Heterosynaptic interactions between septal and entorhinal inputs to the dentate gyrus: long-term potentiation effects

Cooperative interactions between neural pathways, in the production of long-term potentiation, may serve as models of associative memory. Brief, high-frequency activation of the septodentate input to dentate gyrus granule cells was found to produce only a short-term heterosynaptic potentiation of the perforant path-granule cell (PP-GC) population spike. Concurrent tetanization of perforant path and septodentate afferents, however, resulted in significantly greater long-term potentiation of the PP-GC population spike than was produced by tetanization of the perforant path alone.     

Enhanced long-term potentiation induced in rat dentate gyrus by coactivation of septal and entorhinal inputs: Temporal constraints

High-frequency activation of the entorhinal cortical (perforant path) inputs to the rat dentate gyrus can produce a long-term potentiation (LTP) of perforant path-dentate evoked responses. In this paper we examined the enhanced LTP effects produced by coactivation of septal and entorhinal inputs to the dentate gyrus. Trains of electrical stimulation applied to the two inputs were found to increase the magnitude of LTP to a level above that produced by trains applied to the perforant path alone. The largest LTP increments were observed when the septal trains were applied less than 100 ms prior to the perforant path trains. If the septal trains followed the perforant path trains there was no additional increment in LTP magnitude, regardless of the intertrain interval. The relationship of this cooperativity effect to mechanisms of associative learning is discussed.     

NMDA-dependent heterosynaptic long-term depression in the dentate gyrus of anaesthetized rats.

This report examines the inductive mechanisms involved in long-term heterosynaptic depression (LTD) in the dentate gyrus of anaesthetized rats. Associative and non-associative stimulus protocols were implemented, using the ipsilateral medial and lateral perforant path inputs to the dentate gyrus as the test pathways. In all experiments, the medial perforant path (MPP) received the conditioning stimuli which consisted of eight stimulus trains of 2 s duration, spaced 1 minute apart. Within each train the stimuli occurred as a burst of 5 pulses at 100 Hz, repeated at 200 ms intervals. The lateral perforant path (LPP) served as the test pathway in all of the initial experiments. In the associative condition, it received single pulses equally spaced between the medial path bursts. In the non-associative condition, no lateral path stimuli were given during the medial path trains. In both conditions, the application of the conditioning stimuli resulted in a long-term potentiation (LTP) of the medial path evoked responses (P less than 0.001), while the lateral path responses showed LTD (P less than 0.001). A two-way analyses of variance revealed there to be no difference between the two paradigms in the expression of LTP or LTD in naive pathways or in their ability to depress a potentiated pathway (P greater than 0.05) An occlusion test also showed there to be no further decreases in synaptic efficacy with the associative paradigm after the lateral path synapses were saturated with non-associative LTD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of chronic nimodipine on spatial learning and on long-term potentiation

The present study examined the effect of nimodipine on a reference memory task and on the induction and maintenance of long-term potentiation (LTP) in the hippocampal dentate gyrus. Young rats, subcutaneously implanted with either a 30 mg nimodipine or placebo pellet, were trained on the Barnes circular platform task. Retention was tested 15 days following acquisition. Following behavioural testing, recording and stimulating electrodes were implanted in the granule cell layer of the dentate gyrus and the perforant path, respectively. Pre-pellet baseline evoked potentials were collected. Nimodipine or placebo pellets were again subcutaneously implanted, according to the original groupings, and post-pellet baseline evoked potentials were obtained. LTP was then induced in the granule cell population by perforant path tetanization and the decay of LTP was followed for 15 days. Nimodipine significantly decreased the number of trials to reach both the acquisition and the retention criterion on the circular platform task, but did not alter granule cell excitability, LTP threshold, or the magnitude of LTP. Sustained nimodipine administration, however, increased the decay rate of LTP of the population spike, but did not affect the decay rate for LTP of the EPSP. No significant correlations were obtained between behavioural and electrophysiological measures. These results provide further evidence against a simple direct relationship between LTP and spatial learning.     

Early integrative processes physiologically observed in dentate gyrus during an olfactory associative training in rat

Modifications of synaptic efficacy in the dentate gyrus were investigated during an olfactory associative task. A group of rats was trained to discriminate between a patterned electrical stimulation of the lateral olfactory tract, used as an artificial cue, associated with a water reward, and a natural odor associated with a flash of light. Monosynaptic field potential responses evoked by single electrical stimuli to the lateral perforant path were recorded in the granular layer of the ipsilateral dentate gyrus prior to and just after each training session. An early increase in this response was observed just after the first learning session but disappeared 24 hours later. Inversely, a synaptic depression developed across sessions, becoming significant at the onset of a last (fifth) session. When a group of naive animals was pseudo-conditioned, no increase was observed and the synaptic depression was noted since the onset of the second session. In a group of rats similarly trained for only one session, and in which EPSPs were recorded throughout the 24 hours that followed, it was demonstrated that the increase lasted at least two hours, while the significant synaptic depression started after the fourth hour. These results are consistent with the early involvement of the dentate gyrus in learning the association between the cues and their respective rewards. These early integrative processes physiologically observed in dentate gyrus suggest early hippocampal processing before dentate gyrus reactivation via entorhinal cortex which will allow long-term memory storage in cortical areas once the meaning of the olfactory cues is learned.     

Induction of long-term potentiation at perforant path dentate synapses does not affect place learning or memory

In two experiments the authors failed to detect an effect of inducing bilateral, long-lasting synaptic potentiation at perforant path dentate synapses on spatial learning by rats in the Morris place navigation task. Daily sessions of high-frequency stimulation of perforant path axons produced large increases to an asymptotic level in population spike and field excitatory postsynaptic potential recorded in ipsilateral dentate gyrus. Place learning proceeded normally 24 hours after the last of 14 high-frequency stimulation sessions in rats that had previously mastered the procedural aspects of place navigation (Experiment 1) and in rats that were naive (Experiment 2).     

The Basomedial and Basolateral Amygdaloid Nuclei Contribute to the Induction of Long-term Potentiation in the Dentate Gyrus In Vivo

Recent behavioural studies have provided evidence that the amygdala modulates hippocampal-dependent memory. To test the possibility that the amygdala modulates hippocampal synaptic plasticity, we investigated the effects of surgical lesions of the amygdaloid nuclei on the induction of long-term potentiation (LTP) in the dentate gyrus of anaesthetized rats. Previously we reported that LTP in the dentate gyrus was attenuated by lesion of the basolateral amygdala, but was not affected by lesion of the central amygdala. In the present study, dentate gyrus LTP was significantly attenuated by basomedial amygdala lesion but not by medial amygdala lesion. These results suggest that, among the amygdaloid nuclei, the basomedial and basolateral nuclei are involved in the modulation of hippocampal plasticity. The roles of the basomedial and basolateral amygdala were further supported by experiments examining the effects of electrical stimulation of these nuclei. High-frequency stimulation of the basomedial amygdala alone did not induce dentate gyrus LTP, but when applied at the same time as tetanic stimulation of the perforant path increased the magnitude of the dentate gyrus LTP. Similarly, high-frequency stimulation of the basolateral amygdala enhanced LTP induced by tetanic stimulation of the perforant path. Furthermore, facilitation of dentate gyrus LTP by basomedial or basolateral amygdala stimulation was observed even in rats lesioned in either amygdala, suggesting that neurons in the basomedial and basolateral amygdala can modulate dentate gyrus LTP independently. Activity-dependent facilitation of hippocampal plasticity by the basomedial and basolateral amygdala may underlie memory processing associated with emotion.     

Long-term potentiation recruits a trisynaptic excitatory associative network within the mouse dentate gyrus

Granule cells of the hippocampal dentate gyrus receive two powerful excitatory inputs: the perforant path, originating from the entorhinal cortex, and the associational pathway, originating from mossy cells, the principal neurons of the dentate gyrus hilus. We examined the electrophysiological properties of the less well-studied associational pathway and its interaction with the perforant path in the intact mouse hippocampus and then tested homosynaptic, trans-synaptic and associative long-term potentiation of these pathways. The associational pathway was either monosynaptically activated by stimulation within the inner molecular layer or trisynaptically activated after stimulation of the perforant path. Laminar profiles of extracellularly recorded associational pathway field potentials demonstrated a bell-shaped curve with a peak in the inner molecular layer. Tetanization of the perforant path induced not only homosynaptic potentiation of the perforant path (162.4 +/- 6.7% at 0.5-1.5 h after tetanus) but also heterosynaptic potentiation of the associational pathway (115.7 +/- 4.9%). Direct tetanization of the associational pathway within the inner molecular layer was ineffective in either the septo-temporal (97.2 +/- 4.5%) or temporal-septal (104.4 +/- 4.6%) direction. In contrast, conjoint tetanization of the associational pathway with the perforant path potentiated the associational pathway responses in both the septo-temporal (123.4 +/- 5.8%) and the temporal-septal (124.8 +/- 7.3%) directions. Paired-pulse facilitation was attenuated by long-term potentiation in the perforant path and the associational pathway, suggesting pre-synaptic involvement. These results demonstrate that long-term potentiation of the associational pathway and the perforant path is a product of the network properties of the dentate gyrus rather than of each monosynaptic input alone. The architecture of this neural network may be designed for flexible dynamic associations of the afferent perforant path inputs to configure encoded information within hippocampal neuronal ensembles.     

Activation of the medial septal area attenuates LTP of the lateral perforant path and enhances heterosynaptic LTD of the medial perforant path in aged rats

Age-related memory impairments may be due to dysfunction of the septohippocampal system. The medial septal area (MSA) provides the major cholinergic projection to the hippocampus and is critical for memory. Knowledge of the neurobiological mechanisms by which the cholinergic system can attenuate age-related memory loss can facilitate the development of effective cognitive enhancers. At present, one of the best neurobiological models of memory formation is long-term potentiation/long-term depression (LTP/LTD). In previous studies, intraseptal infusion of the muscarinic agonist oxotremorine, which excites MSA neurons, improved memory in aged rats. The present study examined LTP and LTD in aged Fisher 344 rats following intraseptal infusion of oxotremorine. LTP and LTD were assessed using the slope of the EPSP recorded from the hilar region of the dentate gyrus. Induction of LTP was blocked in the lateral perforant path, but not in the medial perforant path, following intraseptal infusions of oxotremorine. The generation and amplitude of heterosynaptic LTD was enhanced in the medial perforant path, but not in the lateral perforant path. The results provide evidence that pharmacological activation of the MSA can modulate LTP and LTD in the hippocampus of aged rats. The implications of these results with respect to memory and synaptic plasticity in the hippocampus are discussed.     

Long-term increases in dentate granule cell responsivity accompany operant conditioning

The efficacy of synaptic transmission from the perforant path (PP) to the granule cells in the dentate gyrus (DG) of freely moving rats was monitored electrophysiologically over the course of training in an appetitively motivated, discriminated operant paradigm. Every day, 22 hr after behavioral sessions, evoked potentials were recorded from the DG following stimulation of the PP over range of current intensities and the amplitudes of the population spikes were measured. Behavioral conditions involved training in an operant conditioning paradigm or a session of free-feeding. Significant increases in population spike amplitudes were observed over the 8 d of training, but not over the 8 d of free-feeding. This training-induced increase in granule cell responsivity persisted for at least 10 d following the cessation of behavioral trials and was in many ways comparable to long-term potentiation (LTP), subsequently observed in these same rats 24 hr after tetanic stimulation. These data confirm and extend previous reports of synaptic enhancements following conditioning and suggest that such increases in synaptic efficacy may encode some aspect of learning.     

Lateral olfactory tract input to dentate gyrus is depressed by prior noradrenergic activation using nucleus paragigantocellularis stimulation

Nucleus paragigantocellularis stimulation potentiates the medial perforant path population spike in the dentate gyrus via β-receptor activation. In this study, the same paragigantocellularis stimulation preceding lateral olfactory tract pulses depressed the lateral perforant path mediated synaptic potential in dentate gyrus. Depression of the lateral olfactory tract input was blocked by a β-antagonist. These in vivo results confirm in vitro reports that norepinephrine induces potentiation of medial perforant path input and depression of lateral perforant path input to dentate gyrus.     

Hippocampal long-term depression as an index of spatial working memory

Long-term potentiation (LTP), a form of synaptic plasticity in the hippocampus, is a cellular model for the neural basis of learning and memory, but few studies have investigated the contribution of long-term depression (LTD), a counterpart of LTP. To address the possible relationship between hippocampal LTD and spatial performance, the spatial cognitive ability of a rat was assessed in a spontaneous alternation test and, thereafter, LTD in response to low-frequency burst stimulation (LFBS) was monitored in the dentate gyrus of the same rat under anaesthesia. To enhance a divergence in the ability for spatial performance, some of the animals received fimbria-fornix (FF) transection 14 days before the experiments. LTD was reliably induced by application of LFBS to the medial perforant path of intact rats, while no apparent LTD was elicited in rats with FF lesions. The behavioural parameters of spatial memory showed a significant correlation with the magnitude of LTD. We found no evidence that the cognitive ability correlated with other electrophysiological parameters, e.g. basal synaptic responses, stimulus intensity to produce half-maximal responses, paired-pulse facilitation or paired-pulse depression. These results suggest that the magnitude of LTD in the dentate gyrus serves as a reliable index of spatial cognitive ability, providing insights into the functional significance of hippocampal LTD.     

Olfactory associative discrimination: a model for studying modifications of synaptic efficacy in neuronal networks supporting long-term memory

This review summarizes research that correlates behavioral performance and cellular physiology leading to modifications in the neuronal networks supporting long-term memory in the mammalian brain. Rats were trained in an olfactory associative discrimination task in which natural odors were replaced by mimetic olfactory stimulations. Olfactory learning induced synaptic modifications that affected behavioral performance along the central olfactory pathways. Starting with an early increase in monosynaptic efficacy in the dentate gyrus on the first session, a polysynaptic modification appeared later on in this hippocampal network, when rats began to make associations between cues and rewards. Therefore, only when rats made consistent associations did a long-term potentiation in the synapses of the piriform cortex pyramidal neurons appear. These modifications may correspond to the long-term storage of the meaning of the cue-reward association in a specific cortical area. Based on these cumulative results, a hypothesis is proposed to account for how, when, and where synaptic modifications in neural networks are required to constitute long-term memory.     

Deficits in LTP and recognition memory in the genetically hypertensive rat are associated with decreased expression of neurotrophic factors and their receptors in the dentate gyrus

We have previously reported that a genetically hypertensive strain of Wistar rat (GH), is deficient in nerve growth factor (NGF) and Trk receptors in dentate gyrus and that these deficits are accompanied by impaired expression of long-term potentiation (LTP) in perforant path-granule cell synapses. Here we confirm this deficit in LTP and report that this strain of rat also displays impairments in long-term recognition memory when compared with normotensive controls. Further analysis of neurotrophin expression in dentate gyrus confirmed the previously-reported deficit in NGF and revealed a decrease in expression of brain-derived neurotrophic factor (BDNF), but not neurotrophin 3 (NT3) or neurotrophin 4 (NT4), in GH rats. These alterations in ligand expression were accompanied by changes in Trk receptor expression; specifically, a decrease in expression of TrkA and TrkB, but not TrkC, in the dentate gyrus of GH, compared with normotensive, rats. We conclude that the impairments in LTP and learning and memory observed in the GH strain are associated with aberrant expression of specific neurotrophic factors and their receptors in the dentate gyrus, adding weight to the evidence indicating a role for these proteins in several forms of synaptic plasticity.     

Blockade of Hippocampal Long-Term Potentiation Following Soman Pretreatment in the Rat

One of the most potent toxins known is the cholinesterase inhibitor, soman, which produces severe convulsions and cell loss in the central nervous system. In these experiments the effect of multiple low doses of soman on the acquisition and maintenance of long-term potentiation (LTP) was determined in rats. LTP is a form of synaptic plasticity that has been studied as a cellular substrate for learning and memory mechanisms. Under urethane anesthesia, electrodes were positioned in the dentate gyrus for recording evoked potentials before and after tetanic stimulation of the perforant path. LTP levels were greatly reduced in rats recovering from convulsion-inducing soman treatment. Rats exposed to similar amounts of soman, but not displaying convulsions, also displayed reduced levels of LTP. The responses recorded from these animals were highly variable, ranging from control levels of potentiation to no LTP. The variability could be attributed to some animals having convulsions that were not detected before surgery or to other interanimal differences in the degree of soman-induced toxicity. The long range goal of the experiments presented here is to develop a better rodent model for studying soman-induced functional changes in the CNS that can be detected prior to the gross morphological changes.     

Acetylcholine modulates averaged sensory evoked responses and perforant path evoked field potentials in the rat dentate gyrus

The effect of localized application of acetylcholine (ACh) on well characterized components of sensory evoked and electrically induced potentials in the dentate gyrus was investigated in rats while performing a tone discrimination task. Local pressure application of ACh to the granule cell layer of the dentate gyrus through the recording pipette increased the amplitude of perforant path evoked population spikes without changing the amplitude of the field EPSP. When the pipette was relocated to the outer molecular layer of the dentate gyrus (OM), ACh application decreased the amplitude of the perforant path field EPSP. Two major components of the averaged auditory evoked potential (AEP) recorded during criterion performance of the discrimination task were significantly changed by dendritic application of ACh. The N1 component of the OM AEP which has been shown to reflect perforant path synaptic activity decreased in amplitude while the N2 component which represents activity from septal connections, was significantly increased. These effects were not due to the pressure ejection procedure nor drug related changes in behavioral performance of the task. The results suggest that ACh may act to differentially modulate the synaptic excitability of dentate granule cells, allowing them to acquire responses to sensory stimulation during the establishment and maintenance of discrimination learning.     

Effect of ganglioside on synaptic plasticity of hippocampus in lead-exposed rats in vivo

Synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD) and depotentiation (DP), is important for learning and memory. Previous studies proved that chronic lead exposure especially during early post-natal development induced impairment on synapse plasticity. The purpose of this study is to evaluate the effect of ganglioside on the lead-induced impairments of LTP and DP in rat dentate gyrus in vivo. The experiments were carried out in three groups of rats (control, lead-exposed, ganglioside-treated lead-exposed, respectively). The input-output (I/O) function, pair pulses reaction, excitatory post-synaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) of adult rats (70-90 days) in response to stimulation applied to the lateral perforant path. The results show that (1) chronic lead exposure impaired LTP/DP measured on both EPSP slope and PS amplitude in DG area of the hippocampus. (2) The amplitudes of LTP/DP of lead-exposed group were significantly increased by supplying ganglioside. These results suggest intraperitoneally injection with ganglioside could reverse the lead-induced impairments of synaptic plasticity in rats and might be effective in attenuating the cognitive deficits induced by lead.     

Increased responsivity of dentate granule cells during nictitating membrane response conditioning in rabbit

We examined the responsivity of dentate gyrus granule cells to perforant path stimulation during classical conditioning of the rabbit nictitating membrane response. Dentate field potentials elicited by perforant path stimulation were recorded during training to test for changes in granule cell responsivity. Results showed above-baseline increases in dentate population spike amplitudes over the course of training in paired but not unpaired animals. In addition, population spike amplitudes were smaller when elicited during tone presentations in both paired and unpaired animals than between trials when no conditioning stimuli were present. While alternative interpretations remain, these results provide preliminary evidence that processes similar to long-term potentiation may occur in the hippocampus during behavioral conditioning.     

An analysis of the increase in granule cell excitability accompanying habituation in the dentate gyrus of the anesthetized rat

Repeated low-frequency stimulation of the perforant path results in a decrement in the population EPSP and population spike recorded in the hilus of the dentate gyrus. The EPSP decrement is accompanied, however, by an increase in the population spike height/population EPSP slope relation, suggesting that an increase in granule cell excitability also occurs. The present experiments explored the mechanisms of this apparent increase in excitability using standard field potential recording techniques to assess perforant path input/output curves in rats anesthetized with sodium pentobarbital. Low-frequency homosynaptic stimulation (512 pulses, 1 Hz) of the perforant path resulted in a decreased spike threshold and overall shift to the left of the function relating population spike height to EPSP slope. These changes were consistently produced, even when granule cell discharge was inhibited by conditioning stimulation of the contralateral hilus. On the other hand, low-frequency heterosynaptic (lateral perforant path) or antidromic (mossy fiber) driving of the granule cells only slightly increased the medial path spike/EPSP relation, and did not alter the spike threshold. The excitability shift accompanying habituation was qualitatively different from that associated with long-term potentiation, but these shifts did not summate. The interpretation which best explains these various results is that granule cell excitability is increased during low-frequency perforant path stimulation by a process of disinhibition, caused by habituation of perforant path excitatory synaptic drive onto feed-forward inhibitory interneurons.     

The amnesic substance 2-deoxy-D-galactose suppresses the maintenance of hippocampal LTP

Male Wistar rats were intraventricularly injected with 2-deoxy-D-galactose (do-gal), a substance interfering with the fucosylation of glycomacromolecules and impairing memory consolidation in various learning tasks. Do-gal was found to have no influence on the monosynaptically evoked field potential (MEFP) recorded in the dentate gyrus upon stimulation of the perforant pathway. However, hippocampal long-term potentiation (LTP) induced in do-gal-pretreated animals by fractionated tetanization of the perforant pathway declined to control levels 2 h after tetanization, whereas it remained constant for 24 h in saline-treated rats. Similar effects were observed in the CA1 region of hippocampal slices. The results indicate a participation of fucosylated macromolecules in the maintenance of LTP. The possible significance of processes involved in LTP for memory formation is discussed.