Hippocampal network connections account for differences in memory performance in the middle‐aged rhesus monkey

Recent neurophysiological and functional neuroimaging studies suggest that the memory decline found with normal aging is not solely due to regional disruptions in the hippocampus, but also is brought about by alterations in the functional coupling between the hippocampus and long‐distance neocortical regions. However, the anatomical basis for this functional “dyscoupling” has not been fully revealed. In this study, we applied a multimodal magnetic resonance imaging technique to noninvasively examine the large‐scale anatomical and functional hippocampal network of a group of middle aged rhesus monkeys. Using diffusion spectrum imaging, we have found that monkeys with lower memory performance had weaker structural white matter connections between the hippocampus and neocortical association areas. Resting state functional imaging revealed somewhat of an opposite result. Monkeys with low memory performance displayed elevated coupling strengths in the network between the hippocampus and the neocortical areas. Taken together with recent findings, this contradictory pattern may be the result of either underlying physiological burden or abnormal neuronal decoupling due to the structural alterations, which induce a neuronal compensation mechanism for the structural loss or interference on task related neuronal activation, respectively. © 2013 Wiley Periodicals, Inc.     

Spatial olfactory learning facilitates long‐term depression in the hippocampus

Recently, it has emerged that visual spatial exploration facilitates synaptic plasticity at different synapses within the trisynaptic network. Particularly striking is the finding that visuospatial contexts facilitate hippocampal long‐term depression (LTD), raising the possibility that this form of plasticity may be important for memory formation. It is not known whether other sensory modalities elicit similar permissive effects on LTD. Here, we explored if spatial olfactory learning facilitates LTD in the hippocampus region of freely behaving rats. Patterned afferent stimulation of the Schaffer collaterals elicited short‐term depression (STD) (<1 h) of evoked responses in the Stratum radiatum of the CA1 region. Coupling of this protocol with novel exploration of a spatial constellation of olfactory cues facilitated short‐term depression into LTD that lasted for over 24 h. Facilitation of LTD did not occur when animals were re‐exposed 1 week later to the same odors in the same spatial constellation. Evaluation of learning behavior revealed that 1 week after the 1st odor exposure, the animals remembered the odors and their relative positions. These data support that the hippocampus can use nonvisuospatial resources, and specifically can use spatial olfactory information, to facilitate LTD and to generate spatial representations. The data also support that a tight relationship exists between the processing of spatial contextual information and the expression of LTD in the hippocampus. © 2013 Wiley Periodicals, Inc.     

The history of long‐term potentiation as a memory mechanism: Controversies,confirmation, and some lessons to remember

The discovery of long‐term potentiation (LTP) provided the first, direct evidence for long‐lasting synaptic plasticity in the living brain. Consequently, LTP was proposed to serve as a mechanism for information storage among neurons, thus providing the basis for the behavioral and psychological phenomena of learning and long‐term memory formation. However, for several decades, the LTP‐memory hypothesis remained highly controversial, with inconsistent and contradictory evidence providing a barrier to its general acceptance. This review summarizes the history of these early debates, challenges, and experimental strategies (successful and unsuccessful) to establish a link between LTP and memory. Together, the empirical evidence, gathered over a period of about four decades, strongly suggests that LTP serves as one of the mechanisms affording learning and memory storage in neuronal circuits. Notably, this body of work also offers some important lessons that apply to the broader fields of behavioral and cognitive neuroscience. As such, the history of LTP as a learning mechanism provides valuable insights to neuroscientists exploring the relations between brain and psychological states.     

Prenatal ethanol exposure has sex‐specific effects on hippocampal long‐term potentiation

Alcohol consumption during pregnancy is deleterious to the developing brain of the fetus and leads to persistent deficits in adulthood. Long‐term potentiation (LTP) is a biological model for learning and memory processes and previous evidence has shown that prenatal ethanol exposure (PNEE) affects LTP in a sex specific manner during adolescence. The objective of this study was to determine if there are sex specific differences in adult animals and to elucidate the underlying molecular mechanisms that contribute to these differences. Pregnant Sprague–Dawley dams were assigned to either; liquid ethanol, pair‐fed or standard chow diet. In vivo electrophysiology was performed in the hippocampal dentate gyrus (DG) of adult offspring. LTP was induced by administering 400 Hz stimuli. Western blot analysis for glutamine synthetase (GS) and glutamate decarboxylase from tissue of the DG indicated that GS expression was increased following PNEE. Surprisingly, adult females did not show any deficit in N‐methyl‐d ‐aspartate (NMDA)‐dependent LTP after PNEE. In contrast, males showed a 40% reduction in LTP. It was indicated that glutamine synthetase expression was increased in PNEE females, suggesting that altered excitatory neurotransmitter replenishment may serve as a compensatory mechanism. Ovariectomizing females did not influence LTP in control or PNEE animals, suggesting that circulating estradiol levels do not play a major role in maintaining LTP levels in PNEE females. These results demonstrate the sexually dimorphic effects of PNEE on the ability for the adult brain to elicit LTP in the DG. The mechanisms for these effects are not fully understood, but an increase in glutamine synthetase in females may underlie this phenomenon. © 2013 Wiley Periodicals, Inc.     

Long-term depression and long-term potentiation in horizontal connections of the barrel cortex

Synaptic plasticity of horizontally orientated connections between barrels, in the barrel cortex of adult mice, was studied in slice preparations cut across rows of barrels. Field potentials were evoked in the middle of one barrel column (in layer IV or V) and recorded in the neighbouring barrel (in layer IV and V). In layer IV, long-term depression (LTD) by 26.5 +/- 5% was first induced by a low-frequency stimulation (2 Hz) applied for 10 min. After 30 min, theta-burst stimulation was delivered to previously depressed connections, resulting in long-term potentiation (LTP) by 28.8 +/- 11.8%. When theta-burst stimulation was delivered without an earlier low-frequency stimulation, no LTP was induced. Similar results were obtained in layer V connections (LTD: 40.6 +/- 12.5%; LTP: 26.9 +/- 12.5%). In layer IV, the application of 100 micro m d,l-2-amino-5-phosphonovaleric acid (APV), an antagonist of NMDA receptors, blocked the induction of both LTD and LTP. These experiments show that a potential for synaptic plasticity is retained in granular and infragranular layers of adult mice.     

The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF^+/?). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF^+/? mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF^+/? mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Diverse impact of neuronal activity at θ frequency on hippocampal long‐term plasticity

Brain oscillatory activity is considered an essential aspect of brain function, and its frequency can vary from <1 Hz to >200 Hz, depending on the brain states and projection. Episodes of rhythmic activity accompany hippocampus‐dependent learning and memory in vivo. Therefore, long‐term synaptic potentiation (LTP) and long‐term depression, which are considered viable substrates of learning and memory, are often experimentally studied in paradigms of patterned high‐frequency (>50 Hz) and low‐frequency (<5 Hz) stimulation. However, the impact of intermediate frequencies on neuronal plasticity remains less well understood. In particular, hippocampal neurons are specifically tuned for activity at θ frequency (4–8 Hz); this band contributes significantly to electroencephalographic signals, and it is likely to be involved in shaping synaptic strength in hippocampal circuits. Here, we review in vitro and in vivo studies showing that variation of θ‐activity duration may affect long‐term modification of synaptic strength and neuronal excitability in the hippocampus. Such θ‐pulse‐induced neuronal plasticity 1) is long‐lasting, 2) may be built on previously stabilized potentiation in the synapse, 3) may produce opposite changes in synaptic strength, and 4) requires complex molecular machinery. Apparently innocuous episodes of low‐frequency synaptic activity may have a profound impact on network signaling, thereby contributing to information processing in the hippocampus and beyond. In addition, θ‐pulse‐induced LTP might be an advantageous protocol in studies of specific molecular mechanisms of synaptic plasticity. © 2015 Wiley Periodicals, Inc.     

Hippocampal long‐term depression in freely behaving mice requires the activation of beta‐adrenergic receptors

In the intact mouse hippocampus patterned afferent stimulation does not lead to long‐term depression (LTD) at Schaffer collateral (Sc)‐CA1 synapses, but the same synapses express robust LTD (<24 h) if test‐pulse or patterned afferent experience is coupled with novel spatial learning. This suggests that the failure of sole afferent stimulation to elicit LTD relates to the absence of neuromodulatory input related to increased arousal or novelty during learning. Locus coeruleus (LC) firing increases during novel experience, and in rats patterned stimulation of the LC together with test‐pulse stimulation of Sc‐CA1 synapses leads to robust LTD in vivo. This effect is mediated by beta‐adrenergic receptors. Here, we explored if activation of beta‐adrenergic receptors supports the expression of LTD in freely behaving mice. We also explored if beta‐adrenergic receptors contribute to endogenous LTD that is expressed following spatial learning. Patterned stimulation of Sc‐CA1 synapses at 3 Hz (200 pulses) resulted in short‐term depression (STD). Pretreatment with isoproterenol, an agonist of beta‐adrenergic receptors, resulted in robust LTD (<24 h). Test‐pulse stimulation under control conditions elicited field potentials that were stable for the 24‐h monitoring period. Coupling of test‐pulses with a novel spatial object recognition task resulted in robust endogenous LTD (<24 h). Pretreatment with propranolol, a beta‐adrenergic receptor antagonist, completely prevented endogenous LTD that was enabled by learning and prevented object recognition learning itself. These data indicate that the absence of LTD in freely behaving mice, under standard recording conditions, does not reflect an inability of mice to express LTD, rather it is due to the absence of a noradrenalin tonus. Our data also support that spatial object recognition requires beta‐adrenergic receptor activation. Furthermore, LTD that is enabled by novel spatial learning critically depends on activation of beta‐adrenergic receptors that are presumably activated by noradrenalin released by the LC in response to the novel experience. © 2013 Wiley Periodicals, Inc.     

Unique regulation of long term potentiation in the rat ventral hippocampus

Morphological and electrophysiological evidence has been accumulated in recent years to indicate that a functional gradient exists along the septo-temporal axis of the hippocampus such that spatial memory is associated primarily with the dorsal (septal) sector while the functions of the ventral sector are not yet clearly defined. Also, the ventral hippocampus (VH) is reported to express a much smaller long term potentiation of responses to afferent stimulation than the dorsal sector. In the present study, we first confirmed that CA1 region of VH slices expresses significantly smaller LTP than the dorsal hippocampus. Strikingly, much larger LTP was obtained in VH slices following low frequency priming stimulation applied prior to the tetanic stimulation. DHPG ((S)-3,5-Dihydroxyphenylglycine hydrate) a metabotropic glutamate receptor agonist, produced a similar potentiating effect on LTP as that produced by the priming stimulation. In both cases, the spectral analysis of spontaneous electrical activity recorded from the same location in the slice revealed an increase in peak amplitude around 30 Hz. MCPG, a metabotropic glutamate receptor antagonist, and both thapsigargin and cyclopiazonic acid, inhibitors of Ca(2+) release from stores, blocked the potentiating action of both DHPG and the priming stimulation. These results indicate that the ventral hippocampus possesses different network properties compared to the dorsal hippocampus and that its ability to undergo plastic changes is controlled by a metabotropic glutamate receptor.     

Long-term potentiation and long-term depression induced by local application of ATP to hippocampal CA1 neurons of the guinea pig

The present study has investigated the role of ATP in the induction of synaptic plasticity, using local application of ATP by picopump administration into the stratum radiatum of guinea pig hippocampal region CA1. Excitatory postsynaptic currents (EPSCs) evoked by stimulation of Schaffer collateral/commissural afferents synapsing on CA1 pyramidal cells of hippocampal slices were monitored in voltage-clamp mode, using whole-cell recording. Brief local application of ATP (1 mM) induced an inward current, usually consisting of early- and late-phase components. Because the late-phase component of an ATP-induced current was largely inhibited by Ca2+-free solution, this component is supposed to depend on extracellular Ca2+. After local application of ATP, long-term synaptic modification of EPSCs was induced: LTP was detected in neurons exhibiting a small late Ca2+ current, while LTD was obtained from recordings showing a large late Ca2+ current in response to ATP application. There was a statistically significant correlation between the magnitude of long-term plastic changes and the size of Ca2+ currents in response to ATP application. Furthermore, there was significant difference between the average size of the Ca2+ current in the LTP group and the size in the LTD group. These results suggest that a small Ca2+ influx in response to ATP application induces LTP, whereas a large one induces LTD in guinea pig hippocampal CA1 neurons.     

The effect of chronic thienorphine administration on long‐term potentiation and synaptic structure in rat hippocampus

Thienorphine is a new nonselective partial agonist of opioid receptors, which is currently under a Phase II clinical trial in China as a new treatment for opioid dependence. In this study, we compared the effect of thienorphine with morphine on long‐term potentiation (LTP) in the lateral perforant path (LPP)‐granule cell synapse of the rat dentate gyrus (DG). Furthermore, the effect of thienorphine on the synaptic structure of the CA1 hippocampal region and the expression of synaptophysin was investigated. Results indicated interesting differences between thienorphine and morphine on the modulation of hippocampal synaptic plasticity. Chronic thienorphine treatment facilitated LTP in the LPP‐DG cell synapses more than chronic morphine treatment. Morphometric measurement and analysis showed that chronic thienorphine administration decreased the length of the active zone and reduced the thickness of CA1 postsynaptic densities compared with the saline group (control), but were elevated compared with the morphine group. Furthermore, the expression of hippocampal synaptophysin was increased with chronic thienorphine administration but reduced with chronic morphine treatment. Taken together, our study clearly demonstrates that chronic thienorphine treatment enhances LTP, modulates hippocampal synaptic structure, and increases the expression of hippocampal synaptophysin. Therefore, further study is warranted to investigate thienorphine as a new treatment for opioid dependence. Synapse 67:779–785, 2013 . © 2013 Wiley Periodicals, Inc.     

NMDAR‐independent hippocampal long‐term depression impairment after status epilepticus in a lithium‐pilocarpine model of temporal lobe epilepsy

Temporal lobe epilepsy is usually associated with cognitive decline and memory deficits. Despite numerous existing studies on various animal models, the mechanisms of these deficits remain largely unclear. A specific form of long‐term synaptic efficacy changes—long‐term depression (LTD)—is thought to play an important role in memory formation and learning. However, extremely little is known about the possible alteration of LTD induction and dynamics after a status epilepticus (SE). In this work, we investigated the acute and delayed effects of lithium‐pilocarpine‐induced SE on NMDAR‐dependent and NMDAR‐independent hippocampal LTD in vitro. We found that SE affected the NMDAR‐dependent and NMDAR‐independent forms of LTD in different manners. The NMDAR‐dependent form of LTD was almost intact 3 days after SE, but it switched from a predominantly presynaptic to a more postsynaptic locus of expression. In contrast, the NMDAR‐independent LTD in the hippocampal Schaffer collaterals‐CA1 synapses was fully abolished 3 days after SE. Our results emphasize the role of non‐NMDA‐dependent synaptic plasticity changes in the processes of epileptogenesis and the potential for therapy development.     

Maintenance of long‐term potentiation in hippocampal mossy fiber—CA3 pathway requires fine‐tuned MMP‐9 proteolytic activity

Mechanisms of synaptic plasticity involve proteolytic activity mediated by a complex system of proteases, including members of metalloproteinase (MMP) family. In particular, MMP‐9 is critical in LTP maintenance in the Schaffer collateral‐CA1 pathway and in the acquisition of hippocampus‐dependent memory. Recent studies from this laboratory revealed that in the mossy fiber‐CA3 (MF‐CA3) projection, where LTP induction and expression are largely presynaptic, MMPs blockade disrupts LTP maintenance and that LTP induction is associated with increased MMP‐9 expression. Here we used acute brain slices from MMP‐9 knock‐out mice and transgenic rats overexpressing MMP‐9 to determine how manipulations in endogenous MMP‐9 affect LTP in the MF‐CA3 projection. Both types of transgenic models showed a normal basal synaptic transmission and short‐term plasticity. Interestingly, the maintenance of LTP induced in slices from knock‐out mice and overexpressing rats was nearly abolished. However, in the presence of active MMP‐9, a gradual fEPSP autopotentiation was observed and tetanization evoked a marked LTP in knock‐out mice. Additionally, in MMP‐9‐treated slices from wild‐type mice, fEPSP autopotentiation also occurred and partially occluded LTP. This indicates that exogenous protease can restore LTP in null mice whereas in the wild‐type, MMP‐9 excess impairs LTP. We expected that LTP maintenance in transgenic rats could be re‐established by a partial MMP blockade but non‐saturating concentrations of MMP inhibitor were ineffective. In conclusion, we demonstrate that LTP maintenance in MF‐CA3 pathway requires fine‐tuned MMP‐9 activity and raises the possibility that altered MMP‐9 level might be detrimental for cognitive processes as observed in some neuropathologies. © 2013 Wiley Periodicals, Inc.     

Spatiotemporal visualization of long-term potentiation and depression in the hippocampal CA1 area

Long-term potentiation (LTP) in the CA1 area of the hippocampus depends critically on the statistical characteristics of its stimulus. The ability of optical imaging to record spatial distribution has made it possible to examine systematically the effect of higher-order statistical characteristics, such as the correlation between successive pairs of inter-stimulus intervals (ISIs) on the induction of LTP. Therefore, the function of frequency (first-order) and temporal pattern (second-order) was examined using this imaging technique. To investigate the dependence of LTP on frequency, periodic stimuli with the same number of pulses were applied at different frequencies (1-10 Hz, n=200) to Schaffer commissural-collateral fibers. While stimulus frequencies from 2-10 Hz induced LTP of varying magnitudes and low-frequency stimuli (1 Hz) induced long-term depression (LTD), spatial distribution remained consistent. These results suggest that induction frequency has a greater effect on the magnitude of LTP than on its spatial distribution. By employing nonperiodic stimuli at the same mean frequency (2 Hz), the effect of varying the temporal structure of a stimulus was also investigated. As the correlation of successive ISIs was increased from negative to positive, not only did the magnitude of LTP increase, there was also a statistically significant change in the spatial distribution of LTP. Interestingly, when a strong negatively correlated stimulus was applied, both LTP and LTD were simultaneously observed in the CA1 area. It was also found that the magnitude of LTP 200-300 mum distal to the cellular layer was larger than that of the LTP induced proximal (<100 microm) to that layer. These results support the hypothesis that the spatial distribution of LTP throughout the hippocampus relies principally on the temporal patterning of input stimulation. This insight into the structure of the CA1 neural network may reveal the importance of stimulus timing events in the spatial encoding of memories.     

Dentate gyrus granule cell firing patterns can induce mossy fiber long‐term potentiation in vitro

Hippocampal granule cells transmit information about behaviorally‐relevant stimuli to CA3 pyramidal cells via mossy fiber synapses. These synapses express a form of long‐term potentiation (mfLTP) that is non‐Hebbian and does not require NMDA receptors. mfLTP is thought to be induced and expressed presynaptically, hence, the major determinant of whether mfLTP occurs is activity in the granule cells. However, it remains unclear whether mfLTP can be induced by activity patterns that granule cells exhibit in vivo, and—if so—what context generates these patterns. To address these issues, we examined granule cell activity from in vivo recordings from rats during performance of a delayed nonmatch‐to‐sample (DNMS) task and found that granule cells exhibit a wide range of spike patterns. In vitro slice experiments in mice demonstrated that some, but not all, of these patterns of activity could induce mfLTP. By further defining the activity thresholds for mfLTP in hippocampal slices, we found that mfLTP can only be induced by spike patterns that fire in high frequency bursts with a low average firing frequency. Using this information, we then screened for suprathreshold bursts of activity during the DNMS task. In a subset of cells, suprathreshold bursts occurred preferentially during the sampling phase of the task. If suprathreshold bursting took place later, during the delay phase, task performance was disrupted. We conclude that mfLTP can be induced by granule cell spike patterns during a memory task, and that the timing of mfLTP induction can predict task performance. © 2010 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.     

Different pH‐dependencies of the two synaptic adhesion molecules N‐cadherin and cadherin‐11 and the possible functional implication for long‐term potentiation

Ca²⁺‐dependent adhesion molecules, cadherins, localised at synaptic sites are critically involved in long‐term potentiation (LTP). N‐cadherin is thought to promote LTP whereas cadherin‐11 seems to counteract LTP. Since high synaptic activity is accompanied by local transient changes of the pH in the synaptic cleft, we studied whether the binding activity of cadherins is dependent on the pH and whether this might play a role during LTP. By atomic force microscopy (AFM) and laser tweezer experiments, we could show on the single molecule level as well as in a cell‐based system that a decrease of the pH from 7.4 to 7.0 will result in a significant weakening of N‐cadherin binding activity but in an increase of cadherin‐11 binding. These differences in the pH dependencies of both molecules could be one explanation for their opposing roles during LTP. High‐frequency stimulation will lead to a local acidosis in the synaptic cleft resulting in weakening of N‐cadherin‐mediated adhesion facilitating synaptic remodeling and LTP induction, whereas cadherin‐11 bonds will be strengthened counteracting synaptic remodeling and LTP generation. Synapse 67:705–715, 2013 . © 2013 Wiley Periodicals, Inc.     

Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phospholipase C

Activation of metabotropic glutamate receptors (mGluRs) with 1-aminocyclopentane-1S,3R-dicarboxylic acid 20 min prior to tetanus facilitates, or “primes,” subsequent induction of long-term potentiation (LTP; Cohen and Abraham, J Neurophysiol 1996;76:953–962). In the present study, we investigated the receptor specificity and associated second messenger pathways involved in the mGluR priming effect by using field potentials recorded from area CA1 of rat hippocampal slices. In controls, mild theta-burst or high-frequency (100 Hz) stimulation induced 16% and 21% LTP, respectively. A 10-min application of the group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) caused a transient depression of synaptic responses but a significant enhancement of subsequent LTP for both tetanus protocols (45% and 41% LTP, respectively). Maximal LTP, induced by stronger tetanization protocols, was not enhanced by DHPG, nor was mild LTP facilitated by post-tetanic application of DHPG. Priming with agonists selective for group II or III mGluRs had no effect on LTP. The mGluR antagonists L-2-amino-3-phosphonopropionic acid and 1-aminoindan-1,5-dicarboxylic acid inhibited the LTP facilitatory effect of DHPG but not the transient response depression, whereas α-methyl-4-carboxyphenylglycine produced the opposite effects. Priming with N-methyl-D-aspartate or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid did not facilitate LTP induction. Prior activation of muscarinic acetylcholine receptors produced at best a weak priming effect. Inhibition of phospholipase C by U-73122 completely abolished the priming of LTP by DHPG. We conclude that mGluR priming of LTP results from biochemical cascades triggered by activation of phospholipase C coupled to group I mGluRs. Hippocampus 1998;8:160–170. © 1998 Wiley-Liss, Inc.     

Blockade of M2‐like muscarinic receptors enhances long‐term potentiation at corticostriatal synapses

Acetylcholine (ACh) exerts a crucial role in learning and memory. The striatum contains the highest concentration of this transmitter in the brain. This structure expresses two different forms of synaptic plasticity, long-term depression (LTD) and long-term potentiation (LTP), which might contribute to the storage of motor skills and some cognitive processes. We have investigated the role of M2-like muscarinic receptors in striatal LTP by utilizing intracellular recordings in vitro from a rat corticostriatal slice preparation. Methoctramine (250 nm ), an antagonist of M2-like muscarinic receptors, enhanced striatal LTP induced in the absence of external magnesium (Mg²⁺) by high-frequency stimulation (HFS) of corticostriatal fibres. Methoctramine did not affect the amplitude of excitatory postsynaptic potentials (EPSPs) when bath applied either before or after the conditioning tetanus suggesting that a critical increase of ACh concentrations is produced only during HFS. Methoctramine per se failed to enhance the NMDA-mediated EPSPs recorded in the absence of external Mg²⁺ and in the presence of 10 μm CNQX. Methoctramine antagonized the presynaptic inhibitory action of neostigmine, an inhibitor of ACh-esterase, and oxotremorine, an agonist of M2-like muscarinic receptors. These data indicate that the activation of M2-like muscarinic receptors exerts a negative influence on striatal LTP, probably by reducing the release of glutamate from corticostriatal fibres and they suggest a complex modulatory effect of ACh in striatal synaptic plasticity.     

Ras‐GRF2 mediates long‐term potentiation,survival, and response to an enriched environment of newborn neurons in the hippocampus

Hippocampal adult neurogenesis contributes to key functions of the dentate gyrus (DG), including contextual discrimination. This is due, at least in part, to the unique form of plasticity that new neurons display at a specific stage of their development when compared with the surrounding principal neurons. In addition, the contribution that newborn neurons make to dentate function can be enhanced by an increase in their numbers induced by a stimulating environment. However, signaling mechanisms that regulate these properties of newborn neurons are poorly understood. Here, we show that Ras‐GRF2 (GRF2), a calcium‐regulated exchange factor that can activate Ras and Rac GTPases, contributes to both of these properties of newborn neurons. Using Ras‐GRF2 knockout mice and wild‐type mice stereotactically injected with retrovirus containing shRNA against the exchange factor, we demonstrate that GRF2 promotes the survival of newborn neurons of the DG at approximately 1–2 weeks after their birth. GRF2 also controls the distinct form of long‐term potentiation that is characteristic of new neurons of the hippocampus through its effector Erk MAP kinase. Moreover, the enhancement of neuron survival that occurs after mice are exposed to an enriched environment also involves GRF2 function. Consistent with these observations, GRF2 knockout mice display defective contextual discrimination. Overall, these findings indicate that GRF2 regulates both the basal level and environmentally induced increase of newborn neuron survival, as well as in the induction of a distinct form of synaptic plasticity of newborn neurons that contributes to distinct features of hippocampus‐derived learning and memory. © 2014 Wiley Periodicals, Inc.