, is necessary for the maintenance of a nondecrementing component of LTP. © 2010 Wiley‐Liss, Inc.     

17β estradiol recruits GluN2B‐containing NMDARs and ERK during induction of long‐term potentiation at temporoammonic‐CA1 synapses

When circulating 17β estradiol (E2) is elevated to proestrous levels, hippocampus‐dependent learning and memory is enhanced in female rodents, nonhuman primates, and women due to heightened synaptic function at hippocampal synapses. We previously reported that proestrous‐like levels of E2 administered to young adult ovariectomized (OVX) female rats increases the magnitude of LTP at CA3 Schaffer collateral (SC)‐CA1 synapses only when dendritic spine density, the NMDAR/AMPAR ratio, and current mediated by GluN2B‐containing NMDA receptors (NMDARs) are simultaneously increased. We also reported that this increase in GluN2B‐mediated NMDAR current in area CA1 is causally related to the E2‐induced increase in novel object recognition, tying together heightened synaptic function with improved learning and memory. In addition to SC inputs, innervation from the entorhinal cortex in the temporoammonic (TA) pathway onto CA1 distal dendrites in stratum lacunosum‐moleculare is critical for spatial memory formation and retrieval. It is not known whether E2 modulates TA‐CA1 synapses similarly to SC‐CA1 synapses. Here, we report that 24 hours post‐E2 injection, dendritic spine density on CA1 pyramidal cell distal dendrites and current mediated by GluN2B‐containing NMDARs at TA‐CA1 synapses is increased, similarly to our previous findings at SC‐CA1 synapses. However, in contrast to SC‐CA1 synapses, AMPAR transmission at TA‐CA1 synapses is significantly increased, and there is no effect on the LTP magnitude. Pharmacological blockade of GluN2B‐containing NMDARs or ERK activation, which occurs downstream of synaptic but not extrasynaptic GluN2B‐containing NMDARs, attenuates the LTP magnitude only in slices from E2‐treated rats. These data show that E2 recruits a causal role for GluN2B‐containing NMDARs and ERK signaling in the induction of LTP, cellular mechanisms not required for LTP induction at TA‐CA1 synapses in vehicle‐treated OVX female rats. © 2015 Wiley Periodicals, Inc.     

Exposure to a novel context following contextual fear conditioning enhances the induction of hippocampal long‐term potentiation

The prior behavioral experience of an animal can influence the direction and the probability of long‐term plasticity induced at the activated synapses. In the present study, we compared alterations in long‐term potentiation in the rat CA1 of the hippocampus following post‐fear conditioning exposure to the conditioning context vs. a novel context. Furthermore, we examined whether the alterations in long‐term potentiation are dependent on the prior formation of context–shock fear memory association. Whereas retrieval of fear memory 1 h after conditioning in the conditioning context was associated with impairment in the magnitude of long‐term potentiation, exposure to a novel context at the same time point was associated with a robust increase in long‐term potentiation. This effect was time‐dependent, as exposure to a novel context 24 h after conditioning resulted in impaired long‐term potentiation. Furthermore, preventing the formation of a fear context–shock association resulted in different modifications to long‐term potentiation levels, regardless of whether association formation was prevented behaviorally (i.e. using a minimal context–shock association) or pharmacologically (using the N‐methyl‐d ‐aspartic acid receptor antagonist MK801). Our findings suggest that exposure to a novel environment following fear conditioning induces a form of metaplasticity that enhances the acquisition of novel information and could prevent acute stress‐associated impairments in long‐term potentiation.     

The α5GABAA receptor modulates the induction of long‐term potentiation at ventral but not dorsal CA1 hippocampal synapses

The hippocampal synapses display conspicuous ability for long‐term plasticity which is thought to underlie learning and memory. Growing evidence shows that this ability differs along the long axis of the hippocampus, with the ventral CA1 hippocampal synapses displaying remarkably lower ability for long‐term potentiation (LTP) compared with their dorsal counterpart when activated with high‐frequency stimulation. Here, we show that low frequency, 10 Hz stimulation induced LTP more reliably in dorsal than in ventral CA1 field. Blockade of alpha5 subunit‐containing GABA_A receptors eliminated the difference between dorsal and ventral hippocampus. We propose that α5GABA_A receptor‐mediated activity plays a crucial role in regulating the threshold for induction of LTP especially at the ventral CA1 hippocampal synapses. This might have important implications for the functional specialization along the hippocampus. Synapse, 2014. © 2014 Wiley Periodicals, Inc.     

Persistent inhibition of hippocampal long‐term potentiation in vivo by learned helplessness stress

The persistent cognitive disruptive effects of stress have been strongly implicated in the pathophysiology of depression and post‐traumatic stress disorder. Here we examined factors influencing the time course of recovery from the inhibitory effect of acute inescapable stressors on the ability to induce long‐term potentiation (LTP) in the dorsal hippocampus in vivo. We tested different forms of LTP, different stressors and different inbred strains of rats. Acute elevated platform stress completely, but transiently (<3 h), inhibited induction of both NMDA receptor‐dependent LTP induced by a standard high frequency (200 Hz) conditioning stimulus and an additional LTP that required voltage‐dependent Ca²⁺ channel activation triggered by strong (400 Hz) conditioning stimulation. In contrast, acute inescapable footshock stress, used to study learned helplessness, inhibited LTP for at least 4 weeks. Contrary to expectations, there was no clear relationship between the ability of the footshock to trigger helpless behavior, a model of stress‐induced depression, and the magnitude of LTP inhibition. Moreover, LTP did not appear to be affected by genetic susceptibility to learned helplessness, a model of genetic vulnerability to depression. This long‐lasting synaptic plasticity disruption may underlie persistent impairment of hippocampus‐dependent cognition by excessive acute inescapable stress. © 2009 Wiley‐Liss, Inc.     

Dopamine receptor mechanisms mediate corticotropin‐releasing factor‐induced long‐term potentiation in the rat amygdala following cocaine withdrawal

Corticotropin‐releasing factor (CRF) in the amygdala is involved in stress responses. Moreover, dopaminergic neurotransmission in the brain reward system including the amygdala plays a significant role in the pathology of cocaine addiction. The present study analysed CRF‐induced synaptic plasticity, its pharmacological sensitivity and interactions with the dopamine (DA) system in the basolateral to lateral capsula central amygdala (lcCeA) pathway after a 2‐week withdrawal from repeated cocaine administration. A physiologically relevant CRF concentration (25 nm ) induced long‐term potentiation (LTP) that was enhanced after cocaine withdrawal. In saline‐treated rats, CRF‐induced LTP was mediated through N‐methyl‐d ‐aspartate (NMDA) receptors, L‐type voltage‐gated calcium channels (L‐VGCCs) and CRF₁ receptors. However, in cocaine‐withdrawn animals, activation of CRF₁ and CRF₂ receptors was found to enhance LTP. This enhanced CRF‐induced LTP after cocaine withdrawal was mediated through endogenous activation of both D1‐ and D2‐like receptors. Furthermore, expression of the D1 receptor (D1R) but not the D2R, D3R, D4R or D5R was significantly increased after cocaine withdrawal. CRF₁ but not CRF₂ protein expression was increased, suggesting that elevated levels of these proteins contributed to the enhancement of CRF‐induced LTP during cocaine withdrawal. CRF interactions with the DA system in the amygdala may represent a fundamental neurochemical and cellular mechanism linking stress to cocaine‐induced neuronal plasticity.     

Dynamics of nascent and active zone ultrastructure as synapses enlarge during long‐term potentiation in mature hippocampus

Nascent zones and active zones are adjacent synaptic regions that share a postsynaptic density, but nascent zones lack the presynaptic vesicles found at active zones. Here dendritic spine synapses were reconstructed through serial section electron microscopy (3DEM) and EM tomography to investigate nascent zone dynamics during long‐term potentiation (LTP) in mature rat hippocampus. LTP was induced with theta‐burst stimulation, and comparisons were made with control stimulation in the same hippocampal slices at 5 minutes, 30 minutes, and 2 hours post‐induction and to perfusion‐fixed hippocampus in vivo. Nascent zones were present at the edges of ～35% of synapses in perfusion‐fixed hippocampus and as many as ～50% of synapses in some hippocampal slice conditions. By 5 minutes, small dense‐core vesicles known to transport active zone proteins moved into more presynaptic boutons. By 30 minutes, nascent zone area decreased, without significant change in synapse area, suggesting that presynaptic vesicles were recruited to preexisting nascent zones. By 2 hours, both nascent and active zones were enlarged. Immunogold labeling revealed glutamate receptors in nascent zones; however, average distances from nascent zones to docked presynaptic vesicles ranged from 170 ± 5 nm in perfusion‐fixed hippocampus to 251 ± 4 nm at enlarged synapses by 2 hours during LTP. Prior stochastic modeling suggests that decrease in glutamate concentration reduces the probability of glutamate receptor activation from 0.4 at the center of release to 0.1 just 200 nm away. Thus, conversion of nascent zones to functional active zones likely requires the recruitment of presynaptic vesicles during LTP. J. Comp. Neurol. 522:3861–3884, 2014. © 2014 Wiley Periodicals, Inc.     

Pyridoxal‐5′‐phosphate phosphatase/chronophin inhibits long‐term potentiation induction in the rat dentate gyrus

Pyridoxal‐5′‐phosphate (PLP)‐phosphatase/chronophin (PLPP/CIN) directly dephosphorylates actin‐depolymerizing factor (ADF)/cofilin as well as PLP. Although PLPP/CIN plays a role in the regulation of F‐actin and vitamin B₆ metabolism, there is no direct evidence to support a correlation between PLPP/CIN and F‐actin polymerization during long‐term potentiation (LTP) induction. In this study, we investigated whether the expression of PLPP/CIN is altered following LTP induction, and whether Tat‐PLPP/CIN transduction affects LTP induction in the rat dentate gyrus (DG). PLPP/CIN immunoreactivity was markedly decreased in dentate granule cells after the induction of LTP. Tat‐PLPP/CIN transduction (20 and 200 μg/kg) decreased the efficiency of high frequency stimulus‐induced potentiation of populations spike amplitude as compared to saline or Tat‐protein‐treated animals. The PLPP/CIN protein level showed an inverse correlation with phosphorylated ADF/cofilin levels and F‐actin content. These findings suggest that PLPP/CIN‐mediated actin dynamics may play an important role in the changes of morphological properties (dendritic spine reorganization) of the hippocampus in LTP. © 2009 Wiley‐Liss, Inc.     

Synaptic recruitment during long-term potentiation at synapses of the medial perforant pathway in the dentate gyrus of the rat brain

Long-term potentiation (LTP) in synapses of the medial perforant pathway of the rat dentate gyrus has been studied using the whole-cell voltage clamp technique and a standard hippocampal slice preparation. The rate of LTP induction by 2–4 brief trains of stimuli at 100 Hz, paired with postsynaptic depolarization to −20 mV, in individual granule neurons was only 42% but the average magnitude was large. In a representative series of nine experiments the average potentiation was 339% (s.d. 255%). The variable magnitude of LTP appeared to be related to the relative size of the NMDA receptor dependent current in individual neurons. LTP was further characterized by the selective enhancement of the AMPA (but not the NMDA) component in the excitatory synaptic responses. This selective enhancement of the AMPA component and a graphical variance analysis suggest that the large magnitude of LTP in dentate gyrus can be best explained by recruitment of previously silent synapses by a combination of pre- and post-synaptic mechanisms. © 1996 Wiley-Liss, Inc.     

An interchangeable role for kainate and metabotropic glutamate receptors in the induction of rat hippocampal mossy fiber long‐term potentiation in vivo

The roles of both kainate receptors (KARs) and metabotropic glutamate receptors (mGluRs) in mossy fiber long‐term potentiation (MF‐LTP) have been extensively studied in hippocampal brain slices, but the findings are controversial. In this study, we have addressed the roles of both mGluRs and KARs in MF‐LTP in anesthetized rats. We found that MF‐LTP could be induced in the presence of either GluK1‐selective KAR antagonists or group I mGluR antagonists. However, LTP was inhibited when the group I mGluRs and the GluK1‐KARs were simultaneously inhibited. Either mGlu1 or mGlu5 receptor activation is sufficient to induce this form of LTP as selective inhibition of either subtype alone, together with the inhibition of KARs, did not inhibit MF‐LTP. These data suggest that mGlu1 receptors, mGlu5 receptors, and GluK1‐KARs are all engaged during high‐frequency stimulation, and that the activation of any one of these receptors alone is sufficient for the induction of MF‐LTP in vivo. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Hippocampal long‐term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta‐adrenoreceptors and the locus coeruleus

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Enhanced spatial memory and hippocampal long‐term potentiation in p75 neurotrophin receptor knockout mice

Previous reports have described increases in the size and number of cholinergic neurons in the basal forebrain in p75 neurotrophin receptor (p75^NTR) knockout mice. In an earlier study, we also found improved spatial memory in these mice, raising the possibility that p75^NTR regulates hippocampal function by its effects on the cholinergic basal forebrain. We therefore investigated hippocampal long‐term potentiation in p75^NTR knockout mice that shared the same genetic background as control 129/Sv mice. We also investigated heterozygous mice, carrying just one functional p75^NTR allele. The p75^NTR knockout mice had enhanced long‐term potentiation in the Schafer collateral fiber synapses of the hippocampus. Heterozygous mice had an intermediate level, greater than controls but less than knockout mice. Hippocampal choline acetyltransferase activity was also markedly elevated in p75^NTR knockout mice, with a smaller increase in heterozygous mice. In the Barnes maze, p75^NTR knockout mice displayed markedly superior learning to controls, and this was evident over the three age brackets tested. At each age, the performance of heterozygous mice was intermediate to the other groups. In the open field test, p75^NTR knockout mice exhibited greater stress‐related behavioral responses, including freezing, than did control animals. There were no differences between the three groups in a test of olfactory function. The dose‐dependent effects of p75^NTR gene copy number on hippocampal plasticity and spatial memory indicate that p75^NTR has profound effects on hippocampal function. Bearing in mind that p75^NTR is very sparsely expressed in the adult hippocampus and has a potent effect on hippocampal choline acetyltransferase activity, the effects of p75^NTR on hippocampal function are likely to be mediated indirectly, by its actions on basal forebrain cholinergic neurons. © 2009 Wiley‐Liss, Inc.     

Age‐related synaptic dysfunction in Tg2576 mice starts as a failure in early long‐term potentiation which develops into a full abolishment of late long‐term potentiation

Tg2576 mice are widely used to study amyloid‐dependent synaptic dysfunction related to Alzheimer's disease. However, conflicting data have been reported for these mice with regard to basal transmission as well as the in vitro correlate of memory, long‐term potentiation (LTP). Some studies show clear impairments, whereas others report no deficiency. The present study uses hippocampal slices from 3‐, 10‐, and 15‐month‐old wild‐type (WT) and Tg2576 mice to evaluate synaptic function in each group, including experiments to investigate basal synaptic transmission, short‐ and long‐term plasticity by inducing paired‐pulse facilitation, and both early and late LTP. We show that synaptic function remains intact in hippocampal slices from Tg2576 mice at 3 months of age. However, both early and late LTP decline progressively during aging in these mice. This deterioration of synaptic plasticity starts affecting early LTP, ultimately leading to the abolishment of both forms of LTP in 15‐month‐old animals. In comparison, WT littermates display normal synaptic parameters during aging. Additional pharmacological investigation into the involvement of NMDA receptors and L‐type voltage‐gated calcium channels in LTP suggests a distinct mechanism of induction among age groups, demonstrating that both early and late LTP are differentially affected by these channels in Tg2576 mice during aging. © 2015 Wiley Periodicals, Inc.     

Caffeine prevents sleep loss‐induced deficits in long‐term potentiation and related signaling molecules in the dentate gyrus

We have previously reported that caffeine prevented sleep deprivation‐induced impairment of long‐term potentiation (LTP) of area CA1 as well as hippocampus‐dependent learning and memory performance in the radial arm water maze. In this report we examined the impact of long‐term (4‐week) caffeine consumption (0.3 g/L in drinking water) on synaptic plasticity ( Alhaider et al., 2010 ) deficit in the dentate gyrus (DG) area of acutely sleep‐deprived rats. The sleep deprivation and caffeine/sleep deprivation groups were sleep‐deprived for 24 h by using the columns‐in‐water technique. We tested the effect of caffeine and/or sleep deprivation on LTP and measured the basal levels as well as stimulated levels of LTP‐related molecules in the DG. The results showed that chronic caffeine administration prevented the impairment of early‐phase LTP (E‐LTP) in the DG of sleep‐deprived rats. Additionally, chronic caffeine treatment prevented the sleep deprivation‐associated decreases in the basal levels of the phosphorylated calcium/calmodulin‐dependent protein kinase II (P‐CaMKII) and brain derived neurotrophic factor (BDNF) as well as in the stimulated levels of P‐CaMKII in the DG area. The results suggest that chronic use of caffeine prevented anomalous changes in the basal levels of P‐CaMKII and BDNF associated with sleep deprivation and as a result contributes to the revival of LTP in the DG region.     

Asymmetries in long‐term and short‐term plasticity at thalamic and cortical inputs to the amygdala in vivo

Converging lines of evidence suggest that synaptic plasticity at auditory inputs to the lateral amygdala (LA) is critical for the formation and storage of auditory fear memories. Auditory information reaches the LA from both thalamic and cortical areas, raising the question of whether they make distinct contributions to fear memory storage. Here we address this by comparing the induction of long‐term potentation (LTP) at the two inputs in vivo in anesthetized rats. We first show, using field potential measurements, that different patterns and frequencies of high‐frequency stimulation (HFS) consistently elicit stronger LTP at cortical inputs than at thalamic inputs. Field potential responses elicited during HFS of thalamic inputs were also smaller than responses during HFS of cortical inputs, suggesting less effective postsynaptic depolarization. Pronounced differences in the short‐term plasticity profiles of the two inputs were also observed: whereas cortical inputs displayed paired‐pulse facilitation, thalamic inputs displayed paired‐pulse depression. These differences in short‐ and long‐term plasticity were not due to stronger inhibition at thalamic inputs: although removal of inhibition enhanced responses to HFS, it did not enhance thalamic LTP and left paired‐pulse depression unaffected. These results highlight the divergent nature of short‐ and long‐term plasticity at thalamic and cortical sensory inputs to the LA, pointing to their different roles in the fear learning system.