Early Long-term Potentiation Research Articles

Diversity of neuropsin (KLK8)‐dependent synaptic associativity in the hippocampal pyramidal neuron

Hippocampal early (E-) long-term potentiation (LTP) and long-term depression (LTD) elicited by a weak stimulus normally fades within 90 min. Late (L-) LTP and LTD elicited by strong stimuli continue for >180 min and require new protein synthesis to persist. If a strong tetanus is applied once to synaptic inputs, even a weak tetanus applied to another synaptic input can evoke persistent LTP. A synaptic tag is hypothesized to enable the capture of newly synthesized synaptic molecules. This process, referred to as synaptic tagging, is found between not only the same processes (i.e. E- and L-LTP; E- and L-LTD) but also between different processes (i.e. E-LTP and L-LTD; E-LTD and L-LTP) induced at two independent synaptic inputs (cross-tagging). However, the mechanisms of synaptic tag setting remain unclear. In our previous study, we found that synaptic associativity in the hippocampal Schaffer collateral pathway depended on neuropsin (kallikrein-related peptidase 8 or KLK8), a plasticity-related extracellular protease. In the present study, we investigated how neuropsin participates in synaptic tagging and cross-tagging. We report that neuropsin is involved in synaptic tagging during LTP at basal and apical dendritic inputs. Moreover, neuropsin is involved in synaptic tagging and cross-tagging during LTP at apical dendritic inputs via integrin β1 and calcium/calmodulin-dependent protein kinase II signalling. Thus, neuropsin is a candidate molecule for the LTP-specific tag setting and regulates the transformation of E- to L-LTP during both synaptic tagging and cross-tagging.

Differential effect of the mGlu5 receptor positive allosteric modulator ADX-47273 on early and late hippocampal LTP

Conflicting findings are reported in the literature about the involvement of the mGlu5 receptor in hippocampal long-term potentiation (LTP), which might be a consequence of different sub-types of LTP induced by the investigators due to the specific experimental conditions used. A comparable controversy came up in the past concerning the influence of different experimental conditions on the involvement of L-type voltage dependent calcium channels (L-VDCCs) and NMDA receptors in hippocampal LTP. In this study, two stimulation protocols with otherwise identical conditions were used to probe modulatory effects of mGlu5 receptor activation in NMDA receptor and L-VDCCs dependent CA1 LTP: weak high frequency stimulation (20 stimuli at 100 Hz) to induce early LTP and repeated strong high frequency stimulation (3 times 100 stimuli at 100 Hz with 5 min interval) to induce late LTP, which - in contrast to early LTP - was shown to be protein-synthesis dependent. Using the NMDA receptor antagonist MK-801 and the L-type calcium channel blocker nifedipine, early LTP was shown to be dependent on NMDA receptors only, whereas late LTP was demonstrated to be dependent on NMDA receptors and L-VDCCs in about equal parts. Moreover, late LTP, but not early LTP, was increased by the mGlu5 receptor positive allosteric modulator ADX-47273, indicating that artificial augmentation of mGlu5 receptor activation by endogenous glutamate may boost the protein-synthesis dependent form of LTP but not the protein-synthesis independent form.

Nuclear Calcium Sensors Reveal that Repetition of Trains of Synaptic Stimuli Boosts Nuclear Calcium Signaling in CA1 Pyramidal Neurons

Nuclear calcium is a key signal in the dialogue between synapse and nucleus that controls the genomic responses required for persistent adaptations, including memory and acquired neuroprotection. The amplitude and duration of nuclear calcium transients specify activity-induced transcriptional changes. However, the precise relationship between synaptic input and nuclear calcium output is unknown. Here, we used stereotaxic delivery to the rat brain of recombinant adeno-associated viruses encoding nuclear-targeted calcium sensors to assess nuclear calcium transients in CA1 pyramidal neurons after stimulation of the Schaffer collaterals. We show that in acute hippocampal slices, a burst of synaptic activity elicits a nuclear calcium signal with a regenerative component at above-threshold stimulation intensities. Using classical stimulation paradigms (i.e., high-frequency stimulation (HFS) and θ burst stimulation (TBS)) to induce early LTP (E-LTP) and transcription-dependent late LTP (L-LTP), we found that the magnitude of nuclear calcium signals and the number of action potentials activated by synaptic stimulation trains are greatly amplified by their repetition. Nuclear calcium signals and action potential generation were reduced by blockade of either NMDA receptors or L-type voltage-gated calcium channels, but not by procedures that lead to internal calcium store depletion or by blockade of metabotropic glutamate receptors. These findings identify a repetition-induced switch in nuclear calcium signaling that correlates with the transition from E-LTP to L-LTP, and may explain why the transcription-dependent phase of L-LTP is not induced by a single HFS or TBS but requires repeated trains of activity. Recombinant, nuclear-targeted indicators may prove useful for further analysis of nuclear calcium signaling in vivo.

Calcium/calmodulin-dependent kinase IV contributes to translation-dependent early synaptic potentiation in the anterior cingulate cortex of adult mice

Calcium/calmodulin-dependent kinase IV (CaMKIV) phosphorylates the major transcription factor, cyclic AMP-responsive element binding protein (CREB), which plays key roles in synaptic plasticity and memory consolidation. Our previous study showed that long-term potentiation (LTP) in the anterior cingulate cortex (ACC) was significantly enhanced in transgenic mice overexpressing CaMKIV. Considering that the CaMKIV-CREB pathway plays a central role in the protein synthesis-dependent LTP, it is possible that upregulation of CaMKIV contributes to enhancement of LTP by promoting protein synthesis. To test this possibility, we examined the effects of transcription and translation inhibitors on synaptic potentiation induced by pairing of synaptic activity with postsynaptic depolarization (paired training) in ACC pyramidal neurons of wild-type and CaMKIV transgenic mice. We found that synaptic potentiation induced by paired training was partially inhibited by transcription or translation inhibitors both in wild-type and CaMKIV transgenic mice; the extent of inhibition was markedly larger in the CaMKIV transgenic mice than in the wild-type mice. Biochemical and immunohistochemical studies revealed that CaMKIV was distributed in the membrane, cytosol and nucleus of ACC neurons. Our results reveal in the first time a transcription- and translation-dependent component of early synaptic LTP in adult ACC synapses, and demonstrate that CaMKIV enhances early synaptic potentiation by activating new protein synthesis.

Myosin IIb Regulates Actin Dynamics during Synaptic Plasticity and Memory Formation

Reorganization of the actin cytoskeleton is essential for synaptic plasticity and memory formation. Presently, the mechanisms that trigger actin dynamics during these brain processes are poorly understood. In this study, we show that myosin II motor activity is downstream of LTP induction and is necessary for the emergence of specialized actin structures that stabilize an early phase of LTP. We also demonstrate that myosin II activity contributes importantly to an actin-dependent process that underlies memory consolidation. Pharmacological treatments that promote actin polymerization reversed the effects of a myosin II inhibitor on LTP and memory. We conclude that myosin II motors regulate plasticity by imparting mechanical forces onto the spine actin cytoskeleton in response to synaptic stimulation. These cytoskeletal forces trigger the emergence of actin structures that stabilize synaptic plasticity. Our studies provide a mechanical framework for understanding cytoskeletal dynamics associated with synaptic plasticity and memory formation.

Chronic caffeine treatment prevents sleep deprivation-induced impairment of cognitive function and synaptic plasticity.

This study was undertaken to provide a detailed account of the effect of chronic treatment with a small dose of caffeine on the deleterious effects of sleep loss on brain function in rats. We investigated the effects of chronic (4 weeks) caffeine treatment (0.3 g/L in drinking water) on memory impairment in acutely (24 h) sleep-deprived adult male Wistar rats. Sleep deprivation was induced using the modified multiple platform model. The effects of caffeine on sleep deprivation-induced hippocampus-dependent learning and memory deficits were studied by 3 approaches: learning and memory performance in the radial arm water maze task, electrophysiological recording of early long-term potentiation (E-LTP) in area CA1 of the hippocampus, and levels of memory- and synaptic plasticity-related signaling molecules after E-LTP induction. The results showed that chronic caffeine treatment prevented impairment of hippocampus-dependent learning, shortterm memory and E-LTP of area CA1 in the sleep-deprived rats. In correlation, chronic caffeine treatment prevented sleep deprivation-associated decrease in the levels of phosphorylated calcium/calmodulin-dependent protein kinase II (P-CaMKII) during expression of E-LTP. The results suggest that long-term use of a low dose of caffeine prevents impairment of short-term memory and E-LTP in acutely sleep-deprived rats.

A Novel Role for Protein Synthesis in Long-Term Neuronal Plasticity: Maintaining Reduced Postburst Afterhyperpolarization

Memory consolidation, the process of transformation of short-term to long-term memory, has been shown to be protein synthesis dependent in a variety of different learning paradigms, brain structures, and species. At the cellular level, protein synthesis was shown to be crucial for induction of long-term synaptic plasticity; application of protein synthesis inhibitors prevents the transformation of early long-term potentiation (LTP) to late LTP. Thus, protein synthesis has been traditionally thought to affect long-term memory consolidation by stabilizing synaptic transmission. However, long-term memory is not supported only by modulation of synaptic strength; modifications in intrinsic neuronal properties also subserve learning-related behavioral changes. Learning-induced reduction in the postburst afterhyperpolarization (AHP), which results with enhanced neuronal excitability and decreased spike frequency adaptation, is apparent in hippocampal and cortical pyramidal neurons. Such postburst AHP reduction lasts for days after training completion and is implicated in maintaining learned skills. Short-term modulation of intrinsic neuronal excitability can be also induced in vitro. Intense synaptic activation induces AHP reduction and enhanced neuronal excitability in hippocampal pyramidal neurons. Here, we show that synaptic activation-induced short-term postburst AHP reduction can be transformed to long-term AHP reduction, such that persists for prolonged time periods. This long-lasting AHP reduction is protein synthesis dependent for up to 1 h after induction. We suggest that, much like synaptic plasticity, activity-induced long-lasting modulation of intrinsic neuronal excitability requires molecular consolidation. It would appear that both synaptic and intrinsic modifications and maintenance are activated jointly to enable long-lasting memories.

Activin plays a key role in the maintenance of long-term memory and late-LTP

A recent study has revealed that fear memory may be vulnerable following retrieval, and is then reconsolidated in a protein synthesis-dependent manner. However, little is known about the molecular mechanisms of these processes. Activin betaA, a member of the TGF-beta superfamily, is increased in activated neuronal circuits and regulates dendritic spine morphology. To clarify the role of activin in the synaptic plasticity of the adult brain, we examined the effect of inhibiting or enhancing activin function on hippocampal long-term potentiation (LTP). We found that follistatin, a specific inhibitor of activin, blocked the maintenance of late LTP (L-LTP) in the hippocampus. In contrast, administration of activin facilitated the maintenance of early LTP (E-LTP). We generated forebrain-specific activin- or follistatin-transgenic mice in which transgene expression is under the control of the Tet-OFF system. Maintenance of hippocampal L-LTP was blocked in the follistatin-transgenic mice. In the contextual fear-conditioning test, we found that follistatin blocked the formation of long-term memory (LTM) without affecting short-term memory (STM). Furthermore, consolidated memory was selectively weakened by the expression of follistatin during retrieval, but not during the maintenance phase. On the other hand, the maintenance of memory was also influenced by activin overexpression during the retrieval phase. Thus, the level of activin in the brain during the retrieval phase plays a key role in the maintenance of long-term memory.

A Role for RhoB in Synaptic Plasticity and the Regulation of Neuronal Morphology

Actin-rich dendritic spines are the locus of excitatory synaptic transmission and plastic events such as long-term potentiation (LTP). Morphological plasticity of spines accompanies activity-dependent changes in synaptic strength. Several Rho GTPase family members are implicated in regulating neuronal and, in particular, spine structure via actin and the actin-binding protein cofilin. However, despite expression in hippocampus and cortex, its ability to modulate actin-regulatory proteins, and its induction during aging, RhoB has been relatively neglected. We previously demonstrated that LTP is associated with specific RhoB activation. Here, we further examined its role in synaptic function using mice with genetic deletion of the RhoB GTPase (RhoB(-/-) mice). Normal basal synaptic transmission accompanied reduced paired-pulse facilitation and post-tetanic potentiation in the hippocampus of RhoB(-/-) mice. Early phase LTP was significantly reduced in RhoB(-/-) animals, whereas the later phase was unaffected. In wild-type mice (RhoB(+/+)), Western blot analysis of potentiated hippocampus showed significant increases in phosphorylated cofilin relative to nonpotentiated slices, which were dramatically impaired in RhoB(-/-) slices. There was also a deficit in phosphorylated Lim kinase levels in the hippocampus from RhoB(-/-) mice. Morphological analysis suggested that lack of RhoB resulted in increased dendritic branching and decreased spine number. Furthermore, an increase in the proportion of stubby relative to thin spines was observed. Moreover, spines demonstrated increased length along with increased head and neck widths. These data implicate RhoB in cofilin regulation and dendritic and spine morphology, highlighting its importance in synaptic plasticity at a structural and functional level.

Late phase of L-LTP elicited in isolated CA1 dendrites cannot be transferred by synaptic capture

In the CA1 region of mouse hippocampal slices, a strong tetanic stimulation triggers a long-lasting long-term potentiation (L-LTP), which requires transcription for the development of its late phase. Nevertheless, we were able to elicit such an L-LTP in CA1 dendrites separated from their somas provided that we restricted our investigations to isolated dendrites where a very robust early LTP was triggered. This particular type of L-LTP, which relied on translation of preexisting messenger RNAs - as it was blocked by anisomycin - could not be captured by another pathway activated only by a weak tetanic stimulation. This suggests that the plasticity-related proteins resulting from translation of messenger RNAs in dendrites cannot pass from the synaptic site where they were synthesized to another one.

Behavioral deficits and subregion-specific suppression of LTP in mice expressing a population of mutant NMDA receptors throughout the hippocampus

The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1(N598R) allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs. Surprisingly, these animals revealed specific functional changes in the dentate gyrus (DG) of the hippocampal formation. Early LTP was expressed normally in area CA1 in vivo, but was completely suppressed at perforant path-granule cell synapses in the DG. In addition, there was a pronounced reduction in the amplitude of the evoked population spike in the DG. These specific changes were accompanied by behavioral impairments in spatial recognition, spatial learning, reversal learning, and retention. Our data show that minor changes in GluN1-dependent NMDAR physiology can cause dramatic consequences in synaptic signaling in a subregion-specific fashion despite the nonredundant nature of the GluN1 gene and its global expression.

Phosphorylation Changes of CaMKII, ERK1/2, PKB/Akt Kinases and CREB Activation During Early Long-Term Potentiation at Schaffer Collateral-CA1 Mouse Hippocampal Synapses

Protein phosphorylation is the main signaling system known to trigger synaptic changes underlying long-term potentiation (LTP). The timing of these phosphorylations plays an essential role to maintain the potentiated state of synapses. However, in mice a simultaneous analysis of phosphorylated proteins during early-LTP (E-LTP) has not been thoroughly carried out. Here we described phosphorylation changes of alphaCaMKII, ERK1/2, PKB/Akt and CREB at different times after E-LTP induced at Schaffer collateral/commissural fiber-CA1 synapses by 1 s 100 Hz tetanic stimulation in mouse hippocampal slices. We found that phosphorylation levels of all the molecules examined rapidly increased after tetanisation and remained above the basal level up to 30 min. Notably, we observed a sustained increment in the phosphorylation level of Akt at Ser473, whereas the phosphorylation level of Akt at Thr308 was unchanged. Unexpectedly, we also detected a marked increase of CREB target genes expression levels, c-fos, Egr-1 and exon-III containing BDNF transcripts. Our findings, besides providing a detailed timing of phosphorylation of the major kinases involved in E-LTP in mice, revealed that a modest LTP induction paradigm specifically triggers CREB-mediated gene expression.

LIM-Kinase1 and CREB regulation of synaptic plasticity and memory

Event Abstract Back to Event LIM-Kinase1 and CREB regulation of synaptic plasticity and memory Zarko Todorovski1, 2* and Zhengping Jia1, 2 1 University of Toronto, Department of Physiology, Canada 2 The Hospital for Sick Children, Neurosciences and Mental Health, Canada Regulation of neuronal structural plasticity is known to be important for learning and memory. LIM-Kinase 1 (LIMK1) is an important regulator of postsynaptic structural morphology by its regulation of actin dynamics by regulating the activity of actin depolymerizing factor (ADF)/cofilin. Previous studies from our lab have shown that LIMK1 knockout mice exhibit abnormal dendritic spine morphology as well as altered hippocampal early long-term potentiation (E-LTP). In addition, a recent study has found that LIMK1 can directly interact with and phosphorylate CREB in hippocampal neuroprogenitor cells. CREB is an important and well-studied transcription factor that facilitates the changes from short-term memory to long-term memory. CREB activation is also known to be important in late long-term potentiation (L-LTP). Based on this evidence we proposed that LIMK1 might play a role in long-term memory and long-term synaptic plasticity via regulation of CREB in mature hippocampal neurons. Accordingly, we have shown that LIMK1 exists in an immunocomplex with CREB in mature hippocampal slices. Moreover, mice lacking LIMK1 were shown to be deficient in L-LTP induced by high frequency stimulation, and L-LTP induced by strong theta burst stimulation. This evidence suggests a role for LIMK1 in L-LTP and long-term synaptic plasticity via regulation of CREB. In addition, mice lacking LIMK1 did not perform as well in fear conditioning tests. LIMK1 knockout mice exhibited less freezing than wild-type littermate controls in the contextual memory test. These results suggest that LIMK1 plays a role in long-term memory. Taken together, these results are indicative of a role for LIMK1 in a long-term memory and long-term synaptic plasticity via regulation of CREB. Conference: B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Todorovski Z and Jia Z (2009). LIM-Kinase1 and CREB regulation of synaptic plasticity and memory. Front. Neurosci. Conference Abstract: B.R.A.I.N. platform in Physiology poster day 2009. doi: 10.3389/conf.neuro.03.2009.17.046 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Dec 2009; Published Online: 18 Dec 2009. * Correspondence: Zarko Todorovski, University of Toronto, Department of Physiology, Toronto, Canada, zarko.todorovski@utoronto.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Zarko Todorovski Zhengping Jia Google Zarko Todorovski Zhengping Jia Google Scholar Zarko Todorovski Zhengping Jia PubMed Zarko Todorovski Zhengping Jia Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Lack of DREAM Protein Enhances Learning and Memory and Slows Brain Aging

Memory deficits in aging affect millions of people and are often disturbing to those concerned. Dissection of the molecular control of learning and memory is paramount to understand and possibly enhance cognitive functions. Old-age memory loss also has been recently linked to altered Ca(2+) homeostasis. We have previously identified DREAM (downstream regulatory element antagonistic modulator), a member of the neuronal Ca(2+) sensor superfamily of EF-hand proteins, with specific roles in different cell compartments. In the nucleus, DREAM is a Ca(2+)-dependent transcriptional repressor, binding to specific DNA signatures, or interacting with nucleoproteins regulating their transcriptional properties. Also, we and others have shown that dream mutant (dream(-/-)) mice exhibit marked analgesia. Here we report that dream(-/-) mice exhibit markedly enhanced learning and synaptic plasticity related to improved cognition. Mechanistically, DREAM functions as a negative regulator of the key memory factor CREB in a Ca(2+)-dependent manner, and loss of DREAM facilitates CREB-dependent transcription during learning. Intriguingly, 18-month-old dream(-/-) mice display learning and memory capacities similar to young mice. Moreover, loss of DREAM protects from brain degeneration in aging. These data identify the Ca(2+)-regulated "pain gene" DREAM as a novel key regulator of memory and brain aging.

Enhanced long‐term potentiation and impaired learning in phosphodiesterase 4D‐knockout (PDE4D−/−) mice

Elevation of intracellular cyclic adenosine monophosphate (cAMP) concentrations and subsequent regulation of downstream target gene expression through phosphorylation of cAMP-responsive element binding protein (CREB) is hypothesized to underlie the mechanism(s) of long-term memory (LTM) formation. The phosphodiesterase 4 (PDE4) enzyme family is believed to play a key role in LTM by regulating cAMP levels. Thus far, four PDE4 isoforms have been identified (PDE4A, B, C and D); however, the requisite involvement of each of these isoforms in mediating LTM has yet to be elucidated. In the present study, genetic knockout mice were used to investigate the involvement of the PDE4D isoform in both in vitro and in vivo models of learning and memory. Hippocampal synaptic transmission measured electrophysiologically in CA1 slice preparations was similar between wild-type and PDE4D (-/-) mice yet, relative to wild-type controls, knockout mice displayed enhanced early long-term potentiation (LTP) following multiple induction protocols. Interestingly, the PDE4D (-/-) animals exhibited significant behavioral deficits in associative learning using a conditioned fear paradigm as compared with control littermates. The impairment in fear conditioning observed in the PDE4D (-/-) mice could not be attributed to differences in acquisition of the task, alterations in locomotor activity or effects on shock sensitivity. Overall, the in vitro and in vivo alterations in synaptic plasticity observed in the PDE4D (-/-) mice may be explained by adaptive responses occurring throughout development, and suggest that the PDE4D isoform may be an important mediator of LTM formation.

The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents

The present study investigated the putative pro-cognitive effects of the novel selective PDE9 inhibitor BAY 73-6691. The effects on basal synaptic transmission and long-term potentiation (LTP) were investigated in rat hippocampal slices. Pro-cognitive effects were assessed in a series of learning and memory tasks using rodents as subjects. BAY 73-6691 had no effect on basal synaptic transmission in hippocampal slices prepared from young adult (7- to 8-week-old) Wistar rats. A dose of 10 μM, but not 30 μM, BAY 73-6691 enhanced early LTP after weak tetanic stimulation. The dose effective in young adult Wistar rats did not affect LTP in hippocampal slices prepared from young (7- to 8-week-old) Fischer 344 X Brown Norway (FBNF1) rats, probably reflecting strain differences. However, it increased basal synaptic transmission and enhanced early LTP after weak tetanic stimulation in hippocampal slices prepared from very old (31- to 35-month-old) FBNF1 rats. BAY 73-6691 enhanced acquisition, consolidation, and retention of long-term memory (LTM) in a social recognition task and tended to enhance LTM in an object recognition task. Bay 73-6691 attenuated the scoplamine-induced retention deficit in a passive avoidance task, and the MK-801-induced short-term memory deficits in a T-maze alternation task. The mechanism of action, possibly through modulation of the NO/cGMP-PKG/CREB pathway, is discussed. Our findings support the notion that PDE9 inhibition may be a novel target for treating memory deficits that are associated with aging and neurodegenerative disorders such as Alzheimer's disease.

Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome

Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O'Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR (alpha-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams.

Muscarinic acetylcholine neurotransmission enhances the late-phase of long-term potentiation in the hippocampal–prefrontal cortex pathway of rats in vivo: A possible involvement of monoaminergic systems

The prefrontal cortex is continuously required for working memory processing during wakefulness, but is particularly hypoactivated during sleep and in psychiatric disorders such as schizophrenia. Ammon's horn CA1 hippocampus subfield (CA1) afferents provide a functional modulatory path that is subjected to synaptic plasticity and a prominent monoaminergic influence. However, little is known about the muscarinic cholinergic effects on prefrontal synapses. Here, we investigated the effects of the muscarinic agonist, pilocarpine (PILO), on the induction and maintenance of CA1-medial prefrontal cortex (mPFC) long-term potentiation (LTP) as well as on brain monoamine levels. Field evoked responses were recorded in urethane-anesthetized rats during baseline (50 min) and after LTP (130 min), and compared with controls. LTP was induced 20 min after PILO administration (15 mg/kg, i.p.) or vehicle (NaCl 0.15 M, i.p.). In a separate group of animals, the hippocampus and mPFC were microdissected 20 min after PILO injection and used to quantify monoamine levels. Our results show that PILO potentiates the late-phase of mPFC LTP without affecting either post-tetanic potentiation or early LTP (20 min). This effect was correlated with a significant decrease in relative delta (1–4 Hz) power and an increase in sigma (10–15 Hz) and gamma (25–40 Hz) powers in CA1. Monoamine levels were specifically altered in the mPFC. We observed a decrease in dopamine, 5-HT, 5-hydroxyindolacetic acid and noradrenaline levels, with no changes in 3,4-hydroxyphenylacetic acid levels. Our data, therefore, suggest that muscarinic activation exerts a boosting effect on mPFC synaptic plasticity and possibly on mPFC-dependent memories, associated to monoaminergic changes.

Neuropsin (KLK8)-Dependent and -Independent Synaptic Tagging in the Schaffer-Collateral Pathway of Mouse Hippocampus

Hippocampal early long-term potentiation (LTP) elicited by a weak (one or two) tetanic stimulus normally fades away within 90 min. Late LTP elicited by strong (four) stimuli lasts >180 min and requires new protein synthesis to persist. If a strong tetanus is injected once into a synapse, even a weak tetanus injected into another synapse can evoke persistent LTP. It was hypothesized that a synaptic tag enables capture of newly synthesized synaptic molecules. Here, we found two synaptic capture mechanisms for a weakly stimulated synapse to acquire persistency (i.e., neuropsin dependent and independent). The single tetanus evokes a neuropsin-dependent form that follows downstream signaling into integrin/actin signal and L-type voltage-dependent Ca2+ channel (LVDCC) pathway. Additionally, a neuropsin-independent form of synaptic capture is evoked by a stronger (two) tetanus than the former. Both forms converging on LVDCC might serve different associative memories depending on their input strength. Our study strongly supports the hypothesis of synaptic tagging and demonstrates that neuropsin-dependent late associativity is particularly important in nonstressful associative memory.

Epinephrine converts long‐term potentiation from transient to durable form in awake rats

Neuroendocrine responses to an emotional or arousing experience modulate memory for the event. Extensive evidence suggests that epinephrine plays an important role in the regulation of memory formation by emotions and arousal. Some forms of synaptic plasticity are similarly responsive to modulation by stress and arousal. The present experiment examined the effects of epinephrine on induction and maintenance of long-term potentiation (LTP) in awake rats. Rats were prepared with bilaterally implanted electrodes for recording evoked field potentials in dentate granule cells following perforant pathway stimulation. LTP was induced with high-frequency stimulation parameters that resulted in modest early potentiation of the EPSP that decayed within 20 min. Epinephrine enhanced the magnitude of early LTP induction and also extended the durability of LTP from minutes to at least several days. Epinephrine did not alter baseline responses or modulate pre-LTP input-output curves. The enhancement of LTP by epinephrine was dose-dependent, following an inverted-U dose-response curve similar to that seen in memory enhancement experiments, suggesting considerable convergence of epinephrine modulation of memory and LTP. In extending substantially the maintenance of LTP after induction, the present finding offer potential means to study the neurobiology of rapid forgetting seen in aged rodents and other animals and the neurobiology of the impaired forgetting seen in post-traumatic stress disorder.