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PubMed1987

Alzheimer's disease: glutamate depletion in the hippocampal perforant pathway zone.

The perforant pathway is the primary source of cortical input to the hippocampal formation. Its cells of origin, in the entorhinal cortex, are destroyed in Alzheimer's disease. Because the principal neurotransmitter of the perforant pathway's excitatory action is thought to be glutamate, we microdissected a portion of the pathway's terminal zone and assayed the excised tissue for glutamate. There was an 83% decrease in the level of free glutamate in subjects with Alzheimer's disease as compared to control subjects not affected by dementia (p less than 0.005). We believe that this diminution in the glutamate content is a direct neurochemical correlate of perforant pathway destruction and that disruption of this crucial corticolimbic pathway contributes to the memory dysfunction in Alzheimer's disease.

Aged↗

PubMed1987

Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease.

The perforant pathway originates from the entorhinal cortex of the anterior parahippocampal gyrus and terminates on the outer dendritic branches of the granule cells of the dentate gyrus and pyramidal cells of the subiculum and hippocampus. It carries the principal cortical input to the hippocampal formation. Destruction of the perforant pathway in experimental animals leads to a partial deafferentation of its target neurons, followed by a robust sprouting of acetylcholinesterase (AChE) terminals in the deafferented perforant pathway zone. In Alzheimer's disease, the cells of origin of the perforant pathway are laden with neurofibrillary tangles. AChE staining in the terminal zone of the perforant pathway in Alzheimer's disease shows several distinct patterns that are not found in control brains. These changes are consistent with the results of experimental studies demonstrating reinnervation in laboratory mammals, including nonhuman primates. The results suggest that in Alzheimer's disease sprouting of AChE-containing systems occurs in the hippocampal formation in response to disease-related cellular damage in the entorhinal cortex.

Acetylcholinesterase↗

PubMed2003

Membrane properties of identified lateral and medial perforant pathway projection neurons.

The physiological characteristics of neurons that project to the hippocampus and dentate gyrus via the medial perforant pathway (projection neurons) are well known, but the characteristics of neurons that project to these areas via the lateral perforant pathway (projection neurons) are less well known. We have used retrograde tracing and whole-cell recording in brain slices to compare the membrane and firing properties of medial perforant pathway and lateral perforant pathway projection neurons in layer II of the medial and lateral entorhinal cortex. The properties of medial perforant pathway projection neurons were identical to those reported previously for spiny stellate neurons in the medial entorhinal cortex. In contrast, lateral perforant pathway projection neurons were characterized by a higher input resistance, a lack of time-dependent inward (anomalous) rectification, and a lack of prominent depolarizing spike afterpotentials. Voltage-clamp recordings suggest that the absence of anomalous rectification in lateral perforant pathway projection neurons is due to smaller hyperpolarization activated cation currents in these cells, and the lack of depolarizing afterpotential may be due to smaller low-threshold calcium currents. Persistent sodium current was also smaller in lateral perforant pathway projection neurons, but the difference in persistent sodium current between medial perforant pathway and lateral perforant projection neurons was much less pronounced than the difference in low voltage activated currents. These results underscore the functional differences between the medial entorhinal cortex and lateral entorhinal cortex, and may help to explain the differing abilities of these cortical areas to participate in certain types of network activity.

Action Potentials↗

PubMed1986

Perforant pathway changes and the memory impairment of Alzheimer's disease.

The perforant pathway is a large neuronal projection that arises from layers II and III of the entorhinal cortex of the parahippocampal gyrus. It is the principal source of cortical input to the hippocampal formation. In 11 cases of Alzheimer's disease, we have found that neurofibrillary tangles develop in the cells of origin of the perforant pathway. In addition, the termination zone of the perforant pathway, in the outer two thirds of the molecular layer of the dentate gyrus, contains a distinct layer of neuritic plaques. None of the 8 control subjects had such changes. These profound alterations effectively disconnect the hippocampal formation from the association and limbic cortices. Because of the central role of the hippocampus and parahippocampal gyrus in learning, it is likely that pathological changes in the perforant pathway, by precluding normal hippocampal operation, account for some aspects of the memory impairment in Alzheimer's disease.

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PubMedDate not supplied

Alzheimer's disease and aging: effects on perforant pathway perikarya and synapses.

The hippocampal perforant pathway originates in the entorhinal cortex (ERC) and terminates in the outer molecular layer of the dentate gyrus (DG). To compare the effects of normal aging and Alzheimer's disease (AD) on the elements of the perforant pathway, we compared relative perikaryal numbers (determined by counting cell bodies and estimating volumes) in layer II of the ERC with synaptic quantities (estimated from immunoreactivity for the synaptic terminal protein synapsin I and DG volume) in the molecular layer of the DG. The brains of 5 young and 9 elderly cognitively normal individuals, and of 9 AD patients were studied. In normal aging we found a significant age-related decline in perikaryal numbers in the ERC without demonstrable synaptic loss in the DG. In AD there was marked and equivalent, (or proportional) reduction in both ERC perikaryal numbers and DG synapses. These data suggest that in normal aging remaining neurons may continue to support a full array of synapses, perhaps due to mechanisms such as axonal sprouting, synaptic enlargement, or synaptic ingrowth. In AD, however, the accelerated neuronal loss may overwhelm such compensatory mechanisms or alternatively, independent synaptic and perikaryal losses may occur.

Adult↗

PubMed1997

Alzheimer's disease, Lewy body disease and aging: a comparative study of the perforant pathway.

The relationship between Alzheimer's disease (AD) and Lewy body disease (LBD) is poorly understood. In AD there is severe loss of neurons comprising the perforant pathway. To assess perforant pathway integrity in pure LBD we compared neuronal counts in layer II of the entorhinal cortex (ERC) in 11 cases of pure LBD that did not meet CERAD pathologic criteria for AD with ERC neuronal counts from seven AD cases with a similar disease duration and six cognitively normal individuals. We counted cell bodies/island in layer II of the ERC using formalin-fixed, paraffin-embedded, tau/cresyl violet-stained sections at the level of the rostral-most body of the hippocampus. There was marked variability in neuronal counts among cases in the LBD group; LBD data overlapped with data from both normal and AD groups. Overall, perforant pathway perikaryal counts in LBD differed significantly from those in AD, but not from those in aged normals (mean perikarya/island = 30.09 +/- 8.95, 7.57 +/- 6.08, and 38.83 +/- 8.98, respectively; F = 26.131, P < 0.001). The percent of remaining neurons bearing neurofibrillary tangles in LBD also overlapped with AD and control groups (16.17 = 13.85%, 87.86 +/- 11.81%, and 24.36 +/- 13.30% of remaining neurons, respectively, F = 65.62, P < 0.001). We conclude that although perforant pathway neuronal loss may occur in LBD, it is more often milder and more variable than that seen in AD.

Adult↗

PubMed1988

A direct demonstration of the perforant pathway terminal zone in Alzheimer's disease using the monoclonal antibody Alz-50.

The perforant pathway links the entorhinal cortex with the hippocampal formation and provides this structure with its major cortical input. The cells of origin of the perforant pathway are destroyed in Alzheimer's disease (AD) and a marked depletion of glutamate, the putative neurotransmitter in its terminal zone, occurs. We report that the monoclonal antibody Alz-50 recognizes an antigen in the terminal zone of the perforant pathway in AD. This observation provides direct evidence for the involvement of the perforant pathway in AD, and demonstrates that Alz-50 can be used to study neural connectivity in AD brains.

Alzheimer Disease↗

PubMed1995

Type 4a metabotropic glutamate receptor: identification of new potent agonists and differentiation from the L-(+)-2-amino-4-phosphonobutanoic acid-sensitive receptor in the lateral perforant pathway in rats.

Before the discovery of the metabotropic glutamate receptors (mGluRs), the glutamate analogue L-2-amino-4-phosphonobutanoic acid (L-AP4) was identified as a potent presynaptic inhibitor of evoked synaptic transmission in the lateral perforant pathway in rats. The localization and L-AP4 sensitivity of the mGluR4a subtype of mGluRs were consistent with the hypothesis that this receptor mediates the synaptic depressant effects of L-AP4 in the lateral perforant pathway. In the present study, the pharmacology of mGluR4a expressed in baby hamster kidney 570 cells was characterized and compared with that previously reported for the lateral perforant pathway responses. The endogenous excitatory amino acid L-aspartate was inactive at mGluR4a, whereas L-homocysteic acid was only 5-fold less potent than L-glutamate. These data suggest that L-homocysteic acid may be an endogenous agonist at mGluR4a. Of the 30 L-AP4 analogues examined, several compounds were identified as agonists at mGluR4a. The cyclopropyl-AP4 analogue (Z)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid inhibited forskolin-stimulated cAMP production with an EC50 of 0.58 microM, which is comparable to that of L-AP4 (EC50 = 0.43 microM). Two other cyclic analogues of L-AP4 were approximately 10-fold less potent as agonists at mGluR4a, i.e., (+/-)-1-amino-3-(phosphonomethylene)cyclobutanecarboxylic acid (EC50 = 4.4 microM) and (E)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid (EC50 = 7.9 microM). Comparison of the potencies of the compounds for activation of mGluR4a with their potencies for inhibition of lateral perforant pathway responses demonstrates that some compounds have comparable activities in the two systems, whereas several compounds are at least 10-fold more potent in one of the systems. In addition, although the mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine blocked the effects of L-AP4 in the lateral perforant pathway, it did not block the effects of L-AP4 at the cloned receptor. These data provide evidence that mGluR4a does not mediate the effects of L-AP4 in the lateral perforant pathway, they provide new tools to identify the function of these receptors in the mammalian central nervous system, and they indicate that the effects of L-AP4 in the lateral perforant pathway are mediated by a (+)-alpha-methyl-4-carboxyphenylglycine-sensitive receptor.

Aminobutyrates↗

PubMed2002

Phosphorylation of P42/P44 MAP kinase and DNA fragmentation in the rat perforant pathway stimulation model of limbic epilepsy.

The intracellular signaling pathways associated with neuronal injury after perforant pathway stimulation of the rodent hippocampus have not been examined. To determine whether activation of the p42/p44 (Erk1/2) MAP kinase (MAPK) phosphorylation cascade is linked to neuronal injury after perforant pathway stimulation (PPS), we stained for phosphorylated Erk1/2 (P-Erk1/2) and for DNA fragmentation, a marker of cell death after PPS. Eighteen Sprague-Dawley rats underwent PPS for 6 (n=6), 12 (n=6), or 24 (n=6) h and were sacrificed either immediately (n=9) or 48 h (n=9) after stimulation. Sham-operated non-stimulated control animals (n=2) and control animals receiving low frequency stimulation only (n=4) were also examined. Brain sections were stained for DNA fragmentation and P-Erk1/2. DNA fragmentation was evident only in granule cells and CA3 pyramidal cells of the stimulated side 48 h after 24 h of PPS. PPS resulted in robust phosphorylation of Erk1/2 that displayed a stereotyped timecourse, appearing first in hilar neurons on the ipsilateral side and later in hilar neurons, granule cells, hippocampal pyramidal and non-neuronal cell populations on both the stimulated and contralateral sides. Both Erk1/2 phosphorylation and DNA fragmentation show definite and reproducible staining patterns after PPS that vary based on duration of stimulation. Populations displaying Erk1/2 activation appeared to differ from those showing DNA fragmentation and neuronal injury.

Animals↗

PubMed2001

Tau, beta-amyloid and beta-amyloid precursor protein distribution in the entorhinal-hippocampal alvear and perforant pathways in the Alzheimer's brain.

It has been suggested that the pathological lesions of Alzheimer's disease (AD) spread along neuronal connections. This study was designed to examine this hypothesis in the alvear and perforant pathways, two well-defined neuroanatomical pathways that project from the entorhinal cortex to the hippocampus. Paraffin-sections of hippocampal-entorhinal cortex from 25 AD cases were immunolabelled for tau, beta-amyloid (Abeta) and beta-amyloid precursor protein (betaAPP). We used image-analysis to quantify immunolabelling at both ends of the alvear and perforant pathways. At the beginning and the end of the alvear pathway, area of immunolabelling in microm2 per area of field (72000 microm2) were as follows: tau 349 and 821 (P<0.01), Abeta 349 and 61 (P<0.05) and betaAPP 18 and 73 (P<0.01). Corresponding values for the perforant pathway were tau 421 and 387, Abeta 382 and 115 (P<0.05) and betaAPP 55 and 83. Tau was significantly greater at the end than at the beginning of the alvear pathway, but similar at both ends of the perforant pathway. There was significantly more Abeta at the beginning than at the end of the alvear and perforant pathway. These results at least in part reinforce previous work [19] that tau-rich areas may be neuronally connected to Abeta-rich areas.

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PubMed1999

Cyclic withdrawal from endogenous and exogenous progesterone increases kainic acid and perforant pathway induced seizures.

Antiseizure effects of progesterone (P) and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha, 5alpha-THP) were investigated following continuous vs. discontinuous P exposure. In Experiments 1, 32 cycling Long-Evans rats were administered kainic acid (32 mg/kg SC), ictal behavior was examined, and plasma 3alpha,5alpha-THP levels were measured by radioimmunoassay. Proestrus/estrus rats showed less ictal activity and had elevated 3alpha,5alpha-THP levels prior to kainic acid compared to diestrus/metestrus subjects. In Experiment 2, 49 ovariectomized (ovx) rats were SC injected with estradiol benzoate (EB; 10 microg) and P (500 microg), to mimic estrus, or sesame oil vehicle (0.2 cc); all subjects were administered kainic acid. Rats tested with EB+P showed a reduced mean duration of full seizures and increased 3alpha,5alpha-THP, whereas those tested 24 h following EB+P had more tonic clonic seizures and lower 3alpha,5alpha-THP concentrations, comparable to ovx control animals. In Experiment 3, 49 ovx rats were stereotaxically implanted with bipolar electrodes into the perforant pathway. Prior to perforant pathway stimulation, rats received cholesterol or EB+P capsules for 1 month, continuously or intermittently. Irrespective of continuous or intermittent EB+P, the presence of progestins at the time of perforant pathway stimulation reduced partial seizure activity. Continuous EB+P capsules resulted in increased 3alpha,5alpha-THP levels compared to all other conditions, and less damage in the hilus of the hippocampus, compared to intermittent EB+P. These data confirm that P and 3alpha,5alpha-THP have antiseizure effects, and further suggest that repeated cycles of endogenous or exogenous P and/or 3alpha,5alpha-THP withdrawal influences seizure threshold and/or hippocampal integrity.

Animals↗

PubMed2000

GABA(B) receptors couple to potassium and calcium channels on identified lateral perforant pathway projection neurons.

Activation of presynaptic GABA(B) receptors inhibits neurotransmitter release at most cortical synapses, at least in part because of inhibition of voltage-gated calcium channels. One synapse where this is not the case is the lateral perforant pathway synapse onto dentate granule cells in the hippocampus. The current study was conducted to determine whether the neurons that make these synapses express GABA(B) receptors that can couple to ion channels. Perforant pathway projection neurons were labeled by injecting retrograde tracer into the dorsal hippocampus. The GABA(B) receptor agonist baclofen (10 microM) activated inwardly rectifying potassium channels and inhibited currents mediated by voltage-gated calcium channels in retrogradely labeled neurons in layer II of the lateral entorhinal cortex. These effects were reversed by coapplication of the selective GABA(B) receptor antagonist CGP 55845A (1 microM). Equivalent effects were produced by 100 microM adenosine, which inhibits neurotransmitter release at lateral perforant pathway synapses. The effects of baclofen and adenosine on inward currents were largely occlusive. These results suggest that the absence of GABA(B) receptor-mediated presynaptic inhibition at lateral perforant pathway synapses is not simply due to a failure to express these receptors and imply that GABA(B) receptors can either be selectively localized or regulated at terminal versus somatodendritic domains.

Adenosine↗

PubMed1997

Alterations of AMPA-selected glutamate subtype immunoreactivity in the dentate gyrus after perforant pathway lesion.

Immunocytochemical techniques were employed to examine the changes in immunolabeling of the alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionate (AMPA) receptor subunits GluR1 and GluR2/3 within the dentate gyrus 1, 3, 7, 14, 30, and 90 days after a unilateral perforant pathway lesion in the rat brain. Completeness of the lesion was confirmed following examination of Nissl-stained tissue sections at all times post-lesion and acetylcholinesterase (AChE)-stained sections 14, 30 and 90 days post-lesion, the latter providing evidence of compensatory sprouting of cholinergic fibers in the outer molecular layer of the dentate gyrus. Compared to the non-lesioned hippocampus there was no difference in the staining pattern of AMPA receptor subunits in the dentate gyrus of the deafferented hippocampus 1, 3, 7 and 14 days following lesioning of the perforant pathway. In contrast, 30 and 90 days post-lesion, GluR1 immunolabeling was increased in the outer molecular layer of the dentate gyrus (i.e., deafferented zone) ipsilateral to lesion. Likewise, GluR2/3 immunolabeling was increased within the same region although the intensity of the response was less than that which was observed for GluR1. These data suggest that the loss of the perforant pathway fibers results in a compensatory increase in GluR1 and to a lesser extent GluR2/3 immunolabeling of the outer molecular layer at 30 and 90 days post-lesion and further suggest that AMPA receptor subunits play a role in perforant pathway signal transduction.

Animals↗

PubMed2001

Simultaneous activation and opioid modulation of long-term potentiation in the dentate gyrus and the hippocampal CA3 region after stimulation of the perforant pathway in freely moving rats.

Recent investigations indicate monosynaptic activation by the perforant pathway (pp) of the dentate gyrus and the CA3 region. While short-term potentiation and long-term potentiation (LTP) and its opioid modulation are frequently described for the dentate gyrus, data for the CA3 region are rare. Therefore, evoked potentials and opioid modulation of LTP were directly compared in both target regions of the pp. Male Wistar rats were chronically implanted with a bipolar stimulation electrode in the pp (angular bundle) and two recording electrodes in the dorsal dentate gyrus and the CA3 region. Stimulation of the pp in the freely behaving animals induced short-latency evoked potentials in both target structures which were compared with respect to waveform, latency, amplitude and signs of short- and long-term neuronal plasticity. The short-latency potential in the CA3 region seemed to be a monosynaptic potential which displayed LTP sensitive to the N-methyl-D-aspartate receptor antagonist, MK 801, and depotentiating stimulation. After application of specific opioid antagonists at the mu-, delta- and kappa-opioid receptor subtypes, naloxone, funaltrexamine, naltrindole and binaltorphimine, different effects on induction and maintenance of LTP of the population spike were found both within the dentate gyrus and between the dentate gyrus and the CA3 region. The results show marked diminution of LTP in the dentate gyrus only for naloxone and naltrindole and only small, if any, effects of naloxone on LTP in the CA3 region. Thus, neuronal plasticity in the direct perforant pathway input to the CA3 region seems not to be under such substantial opioidergic control. LTP would be inducible in that region even when LTP in the input formation, the dentate gyrus, and transsynaptic LTP via the mossy fibres are blocked.

Animals↗

PubMed2002

Alterations of NMDAR1 and NMDAR2a/B immunoreactivity in the hippocampus after perforant pathway lesion.

Immunohistochemical techniques were employed to examine the changes in immunolabeling of the N-methyl-D-aspartate (NMDA) receptor subunits NMDAR1 and NMDAR2A/B within the hippocampus 1, 3, 7, 14 and 30 days after a unilateral perforant pathway lesion was made in a rat brain. At 1 day post-lesion, we observed a decrease in NMDAR1 immunolabeling in the granule cells in the dentate gyrus as well as in the mossy cells in the polymorphic region ipsilateral to the lesion, while an increase in diffuse neuropil labeling was observed. At 3 days post-lesion, we observed a marked increase in NMDAR1 immunolabeling in the outer molecular-layer of the dentate gyrus as well as in the stratum moleculare in the CA fields ipsilateral to the lesion. Although this increase was less marked at 7 and 14 days post-lesion, an increase in NMDAR1 immunolabeling was evident at 30 days post-lesion. In contrast, although a transient increase in NMDAR2A/B immunolabeling was observed in the outer molecular layer at 3 days post-lesion, no other changes were detectable at any of the time points examined. Our study suggests that each subunit of the NMDA receptor displays a different response to deafferentation of the perforant pathway. We have previously observed that changes in the immunoreactivity of the receptor subunits of another class of glutamate receptor, a-amino-3-hydroxy-5-methyl-4-isoaxolepropionate (AMPA), occur at 30 days post-lesion but not after a relatively short survival time. NMDA receptor subunits demonstrate an earlier response to the loss of the perforant pathway fibers than do the AMPA receptor subunits.

Animals↗

PubMed2000

Anti-seizure effects of progesterone and 3alpha,5alpha-THP in kainic acid and perforant pathway models of epilepsy.

The mechanism by which progesterone has its anti-seizure effects is unknown. Progesterone has a high affinity for intracellular progestin receptors, but has weak actions at gamma-aminobutyric acid (GABA)(A) receptors complexes. The progesterone metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) is devoid of activity at intracellular progestin receptors but is a highly effective modulator of GABA(A) receptor complexes. Whether progesterones anti-seizure actions are due to effects of progesterone itself or its metabolite 3alpha,5alpha-THP was investigated. In experiment 1, 25 ovariectomized Long-Evans rats were subcutaneously (s.c.) injected with 0.0, 4.0 or 8.0 mg/kg progesterone or 3alpha,5alpha-THP, 10 min prior to systemic administration of 32 mg/kg kainic acid. Four and 8.0 mg/kg progesterone significantly reduced the duration of partial and full seizures, without influencing the latency to partial or full seizures, or the number of partial or full seizures. 3alpha, 5alpha-THP (4.0 mg/kg) significantly increased the latency to initial partial seizure, and decreased the number and duration of partial seizures. In experiment 2, 60 ovariectomized Long-Evans rats were stereotaxically implanted with bipolar electrodes into the perforant pathway. Prior to perforant pathway stimulation, rats were s.c. injected with either progesterone (4.0 mg/kg, n = 12), 3alpha, 5alpha-THP (4.0 mg/kg, n = 13), progesterone (4.0 mg/kg)+4MA (10.0 mg of a 5alpha-reductase inhibitor, 17b-N, N-diethylcarbamoyl-4-methyl-4-aza,5alpha-androstan-3-one, n = 12), 4MA+vehicle (n = 10), or sesame oil vehicle (n = 13). Administration of progesterone or 3alpha, 5alpha-THP, but not vehicle control, P+4MA, or 4MA, resulted in significant decreases in partial seizures. In experiment 3, whole brain progesterone and 3alpha,5alpha-THP were measured by radioimmunoassay in additional rats (n = 66) administered the hormonal milieu indicated in experiments 1 and 2. Data suggest anti-seizure effects of progesterone may be due, in part, to metabolism to 3alpha,5alpha-THP and subsequent actions at GABA(A) receptor complexes.

Animals↗

PubMedDate not supplied

Alteration in the pattern of nerve terminal protein immunoreactivity in the perforant pathway in Alzheimer's disease and in rats after entorhinal lesions.

Neurons in layer II of the entorhinal cortex consistently develop neurofibrillary tangles in Alzheimer's disease (AD). Experimental neuroanatomical studies have shown that these neurons give rise to the perforant pathway, a major excitatory projection to the hippocampal formation, which terminates in a discrete pattern in the outer portion of the molecular layer of the dentate gyrus. The distribution of two nerve terminal associated proteins, synaptophysin and NT75, was studied in the molecular layer of the dentate gyrus in AD and control cases to determine whether Alzheimer neuronal pathology is associated with loss of synaptic markers. In parallel studies, the effect of ablation of the entorhinal cortex in rats was evaluated. In AD as compared to controls, a decrease in synaptophysin immunostaining was evident in the terminal zone of the perforant pathway. NT75 nerve terminal immunostaining was too weak to interpret in the human hippocampal formation. Both synaptophysin and NT75 immunoreactivity were found in association with some neuritic plaques. In rats, entorhinal lesions resulted in diminished immunoreactivity for both synaptophysin and NT75 in the perforant pathway terminal zone. These results suggest that nerve terminal protein loss is a concomitant feature of neuronal pathology in AD.

Aged↗

PubMed1980

Influence of raphe nuclei on neuronal transmission from perforant pathway through dentate gyrus.

1. In chronically prepared, freely moving rats, electrical stimulation was applied to the perforant pathway and monosynaptic responses were recorded extracellularly in the ipsilateral dentate gyrus. In some tests a stimulus was also applied to the median raphe nucleus (mr) prior to activating the perforant pathway. Experiments were performed during two behavioral conditions: slow-wave sleep (SWS) and the still, alert state (SAL). Two varieties of evoked responses were recorded: those due to synchronous firing of neuronal action potentials (evoked action potentials or EAPs) and those produced by excitatory synaptic activity (evoked synaptic potentials or ESPs). 2. As reported previously (38), perforant path stimulation elicited EAPs of greater magnitude during SWS than during SAL. The application of a prior stimulus to mr (prestimulation) markedly increased the already elevated EAPs observed during SWS. The EAPs during SAL were unaffected by prestimulation. 3. The minimum delay time (time between mr and perforant path stimuli) at which the augmentation of the EAPs appeared during SWS was approximately 5 ms. The augmentation reached a maximum at delay times of 25-40 ms and was present up to a delay time of 150 ms. 4. As in former experiments (38), ESPs recorded in the molecular layer of the dentate gyrus after perforant path stimulation were found to be greater during SAL than during SWS. Prestimulation of mr had no significant effect on the ESPs at any level of the molecular layer during either SWS or SAL. 5. The perforant path afferent volley was recorded at high gain in the dentate gyrus. Its amplitude was found to be solely dependent on perforant path stimulus intensity and not on behavioral state or the prestimulation of mr. 6. In preparations anesthetized with Chloropent (82% chloral hydrate, 18% pentobarbital; Fort Dodge Laboratories, Fort Dodge, IA), prestimulation was applied at each of a number of loci within the pons and medulla, including mr, As in SWS, prestimulating mr resulted in augmented EAPs with a minimum delay time of 5 ms. Similar augmented responses were observed when stimulation was applied at other raphe nuclei (dorsal raphe, pontis, magnus, and pallidus), but there was no augmentation when stimulation was applied at other brain stem sites. Threshold stimulus intensities for producing augmented EAPs in the raphe nuclei were less than 30 microA. 7. In freely moving animals it was first established that the EAP responses during SWS were markedly greater than during SAL. Midline lesions were then made at the rostrocaudal level of mr. Following the lesions, there was no longer any significant difference in the magnitude of the EAPs recorded during the two behaviors. 8. These findings suggest that tonic influences arising from raphe nuclei during SWS may be involved in the facilitation of neuronal transmission through the dentate gyrus observed during this behavioral state.

Animals↗