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PubMed1991

Behavioural, electrophysiological and histopathological changes following sustained stimulation of the perforant pathway input to the hippocampus: effect of the NMDA receptor antagonist, CGP 39551.

Sustained stimulation of the perforant path has been shown to damage the CA1 area and impair spatial memory in rats. The pattern of cell death is similar in human epileptics, who also exhibit memory deficits. In this study we demonstrate that the learning/memory impairment in water maze test and the development of interictal spikes that also followed stimulation-induced damage were antagonized by CGP 39551. Pretreatment with this NMDA receptor antagonist also slightly diminished somatostatin cell loss in the hilus but not CA1 pyramidal cell damage. These results indicate that the impairment of spatial learning/memory seems to be dependent not only on the degree of cell degeneration in the CA1 subfield of the hippocampus but also on the frequency of interictal spikes, at least in this model of epilepsy.

2-Amino-5-phosphonovalerate↗
PubMed1991

The role of the perforant pathway as a trophic factor for neurotransmission in the rat dentate gyrus.

Changes in electrophysiological function in the hilar associational pathway terminating on dentate granule cells in the rat hippocampal formation were studied following unilateral entorhinal cortex lesions. In rats lesioned as pups (postnatal day 4 [PN 4]) or as adults (PN 60) there was a profound loss of paired-pulse inhibition at 30 days postlesion. Inhibition was unaffected at 10 days postlesion. Entorhinal cortex lesions did not affect population spike amplitude, population excitatory postsynaptic potentials slopes, or long-term potentiation compared to the unlesioned hemisphere. The presence of a complete hippocampal commissurotomy had no effect on excitatory or inhibitory parameters. Laminar analyses of extracellular field potentials from animals lesioned as adults revealed an expansion of functional synapses outward into the dentate molecular layer. This expansion was complete by 10 postlesion days. The changes observed with laminar analyses were not contemporaneous with the changes in paired-pulse inhibition. The loss of inhibition in the hilar associational pathway of entorhinal cortex-lesioned animals thus implies a change in local circuit function rather than an effect from sprouted associational fibers directly onto granule cells. The lack of inhibition in the associational pathway in lesioned animals was not due to a failure of local circuit inhibitory function to develop, since the same findings were obtained when lesions were made neonatally or as adults. Rather, the authors suggest that the present findings arise because of the formation of functional, recurrent, excitatory mossy fiber collateral synapses following entorhinal cortex lesions.

Afferent Pathways↗
PubMed1993

The pattern of NADPH-diaphorase staining, a marker of nitric oxide synthase activity, is altered in the perforant pathway terminal zone in Alzheimer's disease.

NADPH-diaphorase positive neurons are relatively spared in Alzheimer's disease (AD). We show here, however, that the pattern of NADPH-diaphorase staining in the neuropil of the hippocampus changes dramatically in the brains of patients with AD. Control individuals displayed a striking band of NADPH-diaphorase staining in the middle 1/3 of the molecular layer of the dentate gyrus; this band was absent in AD. Staining in the molecular layer was reduced 18-31% in AD (P < 0.001) with the greatest loss in the most severely affected cases. NADPH diaphorase is thought to reflect the presence of nitric oxide synthase. Because nitric oxide has been implicated in long-term potentiation, changes in its expression could reflect loss of synapses important for memory formation.

Adult↗
PubMed1985

Perforant pathway-evoked long-term potentiation of CA1 neurons in the hippocampal slice preparation.

Previously, we have presented electrophysiological evidence reaffirming the existence of a controversial hippocampal pathway. These fibers are part of the perforant pathway and terminate directly on the CA1 cells. We now report that, in the hippocampal slice preparation, tetanic stimulation of the perforant pathway produces long-term potentiation (LTP) of CA1 cell responses. LTP of population spikes varied from 150% to 500%. The results were of interest because these axons synapse at distal sites on the apical dendrite. This location is usually thought to be a difficult site to evoke action potentials.

Animals↗
PubMed1998

Characterization of perforant path lesions in rodent models of memory and attention.

Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.

Animals↗
PubMed1998

Androgenic neurosteroids: anti-seizure effects in an animal model of epilepsy.

These studies investigate whether the neurosteroid and 5 alpha-reduced metabolite of testosterone (T), 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-Diol), has anti-seizure effects similar to its parent compound. In experiment 1, ovariectomized (ovx) Long-Evans rats (n = 20) were subcutaneously (s.c.) administered 32 mg/kg kainic acid or saline vehicle 10 min following 0.0, 3.0, or 7.5 mg/kg 3 alpha-Diol in 10% ethanol, propylene glycol vehicle (veh). During 2 h of observation of ictal activity, 3 alpha-Diol (3.0 and 7.5 mg/kg) prior to kainic acid significantly decreased the number and duration of partial and full seizures compared to the 0.0 3 alpha-Diol conditions and produced ictal activity that was comparable to 0.0 mg/kg 3 alpha-Diol no kainic acid controls (procedure controls). Animals that received 7.5 mg/kg 3 alpha-Diol prior to kainic acid had shorter latencies and distances to the hidden platform in a Morris Water Maze task than those that received 0.0 3 alpha-Diol, 1 week following ictal activity. Administration of 3 alpha-Diol (3.0 or 7.5 mg/kg) prior to kainic acid stimulation resulted in a greater number of identifiable neurons in the hilar region of the hippocampus, compared to 0.0 3 alpha-Diol condition. Experiment 2 was conducted to ascertain whether 3 alpha-Diol's anti-seizure effects were comparable to T and possibly a result of metabolism from T. Ovx rats (n = 36) were stereotaxically implanted with bipolar electrodes into the perforant pathway. One hour prior to perforant pathway stimulation, six rats were s.c. injected with either T (7.5 mg/kg), 3 alpha-Diol (7.5 mg/kg), 7.5 mg/kg T + 4MA (a 5 alpha-reductase inhibitor, 17 beta-N,N-diethylcarbamoyl-4-methyl-4aza,5 alpha-androstan-3-one), 4MA alone, 10% propylene glycol vehicle (veh) with perforant pathway stimulation, or veh without perforant pathway stimulation. 3 alpha-Diol and T produced similar seizure activity, water maze performance, and neuronal integrity in the hilar region of the hippocampus that were comparable to unstimulated controls. Because the T and 3 alpha-Diol groups were not different from T + 4MA but tended to be different from 4MA alone on these measures, this suggests that 3 alpha-Diol and T can have similar anti-seizure effects which may be due to actions of neurosteroids.

Anabolic Agents↗
PubMed1999

Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS.

This study evaluates the expression of the chemorepellent semaphorin III (D)/collapsin-1 (sema III) following lesions to the rat CNS. Scar tissue, formed after penetrating injuries to the lateral olfactory tract (LOT), cortex, perforant pathway, and spinal cord, contained numerous spindle-shaped cells expressing high levels of sema III mRNA. The properties of these cells were investigated in detail in the lesioned LOT. Most sema III mRNA-positive cells were located in the core of the scar and expressed proteins characteristic for fibroblast-like cells. Neuropilin-1, a sema III receptor, was expressed in injured neurons with projections to the lesion site, in a subpopulation of scar-associated cells and in blood vessels around the scar. In contrast to lesions made in the mature CNS, LOT transection in neonates did not induce sema III mRNA expression within cells in the lesion and was followed by vigorous axonal regeneration. The concomitant expression of sema III and its receptor neuropilin-1 in the scar suggests that sema III/neuropilin-1-mediated mechanisms are involved in CNS scar formation. The expression of the secreted chemorepellent sema III following CNS injury provides the first evidence that chemorepulsive semaphorins may contribute to the inhibitory effects exerted by scars on the outgrowth of injured CNS neurites. The vigorous regrowth of injured axons in the absence of sema III following early neonatal lesions is consistent with this notion. The inactivation of sema III in scar tissue by either antibody perturbation or by genetic or pharmacological intervention could be a powerful means to promote long-distance regeneration in the adult CNS.

Animals↗
PubMed1986

Modification of excitation and inhibition evoked in dentate gyrus by perforant path stimulation: effects of aminophylline and kindling.

Rats were implanted with chronic electrodes to stimulate the perforant path and record the elicited monosynaptic evoked potentials from the dentate gyrus of the hippocampal formation. Dentate responses were examined in awake and anesthetized animals after exposure to saline and aminophylline (100 mg/kg, IP). In the awake animal, aminophylline treatment did not significantly alter the threshold or elicited amplitude of either the excitatory post-synaptic potential (EPSP) or the population spike (PS). Aminophylline pretreatment markedly enhanced the length and severity of elicited seizures from hippocampal (dentate gyrus) or perforant pathway stimulation. After daily perforant pathway stimulations which established "kindled" seizures, aminophylline significantly increased only the amplitude of the evoked PS in awake animals. In animals anesthetized with chloropent, aminophylline increased significantly before kindling the amplitude of both the EPSP and PS without effecting thresholds for each. After perforant pathway kindling, only the PS amplitude was increased significantly by aminophylline. Inhibition, thought to be from GABA-mediated recurrent collaterals, was found to be increased rather than decreased by kindling. Further, aminophylline treatment did not result in reduction of this inhibition before or after kindling. These data suggest that at this dose of aminophylline neither enhanced transmitter release at this synapse as measured by the amplitude of the EPSP, nor reduced recurrent collateral inhibition significantly contributed to the prolongation of elicited seizure afterdischarge. The increase in PS amplitude reflecting an increased number of granule cells excited to discharge with perforant path stimulation after aminophylline was noted in awake animals but was greatest in the anesthetized animals. Although the number of granule cells excited to discharge was increased by aminophylline, the small increase in amplitude seen compared to the effects of other neurotoxins on this synapse makes this an unlikely explanation for the profound increased seizure response seen after aminophylline.

Aminophylline↗
PubMed2004

Distinct properties of presynaptic group II and III metabotropic glutamate receptor-mediated inhibition of perforant pathway-CA1 EPSCs.

I have compared the effects of group II or III metabotropic glutamate receptor (mGluR) activation on monosynaptic excitatory responses recorded intracellularly from CA1 pyramidal neurons of rat hippocampus and evoked by perforant pathway stimulation in vitro. The excitatory postsynaptic currents (EPSCs) were reduced either by the group II mGluR agonist LY354740 (500 nM, 31 +/- 6% of control) or by the group III agonist L-AP4 (400 microM, 53 +/- 5% of control). Both drugs enhanced EPSC paired-pulse facilitation (range 125-189% of control). These effects were blocked by the broad-spectrum mGluR antagonist LY341495 (1 or 20 microM) which when applied alone did not significantly change the EPSCs elicited at low (0.1-0.2 Hz) or higher (1-100 Hz) frequency of stimulation. Prior reduction of the EPSCs induced by L-AP4 did not occlude the subsequent inhibition elicited by LY354740. The effect of LY354740, but not that of L-AP4, was blocked in the presence of the cAMP analogue Sp-cAMPS (20 microM) and with the K(+) channel antagonist alpha-dendrotoxin (125 nM). In contrast, the effect of L-AP4, but not that of LY354740, was prevented by the calmodulin inhibitor ophiobolin A (25 microM) and with the N-type Ca(2+) channel antagonist omega-conotoxin-GVIA (1 microM). In the presence of the P/Q type Ca(2+) channel antagonist omega-agatoxin-IVA (400 nM), the EPSCs were depressed either by LY354740 or by L-AP4. Groups II and III mGluRs are segregated at the presynaptic terminal, and there are distinct differences between the properties of the presynaptic inhibition mediated by these two groups of receptors.

Amino Acids↗
PubMed1986

Anterograde transsynaptic transport of WGA-HRP in the limbic system of rat and monkey.

The lectin tracer, wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), was injected into the entorhinal cortex in rat and monkey brains. Tracer labeling was followed in the entorhinal projection to dentate gyrus and hippocampus, i.e. along the perforant pathway. Besides labeling perforant pathway terminals in the outer two-thirds of stratum moleculare in the dentate gyrus, reaction product was also observed within stratum granulosum. We conclude that labeling of dentate granule cells was the result of anterograde transsynaptic transport of WGA-HRP. The evidence thus provides an example of anterograde transsynaptic transport: in the limbic system; and at an excitatory synapse.

Animals↗
PubMed1989

Functional deficits after sustained stimulation of the perforant path.

Several reports have implicated the overactivity of hippocampal glutaminergic systems in neurodegenerative conditions including Senile dementia of the Alzheimer's type (SDAT). The neurobiological effects of hippocampal glutaminergic hyperactivity were studied by perforant pathway stimulation. Forty-five minutes of sustained perforant pathway stimulation produced a 50% or greater increase in motor activity 1, 2, and 3 weeks after stimulation. Robust retention deficits in a 48-h step-through passive avoidance task were evident 2 weeks post-stimulation. Furthermore, animals receiving stimulation were impaired in the acquisition of a spatial task in the Morris water maze. Stimulated animals exhibited little reduction in their escape latencies over the testing period. The learning and memory deficits were associated with a loss of CA1 and CA3 pyramidal cells and pretreatment with the N-methyl-D-aspartate antagonist MK-801 reduced this cell loss, particularly in the CA1 region of the hippocampus. These results suggest that sustained stimulation of the perforant pathway may be useful in studying neurological deficits associated with glutaminergic hyperfunction.

Animals↗
PubMed1993

Long-term potentiation of perforant path synapses in hippocampal CA1 in vitro.

This paper reports a study of long-term potentiation (LTP) of perforant path synapses in CA1. Using rat hippocampal slices with CA3 and the dentate gyrus removed, stimulation of the perforant path evoked a population excitatory postsynaptic potential (pEPSP) that was negative-going in s. lacunosum-moleculare of CA1. High-frequency conditioning stimulation of the perforant pathway induced LTP of the perforant path pEPSP in slices disinhibited by the GABAA receptor antagonist bicuculline methiodide (20 microM). Conditioning of the perforant pathway in normal medium, however, failed to induce LTP. Potentiation of the perforant path pEPSP in the presence of bicuculline lasted at least 1 h, was specific to the tetanized pathway, and based on a threshold property, appeared associative in nature.

Animals↗
PubMed2002

Kindling induces the mRNA expression of methyl DNA-binding factors in the adult rat hippocampus.

We have investigated the gene expression responses of a family of methyl CpG-binding domain-containing factors (MeCP2, MBD1, MBD2, and MBD3) in the hippocampus of electrically kindled rats. Expression was examined in both amygdala- and partial perforant-pathway-kindled subjects, 24 h and 28 days following the final stimulation. In general, the responses of MBDs 2 and 3 paralleled each another, both temporally and spatially. The expression of both genes was significantly elevated in all hippocampal subfields at 24 h following either the fifth stage 5 seizure (amygdala kindling) or the 15th stimulation of the perforant pathway. This induced expression was transient, however, as the expression of both genes returned to control levels by 28 days. This pattern of response contrasted to that observed for MeCP2 and MBD1. MeCP2 displayed no change in expression either 24 h or 28 days after amygdala kindling, but did display a late-developing, significant increase in expression in the dentate gyrus at 28 days following perforant-pathway kindling. The expression of MBD1 was unchanged by partial perforant-pathway kindling, but was induced in the dentate gyrus 28 days after amygdala kindling. These results demonstrate that electrical kindling alters the hippocampal expression of methyl DNA-binding factors, but does not affect each factor equivalently. The responsive patterns observed suggest that this family of transcriptional regulators can be differentially altered in the hippocampus by seizure activity.

Amygdala↗
PubMed1996

Fibroblast growth factor-2 protects entorhinal layer II glutamatergic neurons from axotomy-induced death.

The entorhinal cortex is a major relay between the hippocampus and other cortical and subcortical regions. Glutamatergic axons from layer II neurons form the entorhinal cortical projection to the hippocampus via the perforant pathway. We have demonstrated previously that lesion of the perforant pathway causes the death of approximately 30% of entorhinal layer II (ECL2) neurons. To elucidate mechanisms contributing to neuronal death and to investigate strategies preventing it, we identified the phenotype of the vulnerable neuronal population. Sections were immunolabeled with antibodies to the neuronal markers NeuN, glutamate, and calbindin-D28k, and to receptors for fibroblast growth factor-2 (FGFR1) and NMDA (NMDAR1) and were examined using confocal microscopy. Calbindin immunoreactivity was strikingly lamina-specific to ECL2, where one-third of all ECL2 neurons were calbindin-positive. Localization of glutamate revealed that half of the glutamatergic ECL2 neurons coexpressed calbindin. Quantification using unbiased stereology at 9 weeks after lesion of the perforant pathway revealed that the only ECL2 neuronal population that experienced a significant (70%) loss (20% of the total) was the population of glutamatergic ECL2 neurons that did not coexpress calbindin. All ECL2 neurons expressed FGFR1; therefore, we tested the role of FGF-2 in the survival of glutamatergic ECL2 neurons. We grafted fibroblasts genetically engineered to express nerve growth factor or FGF-2 and found that only FGF-2 grafts prevented loss of the vulnerable glutamatergic/calbindin-negative neurons. We present a hypothesis for the selective vulnerability of these glutamatergic/calbindin-negative ECL2 neurons and address the role of FGF-2 in neuronal rescue.

Afferent Pathways↗