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PubMed2002

Differential regulation of synaptic transmission by mGlu2 and mGlu3 at the perforant path inputs to the dentate gyrus and CA1 revealed in mGlu2 -/- mice.

Group II metabotropic glutamate (mGlu) receptors can act as presynaptic autoinhibitory receptors at perforant path inputs to the hippocampus under conditions of high frequency synaptic activation. We have used mGlu2 -/- mice to examine the relative roles of mGlu2 and mGlu3 in the regulation of perforant path synaptic transmission mediated by both the selective group II receptor agonist, DCG-IV, and by synaptically released glutamate. Field excitatory postsynaptic potentials evoked by stimulation of either the perforant path inputs to the dentate gyrus mid-moleculare or the CA1 stratum lacunosum moleculare were inhibited by DCG-IV with IC(50) values and maximum percentage inhibition of: 169 nM (60%) and 41 nM (72%) in wild-type mice and 273 nM (19%) and 116 nM (49%) in mGlu2 -/- mice, respectively. Activation of presynaptic group II mGlu autoreceptors by synaptically released glutamate, as revealed by a LY341495-mediated increase in the relative amplitude of a test fEPSP evoked after a conditioning burst, was observed in both the dentate gyrus and the stratum lacunosum of wild-type, but not mGlu2 -/- mice. These observations demonstrate that activation of mGlu3 receptors can regulate synaptic transmission at perforant path synapses but suggest that mGlu2 is the major presynaptic group II autoreceptor activated by synaptically released glutamate.

Animals↗
PubMed2002

Modulation of lateral perforant path excitatory responses by metabotropic glutamate 8 (mGlu8) receptors.

The contribution of metabotropic glutamate 8 (mGlu8) receptors to modulation of medial and lateral perforant path (MPP and LPP) inputs to the dentate gyrus was investigated using electrophysiological recording of field excitatory postsynaptic potentials (fEPSPs) from hippocampal slices taken from wild-type and mGlu8 receptor knockout animals. Application of the selective group III mGlu receptor agonist, L-AP4 (1-100 microM), reduced fEPSPs evoked by LPP, but not MPP stimulation in wild-type slices in a concentration-dependent manner (EC(50) = 4.7 microM). The selective mGlu8 receptor agonist, DCPG (1-30 microM) also suppressed LPP fEPSPs with an EC(50) value of 3.1 microM. The L-AP4-induced reduction in LPP fEPSPs could be blocked by the group III antagonist, MSOP (100 microM) in wild-type slices and was eliminated in mGlu8 receptor-deficient slices. Additional experiments showed that MPP fEPSPs were suppressed by the group II agonist, LY379268 (0.01-3 microM) in control slices (EC(50) = 153.1 nM); an effect that was not altered in mGlu8 receptor knockout slices (EC(50) = 153.8 nM). In addition, LY379268 had little effect on fEPSPs evoked by LPP stimulation in mGlu8 receptor-deficient slices. In conjunction with recent receptor localization studies, these results suggest that the mGlu8 receptors serve as autoreceptors on LPP afferents to the dentate gyrus.

Animals↗
PubMed2003

An increased expression of the mGlu5 receptor protein following LTP induction at the perforant path-dentate gyrus synapse in freely moving rats.

The involvement of metabotropic glutamate (mGlu) receptors in the induction of long-term potentiation (LTP) in vivo has been consistently documented. We have investigated whether LTP induction in the dentate gyrus of rats leads to changes in expression of mGlu2/3 or -5 receptor subtypes in the hippocampus. LTP was induced at the medial perforant path-dentate gyrus synapses, and mGlu receptor expression was examined by Western blot or in situ hybridization. An up-regulation of mGlu5 receptors was observed in the hippocampus both 24 and 48 h following LTP induction. This effect was restricted to the dentate gyrus and CA1 region, whereas no changes in mGlu5 receptor protein (but an increase in mRNA levels) were observed in the CA3 region. The increased expression of mGlu5 receptors was directly related to the induction of LTP, because it was not observed when tetanic stimulation was carried out in animals treated with the NMDA receptor antagonist, 2-amino-5-phosphonopentanoate (AP5). Western blot analysis also showed a reduced expression of mGlu2/3 receptors in the whole hippocampus 24 h after LTP induction, indicating that the increased expression of mGlu5 receptors was specific. These data suggest that an up-regulation of mGlu5 receptors is a component of the plastic changes that follow the induction of LTP at the perforant path-dentate gyrus synapse.

2-Amino-5-phosphonovalerate↗
PubMed2004

GABA(B) receptor activation and limbic network ictogenesis.

Rat brain slices containing interconnected hippocampus and entorhinal cortex (EC) responded to 4-aminopyridine (50 microM) application by generating: (i) CA3-driven interictal discharges that propagated to the EC; and (ii) N-methyl-D-aspartic (NMDA) acid receptor-dependent ictal events originating in EC (cf. J. Neurosci. 17 (1997) 9308 for experiments made in brain slices). Ictal discharges disappeared within 1-2 h, but were re-established by cutting the Schaffer collaterals, which abolished CA3-driven interictal discharge propagation to EC. In intact slices, GABA(B) receptor activation by baclofen (5-40 microM): (i) depressed CA3-driven interictal activity; and (ii) disclosed non-NMDA glutamatergic receptor-dependent ictal discharges originating in CA3 and propagating to EC. These effects were reversed by the GABA(B) receptor antagonist CGP 35348 (0.5 mM). Application of increasing baclofen doses to slices in which hippocampus and EC networks were surgically isolated decreased epileptiform events with an IC50 that was lower in EC (0.6 microM; n = 12) than in CA3 (2.5 microM; n = 12). Hence, under control conditions, EC ictogenesis depends on NMDA receptor function and is controlled by CA3-driven output activity; in contrast, following GABA(B) receptor activation EC excitability is depressed to a greater extent than CA3, which leads to non-NMDA glutamatergic receptor-mediated ictogenesis in CA3. We propose that GABA(B) receptor modulation may represent an important mechanism for setting the site of initiation, the modalities of propagation and the glutamatergic receptor properties of ictogenesis in the limbic system and, perhaps, in mesial temporal lobe epilepsy patients.

4-Aminopyridine↗
PubMedDate not supplied

Synapses in hippocampus occupy only 1-2% of cell membranes and are spaced less than half-micron apart: a quantitative ultrastructural analysis with discussion of physiological implications.

Relatively little information exists regarding the spatial structure of synaptic neuropil in the brain. The present electron microscopic study employs unbiased stereological techniques and Monte Carlo simulations to characterise quantitatively the spatial organisation of synaptic circuitry in the dentate gyrus of the hippocampus, an area of particular importance in mechanisms of learning and the subject of a number of experimental neurobiological models of synaptic plasticity such as long-term potentiation. Firstly, tissue shrinkage/expansion resulting from embedding was assessed by imaging 300-microm thick hippocampal slices in the course of the entire embedding protocol, giving a value of 94.3 +/- 1.1% for distance measures and 84.3 +/- 2.8% for volumetric measures. Secondly, numeric synaptic density, Nv, was estimated using the disector. Thirdly, accumulated area of post-synaptic densities (PSDs) per tissue volume, Sv, and the overall cell membrane area per tissue volume, Sv*, were assessed using unbiased stereological rules coupled with image analysis of single sections. Finally, the mean area of individual PSDs was derived as a ratio Sv/Nv giving: 0.0394 microm2 for axo-spinous PSDs (thus representing approximately 1.3% of total cell membranes) and 0.0769 microm2 for dendritic shaft PSDs (approximately 0.25% of total cell membranes). From these data, the mean nearest neighbour distance between synapses was estimated using Monte Carlo simulations of a random 3D arrangement of synapses constrained by PSD sizes (a truncated Poisson process), giving a value of 0.48-0.51 microm. The physiological importance of the morphometric data obtained is discussed in terms of assessing (i) the role of synaptic environment in modifying synaptic efficacy and (ii) the plausibility of cross talk between synapses in relation to extrasynaptic neurotransmitter diffusion and transient depletion of extracellular Ca2+.

Animals↗
PubMedDate not supplied

Evidence that nerve growth factor plays a role in long-term potentiation in the rat dentate gyrus.

An inbred strain of Wistar rat (GH), which is deficient in nerve growth factor (NGF), was used to assess the possible role of NGF in the generation of long-term potentiation in perforant path-granule cell synapses. The data show that NGF was significantly decreased in the dentate gyrus of GH rats, that this deficit was accompanied by an impairment in long-term potentiation (LTP) and that intraventricular injection of NGF substantially reversed this impairment. Analysis of depolarization-induced glutamate release in synaptosomes prepared from dentate gyrus of control rats revealed that NGF alone was without effect, but in combination with the metabotropic glutamate receptor agonist, aminocyclopentane-1,3-dicarboxylic acid (ACPD), NGF induced a significant increase in release. This effect was occluded by prior induction of LTP, suggesting that the interaction between these agents may be required to enhance transmitter release which accompanies LTP in dentate gyrus. In contrast to the effect of NGF and ACPD on glutamate release in control rats, the combination of these agents had no effect on release in synaptosomes prepared from GH rats, which might be explained by the marked decrease in trk receptors in dentate gyrus of GH rats. It was concluded that the impaired ability of GH rats to sustain LTP is associated with a reduction in NGF concentration, a reduction in stimulated release of NGF and a decrease in trk receptors in dentate gyrus. It is proposed that these data indicate a role for NGF in the generation of long-term potentiation in perforant path-granule cell synapses.

Animals↗
PubMed1999

Decreased sensitivity to Group III mGluR agonists in the lateral perforant path following kindling.

The ability of the selective Group III mGluR agonist L-serine-O-phosphate (L-SOP) to inhibit lateral perforant path (LPP) evoked responses in the dentate gyrus was tested in hippocampal slices from commissurally-kindled rats 1-2 days after the last seizure, implanted controls, and fully-kindled rats rested for 28 days without stimulated seizures (28 days post-seizure, 28 dps). L-SOP was more potent in controls than kindled or 28 dps animals, decreasing the fEPSP slope with IC50s of 2.4 microM, 18.7 microM and 10.5 microM, respectively. Paired pulse facilitation (PPF, 50 ms) was comparable in control and kindled rats, but was markedly reduced in 28 dps rats, indicating increased release probability. Inhibition of the field excitatory postsynaptic potentials (fEPSP) by L-SOP was correlated with enhanced PPF in all groups, affirming a presynaptic site of action. At moderate levels of L-SOP-induced inhibition (20-60%), PPF showed significantly greater enhancement in 28 dps than in the other two groups. These results are interpreted as showing a functional reduction of the presynaptic inhibitory Group III mGluR (probably mGluR8) response in the LPP after kindling. Furthermore, PPF changes indicate that the kindled state may be associated with a long-lasting increase in the probability of release from LPP terminals, which may be temporarily masked or counterbalanced by recent seizures.

Animals↗
PubMedDate not supplied

Air righting: role of the NMDA receptor channel and hippocampal LTP.

Air righting results in an animal turning over when it is dropped from a height in an inverted position. In the rat, air righting is a complex set of movements that depends only on an intact labyrinth and the normal vestibular input. Visual modulation of air righting does not develop until adulthood; and the ability to estimate the time to impact requires bilateral visual cues and indicates that air righting is a complex set of perceptually controlled movements and learning. The general purpose of this study was to determine the role of the NMDA receptor-ion channel on air righting and hippocampal LTP. Specifically: to measure the effects of various doses of CPP, an NMDA receptor antagonist, and MK-801, an ion channel blocker, on (a) air righting and (b) hippocampal LTP induction in medial perforant path-granule cell synapses. The following doses were used: CPP-0, 1, 5, and 10 mg/kg i.p.; MK-801-0. 0, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg i.p. Data were analyzed by appropriate ANOVAs and post hoc tests. Results were significant and demonstrate dose-dependent impairment of air righting and inhibition of LTP for both CPP and MK-801, implicating the role of the NMDA receptor and Na(+)/K(+)/Ca(2)+ channel in these effects. Air righting is a complex behavior and appears to be dependent upon NMDA mediated hippocampal LTP.

Analysis of Variance↗
PubMedDate not supplied

Acute and chronic intracerebroventricular morphine infusions affect long-term potentiation differently in the lateral perforant path.

Experiments were performed to investigate the effects of acute and chronic intracerebroventricular (icv) morphine infusions via osmotic minipumps on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of the rat dentate gyrus. Although significant antinociceptive activity was observed when morphine was infused (25 nmol/microl/h) for 30 min or 1 h, the activity was not observed in rats receiving morphine chronically for 72 h, and the tail-flick latency of this group was comparable to that of rats receiving saline. LTP induction was significantly attenuated after acute morphine infusion (1 h) in LPP-granule cell synapses of the dentate gyrus. In contrast, LTP induction was augmented after chronic morphine infusion for 72 h. Bath-perfused morphine augmented the baseline population spike (PS) amplitude in rats treated with saline, whereas it attenuated the LTP induced by chronic morphine infusion. Returning the LTP to the level of saline infusion after in vitro morphine perfusion suggests that enhancement of the LTP is a withdrawal-like phenomenon. These results suggest a difference between the effects of acute and chronic intracerebroventricular morphine infusions on synaptic plasticity in the LPP-granule cell synapses of the dentate gyrus.

Analgesics, Opioid↗
PubMed2001

Selective cholinergic denervation inhibits expression of long-term potentiation in the adult but not infant rat hippocampus.

The present study assessed the role of the cholinergic systems on the expression of perforant path long-term potentiation (LTP) in rat hippocampal slices from the infant and adult brain. To denervate the cholinergic systems, 192 IgG--saporin was injected into the lateral ventricle of the infant (2-weeks-old) and adult (6-weeks-old) rat brain. There, choline acetyltransferase-immunoreactive fibers were barely detectable 2 weeks and 2 months after injection for both the groups. For the infant rats, perforant path LTP was not affected by selective cholinergic denervation; the probability of LTP development was 0.83 (five out of six slices) and 0.78 (seven out of nine slices) at 2 weeks and 2 months later in 192 IgG--saporin-treated slices, as compared with 0.83 at each period in control saline-treated slices. In contrast, the expression of the LTP was blocked by selective cholinergic denervation for the adult rats; the probability of LTP development was 0 (zero out of 10 slices) and 0.38 (three out of eight slices) at 2 weeks and 2 months later in 192 IgG--saporin-treated slices, as compared with 0.8 (eight out of 10 slices) and 0.83 (five out of six slices) at each period in control saline-treated slices. The results of the present study thus suggest that the cholinergic systems play a crucial role in the expression of LTP in the adult brain and that the denervated systems in the infant brain could be compensated by the sprouting of non-cholinergic fibers.

Age Factors↗
PubMed1999

Dentate granule cell function after neonatal treatment with parachloroamphetamine or 5,7-dihydroxytryptamine.

In vitro, extracellular electrophysiological recording was used to test granule cell responses in P60 rats after neonatal PCA and 5, 7-DHT. Granule cell population EPSP and spike responses were in the normal range for both PCA and 5,7-DHT groups. However, the degree of paired pulse facilitation was reduced in both of these groups relative to control, reflecting a diminished synaptic drive. Synaptic potentiation in the 5,7-DHT group was not different from control, but was significantly reduced in slices from PCA-treated rats.

5,7-Dihydroxytryptamine↗
PubMed1999

Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study.

Previous studies have demonstrated that recurrent seizures during the neonatal period lead to permanent changes in seizure threshold and learning and memory. The pathophysiological mechanisms for these changes are not clear. To determine if neonatal seizures cause changes in hippocampal excitability or inhibition, we subjected rats to 50 flurothyl-induced seizures during the first 10 days of life (five seizures per day). When the rats were adults, we examined seizure threshold using flurothyl inhalation, and learning and memory in the water maze. In separate groups of animals, we evaluated in vivo paired-pulse facilitation and inhibition in either CA1 with stimulation of the Schaffer collaterals or dentate gyrus with stimulation of the perforant path. Following these studies, the animals were sacrificed and the brains evaluated for mossy fiber sprouting with the Timm stain. Compared to control animals, rats with 50 flurothyl seizures had a reduced seizure threshold, impaired learning and memory in the water maze, and sprouting of mossy fibers in the CA3 pyramidal cell layer and molecular layer of the dentate gyrus. No significant differences in impaired paired-pulse inhibition was noted between the flurothyl-treated and control rats. This study demonstrates that recurrent neonatal seizures result in changes of neuronal connectivity and alterations in seizure susceptibility, learning and memory. However, the degree of impairment following 50 seizures was modest, demonstrating that the immature brain is remarkably resilient to seizure-induced damage.

Animals↗
PubMed2004

Cognitive deficits in adult rats by lead intoxication are related with regional specific inhibition of cNOS.

It is well known that lead can affect several cognitive abilities in developing animals. In this work, we investigate the effects of different sub-chronic lead doses (0, 65, 125, 250 and 500 ppm of lead acetate in their drinking water for 14 days) in the performance of male adult rats in a water maze, cue maze and inhibitory avoidance tasks. We found that the acquisition of these tasks was not affected by lead, however, the highest dosage of lead (500 ppm) impaired memory consolidation in spatial and inhibitory avoidance tasks, but not in cue maze task while the 250 ppm dose only affected retrieval of spatial memory. Additionally, hippocampal long-term potentiation (LTP) induction in the perforant path after exposing adult rats to different doses of lead was studied. LTP induction was affected in a dose-dependent manner, and treatments of 250 and 500 ppm completely blocked LTP. We investigated the effects of lead intoxication on the activity of constitutive nitric oxide synthase (cNOS) in different brain regions of adult animals. The activity of cNOS was significantly inhibited in the hippocampus and cerebellum but not in the frontal cortex and brain stem, although lead had accumulated in all brain regions. These results suggest that lead intoxication can impair memory in adult animals and this impairment might be related with region-specific effects on cNOS activity.

Analysis of Variance↗
PubMed1998

Testicular hormones do not regulate sexually dimorphic Pavlovian fear conditioning or perforant-path long-term potentiation in adult male rats.

We recently reported that Pavlovian fear conditioning and hippocampal perforant-path long-term potentiation (LTP) are sexually dimorphic in rats. Males show greater contextual fear conditioning, which depends on the hippocampus, as well as greater hippocampal LTP. In order to examine the role of circulating gonadal hormones in adult male rats, animals were castrated in two experiments, and Pavlovian fear conditioning and in vivo perforant-path LTP were examined. It was found that sexually-dimorphic LTP and fear conditioning are not regulated by the activational effects of testicular hormones in adult male rats. That is, in every respect, castrated male rats were similar to intact male rats in Pavlovian fear conditioning and hippocampal LTP. It is likely that sexual dimorphism in this system is established earlier in development by the organizational effects of gonadal hormones.

Animals↗
PubMed1998

Modelling recovery of cognitive function after traumatic brain injury: spatial navigation in the Morris water maze after complete or partial transections of the perforant path in rats.

The Morris water maze (MWM) has been used to assess cognitive function in rats after a variety of lesions designed to model brain damage and to assess the effects of drugs, growth factors, and neural transplants on post-operative deficits. The present study examined recovery of spatial navigation in the MWM over time in order to model the spontaneous recovery of cognitive function seen in humans. Diffuse axonal injury, a neuropathology commonly associated with traumatic brain injury (TBI), was modelled by transecting the perforant path (PP) bilaterally, either caudal to the hippocampus or dorsal to it at the decussation of the dorsal hippocampal commissure. Both groups with PP cuts showed substantial deficits initially, but spatial performance recovered with time and training. Recovery of platform finding was nearly complete within 14 days of testing, but recovery of platform searching did not occur for 2 or 3 more weeks. When the platform was moved to a new location, a continuing deficit in learning rate was revealed. When the platform was moved to a new position every day, this deficit was even more evident. These results illustrate the multi-faceted nature of recovery after brain injury and provide a new model for assessing the effects of manipulations designed to modulate recovery.

Animals↗
PubMed2000

Perforant path stimulation in rats produces seizures, loss of hippocampal neurons, and a deficit in spatial mapping which are reduced by prior MK-801.

Severe temporal lobe epilepsy in humans is often associated with loss of neurons in the hippocampus and memory deficits. In Experiment 1, 60 min of continuous electrical stimulation of the perforant path sufficient to produce seizures resembling status epilepticus and loss of hilar and pyramidal cells in the hippocampus, produced a deficit in spatial mapping in the Morris water tank. In particular, the previously stimulated rats took longer and swam farther to find a hidden, but not a visually cued, platform, and, in contrast to the unstimulated control rats, were not disrupted by movement of the platform to a new location. In Experiment 2, a single injection of the non-competitive NMDA receptor antagonist, MK-801 (1.0 mg/kg), just prior to the perforant path stimulation reduced the seizures, hippocampal neuronal loss, and deficit in spatial mapping. These data suggest that temporal lobe seizures can induce deficits in spatial memory by selectively destroying neurons within the hippocampus, and that the mechanism by which this occurs involves the activation of NMDA receptors, and, perhaps, consequent excitotoxicity.

Animals↗
PubMed1998

Increased expression of dendritic mRNA following the induction of long-term potentiation.

A small number of mRNAs, including Ca2+/calmodulin-dependent protein kinase II alpha-subunit (CamKIIalpha) mRNA and microtubule-associated protein 2 (MAP2) mRNA, are present in the dendrites of neurones as well as in the cell bodies. We show here that the induction of long-term potentiation (LTP) in the hippocampal perforant path/granule cell synapses in anaesthetised rats is associated with increased levels of CamKIIalpha mRNA and MAP2 mRNA in the granule cell dendrites after 2 h. Similarly, induction of LTP in the Schaffer collateral/CA1 pyramidal cell synapses in hippocampal slices maintained in vitro also results in elevated dendritic levels of CamKIIalpha mRNA and MAP2 mRNA 2 h later. In both models, the levels of various other mRNA species restricted to the cell body region were unaffected by the induction of LTP. Increased expression of dendritic CamKIIalpha mRNA and MAP2 mRNA appears to be a general feature of hippocampal plasticity, since it occurs following LTP induction in both the dentate gyrus and the CA1 region. The elevation of mRNA levels in a restricted region close to the afferent synapses would allow a highly-localised enhancement of the synthesis of the corresponding proteins, providing an elegant mechanism for protein-synthesis-dependent synaptic plasticity to maintain a high degree of anatomical specificity.

Animals↗
PubMed1998

Synaptic activity-dependent modulation of mitochondrial gene expression in the rat hippocampus.

In order to identify genes that may underlie the maintenance of long-term potentiation (LTP) at perforant path synapses, complementary DNA libraries were synthesised from dentate gyrus total RNA extracts prepared 48 h after the induction of LTP and from control dentate gyrus extracts. Through differential screening of the LTP library we have identified the mitochondrial 12S rRNA (mt12SrRNA) as a transcript that was elevated at this late time. Northern blot analyses showed that the elevation in mt12SrRNA expression began around 8 h and persisted for at least 2 weeks post-tetanus. We then examined the expression patterns of other mitochondrially-encoded genes and demonstrated a similar elevation in their expression. mt12SrRNA levels were also elevated in other hippocampal regions, including areas CA3 and CA1 and were elevated following low-frequency stimulation or in the presence of an N-methyl-D-aspartate receptor antagonist where induction of LTP was precluded. Taken together, these observations suggest that a long-lasting up-regulation of energy production may be triggered by synaptic activity and this activity need not be of sufficient strength to induce LTP, but may be related to the induction of a metaplastic state.

Animals↗