Layers Of Entorhinal Cortex Research Articles

Interictal high-frequency oscillations (80-500 Hz) in the human epileptic brain: entorhinal cortex.

Unique high-frequency oscillations of 250 to 500 Hz, termed fast ripples, have been identified in seizure-generating limbic areas in rats made epileptic by intrahippocampal injection of kainic acid, and in patients with mesial temporal lobe epilepsy. In the rat, fast ripples clearly are generated by a different neuronal population than normally occurring endogenous ripple oscillations (100-200 Hz), but this distinction has not been previously evaluated in humans. The characteristics of oscillations in the ripple and fast ripple frequency bands were compared in the entorhinal cortex of patients with mesial temporal lobe epilepsy using local field potential and unit recordings from chronically implanted bundles of eight microelectrodes with tips spaced 500 microm apart. The results showed that ripple oscillations possessed different voltage versus depth profiles compared with fast ripple oscillations. Fast ripple oscillations usually demonstrated a reversal of polarity in the middle layers of entorhinal cortex, whereas ripple oscillations rarely showed reversals across entorhinal cortex layers. There was no significant difference in the amplitude distributions of ripple and fast ripple oscillations. Furthermore, multiunit synchronization was significantly increased during fast ripple oscillations compared with ripple oscillations (p < 0.001). These data recorded from the mesial temporal lobe of epileptic patients suggest that the cellular networks underlying fast ripple generation are more localized than those involved in the generation of normally occurring ripple oscillations. Results from this study are consistent with previous studies in the intrahippocampal kainic acid rat model of chronic epilepsy that provide evidence supporting the view that fast ripples in the human brain reflect localized pathological events related to epileptogenesis.

Memory impairment in temporal lobe epilepsy: the role of entorhinal lesions

Temporal lobe epilepsy (TLE) patients are frequently afflicted with deficits in spatial and other forms of declarative memory. This impairment is likely associated with the medial temporal lobe, which suffers widespread damage in the disease. Physiological and lesion studies, as well as examinations of the complex connectivity of the medial temporal lobe in animals and humans, have identified the entorhinal cortex (EC) as a key structure in the function and dysfunction of this brain region. Lesions in EC layer III, which normally provides monosynaptic input to area CA1 of the hippocampus, frequently occur in TLE and may be causally related to the memory impairments seen in the disease. Lesions that are initially largely restricted to EC layer III can be produced in rats by focal intra-entorhinal injections of ‘indirect excitotoxins’ such as aminooxyacetic acid or γ-acetylenic GABA. These animals eventually show more extensive neurodegeneration in temporal lobe structures and, after a latent period, exhibit spontaneously recurring seizure activity. These progressive features, which may mimic events that occur in TLE, provide new opportunities to explore the role of the EC in memory deficits associated with TLE. These animals will also be useful for evaluating new treatment strategies that focus on the prevention of pathological events in the EC.

Variation in Effective Stimulus Patterns for Induction of Long-Term Potentiation Across Different Layers of Rat Entorhinal Cortex

Neuronal activities in superficial (II and III) and deep (V and VI) layers of the entorhinal cortex (EC) are preferentially modulated by theta and sharp wave (SPW) EEG, respectively. We investigated the possibility that distinct EEG patterns represent optimal stimulus patterns for induction of long-term potentiation (LTP) in different layers of the EC. We examined effects of three different stimulation patterns on LTP induction in layers I, II-III, and V of medial EC slices of the rat. The stimulation patterns we used were a single, long high-frequency train (1 sec at 100 Hz, repeated 3x), theta burst stimulation [TBS; 10 bursts (four pulses, 100 Hz) at 5 Hz, repeated 3x], and SPW-like burst stimulation [ SPWBS; three bursts (20 pulses, 200 Hz) at 2 Hz, repeated 6x]. Similar degrees of LTP were induced by the three stimulation patterns in layer I. In layers II--III and layer V, however, the largest degrees of LTP were induced by TBS and SPWBS, respectively. These results suggest that burst stimulation constructed to mimic naturally occurring patterns of neuronal activity in the corresponding layer is optimal for LTP induction in layers II-III and layer V of the EC. The differences may play important roles in shaping hippocampal-neocortical interactions in encoding and retrieval of memory.

Excitatory Afferents to the Entorhinal Cortex Play a Role in Temporal Lobe Epileptogenesis

Ibotenate Injections into the Pre- and Parasubiculum Provide Partial Protection Against Kainate-Induced Epileptic Damage in Layer III of Rat Entorhinal Cortex PurposeA loss of neurons in layer III of the entorhinal cortex (EC) is often observed in patients with temporal lobe epilepsy and in animal models of the disorder. We hypothesized that the susceptibility of layer III of the EC to prolonged seizure activity might be mediated by excitatory afferents originating in the presubiculum. MethodsExperiments were designed to ablate the presubiculum unilaterally by focal ibotenate injections and to evaluate the effect of this deafferentation on the vulnerability of EC layer III neurons to the chemoconvulsant kainate (injected systemically 5 days later). ResultsAfter treatment with kainate, 11 of the 15 rats preinjected with ibotenate showed clear-cut, partial neuroprotection in layer III of the EC ipsilateral to the ibotenate lesion. Serial reconstruction of the ibotenate-induced primary lesion revealed that entorhinal neurons were protected only in animals that had lesions in the pre- and parasubiculum, especially in the deep layers (IV-VI). ConclusionsThe deep layers of the pre- and parasubiculum appear to control the seizure-induced damage of EC layer III. This phenomenon may be of relevance for epileptogenesis and for the pathogenesis of temporal lobe epilepsy.

Excitatory Afferents to the Entorhinal Cortex Play a Role in Temporal Lobe Epileptogenesis.

Ibotenate Injections into the Pre- and Parasubiculum Provide Partial Protection Against Kainate-Induced Epileptic Damage in Layer III of Rat Entorhinal Cortex Eid T, Du F, Schwarcz R Epilepsia 2001;42:817–824 Purpose A loss of neurons in layer III of the entorhinal cortex (EC) is often observed in patients with temporal lobe epilepsy and in animal models of the disorder. We hypothesized that the susceptibility of layer III of the EC to prolonged seizure activity might be mediated by excitatory afferents originating in the presubiculum. Methods Experiments were designed to ablate the presubiculum unilaterally by focal ibotenate injections and to evaluate the effect of this deafferentation on the vulnerability of EC layer III neurons to the chemoconvulsant kainate (injected systemically 5 days later). Results After treatment with kainate, 11 of the 15 rats preinjected with ibotenate showed clear-cut, partial neuroprotection in layer III of the EC ipsilateral to the ibotenate lesion. Serial reconstruction of the ibotenate-induced primary lesion revealed that entorhinal neurons were protected only in animals that had lesions in the pre- and parasubiculum, especially in the deep layers (IV-VI). Conclusions The deep layers of the pre- and parasubiculum appear to control the seizure-induced damage of EC layer III. This phenomenon may be of relevance for epileptogenesis and for the pathogenesis of temporal lobe epilepsy.

Kainic acid and seizure-induced Fos in subtypes of cerebrocortical neurons

Kainic acid injected in vivo into adult rats evokes the expression of the immediate early gene c-fos in the dentate gyrus and associated structures before a seizure occurs and in these and additional regions after a single motor seizure. The aim of this study was to identify cortical cell classes expressing Fos that correlate with these phenomena. Fos expression occurred before a seizure in the middle layers of entorhinal cortex in excitatory neurons and predominantly in calbindin D28-K-containing inhibitory neurons. Given the early Fos-labeling of these cells, we suggest they are associated with the hippocampal EEG events also seen at this stage of the effects of kainic acid. After a motor seizure Fos induction occurred in primary motor, sensory, piriform and entorhinal cortices, mainly in excitatory neurons, but also in a proportion of calcium binding protein-containing neurons proportionate to the degree of activation of the region as determined by Fos. Nearly 100% of neurons were Fos+ in entorhinal cortex, whereas 80% of excitatory and 50% of calcium binding protein-containing neurons were Fos+ in piriform cortex with lower proportions in neocortex. Of the calcium binding protein-containing neocortical neurons, calbindin D28-K cells exhibited the highest proportion of double labeling with Fos. This pattern of neocortical activation by kainic acid, a glutamate agonist, is only slightly different to that seen after seizures caused by blockade of gamma aminobutyric acid receptors suggesting that seizures caused by different mechanisms utilize similar neo-cortical circuitry. J Neurosci. Res. 66:1094–1100, 2001. © 2001 Wiley-Liss, Inc.

Cholinergic modulation of synaptic physiology in deep layer entorhinal cortex of the rat.

We have recently shown that cholinergic effects on synaptic transmission and plasticity in the superficial (II/III) layers of the rat medial entorhinal cortex (EC) are similar, but not identical, to those in the hippocampus (Yun et al. [2000] Neuroscience 97:671-676). Because the superficial and deep layers of the EC preferentially convey afferent and efferent hippocampal projections, respectively, it is of interest to compare cholinergic effects between the two regions. We therefore investigated the physiological effects of cholinergic agents in the layer V of medial EC slices under experimental conditions identical to those in the previous study. Bath application of carbachol (0.5 microM) induced transient depression of field potential responses in all cases tested (30 of 30; 18.5% +/- 2.3%) and rarely induced long-lasting potentiation (only 3 of 30; 20.4% +/- 3.2% in successful cases). At 5 microM, carbachol induced transient depression only (20 of 20, 48.9% +/- 2.8%), which was blocked by atropine (10 microM). Paired-pulse facilitation was enhanced during carbachol-induced depression, suggesting presynaptic action of carbachol. Long-term potentiation (LTP) could be induced in the presence of 10 microM atropine by theta burst stimulation, but its magnitude was significantly lower (9.1% +/- 4.7%, n = 15) compared to LTP in control slices (22.4% +/- 3.9%, n = 20). These results, combined with our previous findings, demonstrate remarkably similar cholinergic modulation of synaptic transmission and plasticity across the superficial and deep layers of EC.

Estrogen (E2) and glucocorticoid (Gc) effects on microglia and Aβ clearance in vitro and in vivo

The accumulation of fibrillar aggregates of beta Amyloid (Aβ) in Alzheimer's Disease (AD) brain is associated with chronic brain inflammation. Although activated microglia (μglia) can potentially clear toxic amyloid, chronic activation may lead to excessive production of neurotoxins. Recent epidemiological and clinical data have raised questions about the use of anti-inflammatory steroids (glucocorticoids, Gcs) and estrogens for treatment or prevention of AD. Since very little is known about steroid effects on μglial interactions with amyloid, we investigated the effects of the synthetic Gc dexamethasone (DXM) and 17-β estradiol (E2) in vitro in a murine μglial-like N9 cell line on toxin production and intracellular Aβ accumulation. To determine whether the steroid alterations of Aβ uptake in vitro had relevance in vivo, we examined the effects of these steroids on Aβ accumulation and μglial responses to Aβ infused into rat brain. Our in vitro data demonstrate for the first time that Gc dose-dependently enhanced μglial Aβ accumulation and support previous work showing that E2 enhances Aβ uptake. Despite both steroids enhancing uptake, degradation was impeded, particularly with Gcs. Distinct differences between the two steroids were observed in their effect on toxin production and cell viability. Gc dose-dependently increased toxicity and potentiated Aβ induction of nitric oxide, while E2 promoted cell viability and inhibited Aβ induction of nitric oxide. The steroid enhancement of μglial uptake and impedence of degradation observed in vitro were consistent with observations from in vivo studies. In the brains of Aβ-infused rats, the μglial staining in entorhinal cortex layer 3, not associated with Aβ deposits was increased in response to Aβ infusion and this effect was blocked by feeding rats prednisolone. In contrast, E2 enhanced μglial staining in Aβ-infused rats. Aβ-immunoreactive (ir) deposits were quantitatively smaller, appeared denser, and were associated with robust μglial responses. Despite the fact that steroid produced a smaller more focal deposit, total extracted Aβ in cortical homogenate was elevated. Together, the in vivo and in vitro data support a role for steroids in plaque compaction. Our data are also consistent with the hypothesis that although E2 is less potent than Gc in impeding Aβ degradation, long term exposure to both steroids could reduce Aβ clearance and clinical utility. These data showing Gc potentiation of Aβ-induced μglial toxins may help explain the lack of epidemiological correlation for AD. The failure of both steroids to accelerate Aβ degradation may explain their lack of efficacy for treatment of AD.

A novel fluorescent method for direct visualization of neurofibrillary pathology in Alzheimer's disease

Methods currently available for detecting neurofibrillary pathology are indirect and depend on staining with exogenous chemicals or antibodies. In the present study, we report a novel method named intrinsic fluorescence induction (IFI), which allows direct visualization of neurofibrillary tangles (NFTs), neuropil threads (NTs), and neuritic plaques (NPs) in tissue sections of Alzheimer's disease (AD) brain. The IFI method is based on both induction of a red intrinsic fluorescence and quenching red background autofluorescence. The IFI procedure includes sustained hydrophobic treatment, protein secondary structure enhancement and incubation in high concentration of phosphate buffer. Following this procedure, a unique red fluorescence is generated from the structures of NFTs, NTs, and NPs in brain sections from AD patients. Sequential application of mild permanganate oxidation and 1% sodium borohydride selectively removes the red background autofluorescence, while the latter enhances the intrinsic fluorescence of neurofibrillary pathology. Comparative studies reveal that the IFI method is as sensitive as Gallyas silver staining, and more sensitive than Bielschowsky silver staining or PHF-1 immunostaining in detecting NFTs in the pre-α layer of entorhinal cortex and the pri-α layer of the entorhinal/transentorhinal cortex. Furthermore, the IFI method is sensitive in displaying plaque neurites and threads, but not NFTs in the hippocampus. This novel finding provides a direct method for detecting neurofibrillary pathology in particular regions of AD brain and a novel tool for AD research.

Ibotenate injections into the pre- and parasubiculum provide partial protection against kainate-induced epileptic damage in layer III of rat entorhinal cortex.

A loss of neurons in layer III of the entorhinal cortex (EC) is often observed in patients with temporal lobe epilepsy and in animal models of the disorder. We hypothesized that the susceptibility of layer III of the EC to prolonged seizure activity might be mediated by excitatory afferents originating in the presubiculum. Experiments were designed to ablate the presubiculum unilaterally by focal ibotenate injections and to evaluate the effect of this deafferentation on the vulnerability of EC layer III neurons to the chemoconvulsant kainate (injected systemically 5 days later). After treatment with kainate, 11 of the 15 rats preinjected with ibotenate showed clear-cut, partial neuroprotection in layer III of the EC ipsilateral to the ibotenate lesion. Serial reconstruction of the ibotenate-induced primary lesion revealed that entorhinal neurons were protected only in animals that had lesions in the pre- and parasubiculum, especially in the deep layers (IV-VI). The deep layers of the pre- and parasubiculum appear to control the seizure-induced damage of EC layer III. This phenomenon may be of relevance for epileptogenesis and for the pathogenesis of temporal lobe epilepsy.

Activation of presynaptic group III metabotropic glutamate receptors depresses spontaneous inhibition in layer V of the rat entorhinal cortex

Whole cell voltage clamp recording was used to investigate neurotransmitter release onto neurones in deep and superficial layers of rat entorhinal cortex in vitro. Activation of metabotropic glutamate receptors with the agonist (1 S,3 R,4 S)-1-aminocyclopentane-1,2,4-tricarboxylic acid depressed spontaneous release of the inhibitory neurotransmitter GABA in layer V, but not in layer II. Depression of transmitter release did not persist in the presence of the sodium channel blocker tetrodotoxin. It seems likely that activation of presynaptic glutamate heteroreceptors inhibits action potential dependent release of neurotransmitter via a direct action at the presynaptic terminal. We confirmed that depression of inhibitory neurotransmission in layer V was mediated by group III metabotropic glutamate receptors using a specific group III antagonist, ( RS)-cyclopropyl-4-phosphonophenylglycine. Application of the antagonist alone did not alter the frequency of spontaneous neurotransmitter release, suggesting that the metabotropic glutamate receptor is not tonically active. In layer V of the entorhinal cortex, activation of presynaptic metabotropic glutamate receptors enhances spontaneous glutamate release, and inhibits spontaneous release of GABA. These effects may combine to increase random action potential firing in this layer, thereby reducing its capacity for synchrony generation. Our results are consistent with an anticonvulsant action for group III metabotropic glutamate receptors in the entorhinal cortex.

Uncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptors alter the mRNA expression of proteins associated with the NMDA receptor complex.

N-methyl-D-aspartate (NMDA) receptor function appears to be under complex control during physiological and pharmacological states. We have investigated the effects of acute administration of uncompetitive NMDA receptor antagonists on mRNA levels of NMDA receptor subunits and on molecules known to cluster or phosphorylate the receptor utilizing in situ hybridization on rat brain sections. A high dose (5 mg/kg; 4 hr) of dizocilpine (MK-801) decreased mRNA levels of NMDA receptor subunits NR2C and NR2B in the entorhinal and parietal cortices, respectively. MK-801 increased mRNA levels of synapse-associated protein-90/postsynaptic density-95 (SAP90/PSD-95) and a gamma-isoform of protein kinase C (PKCgamma) in cortical regions. Synapse-associated protein-97 (SAP97) mRNA levels were increased in the entorhinal cortex layer III after MK-801 or after relatively high doses of other uncompetitive NMDA receptor antagonists: phencyclidine (15 mg/kg; 6 hr) and memantine (50 mg/kg; 6 hr). Memantine also increased SAP97 mRNA expression in other cortical regions, but this effect was not observed with MK-801 or phencyclidine. NMDA receptor uncompetitive antagonists alter the expression of multiple receptor components and such events may ultimately play a role in adaptation or toxic responses.

Properties of entorhinal cortex deep layer neurons projecting to the rat dentate gyrus.

Medial entorhinal cortex (EC) deep layer neurons projecting to the dentate gyrus (DG) were studied. Neurons, retrogradely-labelled with rhodamine-dextran-amine were characterized electrophysiologically with the patch clamp technique and finally labelled with biocytin. Pyramidal and nonpyramidal neurons form projections from the deep layers of the EC to the molecular layer of the DG. In addition, both classes of projection neurons send ascending axon collaterals to the superficial layers of the EC. Both classes of neurons were characterized physiologically by regular action potential firing upon depolarizing current injection. While a substantial number of pyramidal projection cells showed intrinsic membrane potential oscillations, none of the studied nonpyramidal cells exhibited oscillations. Despite the morphological similarity of bipolar and multipolar cells to those of GABAergic interneurons in the EC, their electrophysiological characteristics were similar to those of principal neurons and immunocytochemistry for GABA was negative. We conclude, that neurons of the deep layers of the medial EC projecting to the DG may function as both local circuit and projecting neurons thereby contributing to synchronization between deep layers of the EC, superficial layers of the EC and the DG.

Persistent sodium channel activity mediates subthreshold membrane potential oscillations and low-threshold spikes in rat entorhinal cortex layer V neurons

Entorhinal cortex layer V occupies a critical position in temporal lobe circuitry since, on the one hand, it serves as the main conduit for the flow of information out of the hippocampal formation back to the neocortex and, on the other, it closes a hippocampal–entorhinal loop by projecting upon the superficial cell layers that give rise to the perforant path. Recent in vitro electrophysiological studies have shown that rat entorhinal cortex layer V cells are endowed with the ability to generate subthreshold oscillations and all-or-none, low-threshold depolarizing potentials. In the present study, by applying current-clamp, voltage-clamp and single-channel recording techniques in rat slices and dissociated neurons, we investigated whether entorhinal cortex layer V cells express a persistent sodium current and sustained sodium channel activity to evaluate the contribution of this activity to the subthreshold behavior of the cells. Sharp-electrode recording in slices demonstrated that layer V cells display tetrodotoxin-sensitive inward rectification in the depolarizing direction, suggesting that a persistent sodium current is present in the cells. Subthreshold oscillations and low-threshold regenerative events were also abolished by tetrodotoxin, suggesting that their generation also requires the activation of such a low-threshold sodium current. The presence of a persistent sodium current was confirmed in whole-cell voltage-clamp experiments, which revealed that its activation “threshold” was negative by about 10 mV to that of the transient sodium current. Furthermore, stationary noise analysis and cell-attached, patch-clamp recordings indicated that whole-cell persistent sodium currents were mediated by persistent sodium channel activity, consisting of relatively high-conductance (∼18 pS) sustained openings. The presence of a persistent sodium current in entorhinal cortex layer V cells can cause the generation of oscillatory behavior, bursting activity and sustained discharge; this might be implicated in the encoding of memories in which the entorhinal cortex participates but, under pathological situations, may also contribute to epileptogenesis and neurodegeneration.

Projections from the hippocampal and parahippocampal regions to the entorhinal cortex. An anterograde and retrograde tract-tracing study in the cat.

Projections from the hippocampal and parahippocampal regions to the entorhinal cortex (EC) were examined in the cat by anterograde and retrograde tract-tracing with Phaseolus vulgaris leucoagglutinin and cholera toxin B subunit. CA1 fibers to EC were distributed more densely in the medial EC than in the lateral EC; these were seen in all EC layers, but most densely in layers II and III. The septotemporal axis of the area of origin of CA1-EC fibers corresponded to a caudal-to-rostral axis of the area of their termination in the EC. CA2 and CA4 also sent a small number of fibers to the EC. The subiculum sent fibers mainly to the lateral EC; more densely to layers IV-VI than to layers I-III. The septotemporal axis of the area of origin of subiculum-EC fibers corresponded to a caudolateral-to-rostromedial axis of their termination in the EC. Distribution pattern of fibers from the prosubiculum regions close to CA1 or from prosubiculum regions close to the subiculum was similar to that of CA1 fibers or subiculum fibers, respectively. The presubiculum sent fibers mainly to the medial EC; most densely to layers I and III. The parasubiculum sent fibers mainly to the medial EC; most densely to layer II. Fibers to the contralateral EC were detected only from the presubiculum; they originated from the superficial layers and terminated in layer III of the medial entorhinal area.

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Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. Several studies have demonstrated that RIN has a significant anticonvulsant effect in many types of epilepsy models in vivo. However, the mechanisms of the anticonvulsant effect remain elusive. Using combined methods of behavioral testing, immunofluorescence and electrophysiological recordings, we characterized the anticonvulsant effect of RIN in a pilocarpine-induced status epilepticus (SE) rat model of temporal lobe epilepsy (TLE) and investigated the underlying cellular mechanisms. In one set of experiments, rats received RIN treatment prior to pilocarpine injection. In a second set of experiments, rats received RIN treatment following the onset of stage 3 seizures. Pretreatment and posttreatment with RIN effectively reduced the seizure severity in the acute phase of TLE. Furthermore, RIN protected medial entorhinal cortex (mEC) layer III neurons from neuronal death and terminated spontaneous epileptiform discharge of mEC layer II neurons in SE-experienced rats. Whole-cell voltage-clamp recordings indicated that RIN inhibited neuronal hyperexcitability via inhibition of the persistent sodium current (INaP) and NMDA receptor current. Immunofluorescence experiments also demonstrated that RIN rectified the pilocarpine-induced upregulation of Nav1.6 and NR2B protein expression. In conclusion, our results identified RIN as an anticonvulsant agent that inhibited ictal discharge via INap and NMDA receptor current inhibition.

Kainic acid and seizure-induced Fos in subtypes of cerebrocortical neurons.

Kainic acid injected in vivo into adult rats evokes the expression of the immediate early gene c-fos in the dentate gyrus and associated structures before a seizure occurs and in these and additional regions after a single motor seizure. The aim of this study was to identify cortical cell classes expressing Fos that correlate with these phenomena. Fos expression occurred before a seizure in the middle layers of entorhinal cortex in excitatory neurons and predominantly in calbindin D28-K-containing inhibitory neurons. Given the early Fos-labeling of these cells, we suggest they are associated with the hippocampal EEG events also seen at this stage of the effects of kainic acid. After a motor seizure Fos induction occurred in primary motor, sensory, piriform and entorhinal cortices, mainly in excitatory neurons, but also in a proportion of calcium binding protein-containing neurons proportionate to the degree of activation of the region as determined by Fos. Nearly 100% of neurons were Fos+ in entorhinal cortex, whereas 80% of excitatory and 50% of calcium binding protein-containing neurons were Fos+ in piriform cortex with lower proportions in neocortex. Of the calcium binding protein-containing neocortical neurons, calbindin D28-K cells exhibited the highest proportion of double labeling with Fos. This pattern of neocortical activation by kainic acid, a glutamate agonist, is only slightly different to that seen after seizures caused by blockade of gamma aminobutyric acid receptors suggesting that seizures caused by different mechanisms utilize similar neo-cortical circuitry.

Amyloid beta-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex.

The deposition of the amyloid beta-protein (Abeta) is a pathological hallmark of Alzheimer's disease (AD). Abeta is a peptide consisting of 39-43 amino acids and is derived by beta- and gamma-secretase cleavage from the Abeta protein precursor (AbetaPP). An N-terminal-truncated form of Abeta can occur following alpha- and gamma-secretase cleavage of AbetaPP. Fleecy amyloid is a recently identified distinct type of Abeta deposits occurring in the internal layers (pri-alpha, pri-beta and pri-gamma) of the human entorhinal cortex. Fleecy amyloid consists exclusively of N-terminal-truncated Abeta and is a transient form of Abeta deposits, which disappears in late-stage beta-amyloidosis. In this study, the entorhinal cortex of 15 cases with AD-related pathology was used to examine astrocytes in the vicinity of N-terminal-truncated Abeta in fleecy amyloid of the layers pri-alpha, pri-beta, and pri-gamma in comparison to astrocytes in the vicinity of full-length Abeta in layers pre-beta and pre-gamma. Immunohistochemistry was performed with antibodies directed against AbetaPP, Abeta40, Abeta42, APbeta17-24, Abeta1-17 and Abeta8-17 as well as by double-labeling with antibodies directed against Abeta17-24, Abeta42, and glial fibrillary acid protein (GFAP). A large number of GFAP-positive astrocytes containing N-terminal-truncated Abeta fragments appeared in the vicinity of N-terminal-truncated Abeta, whereas Abeta-containing astrocytes were rarely seen in the vicinity of full-length Abeta. These results suggest that N-terminal-truncated Abeta peptide may be cleared preferentially from the extracellular space by astrocytic uptake and processing. Such an astroglial uptake of N-terminal-truncated Abeta may account for the transient nature of fleecy amyloid and point to the use of N-terminal truncation of Abeta in potential therapeutic strategies aimed at preventing the brain from amassing full-length Abeta deposits.

Propagation of synchronous burst discharges from entorhinal cortex to morphologically and electrophysiologically identified neurons of rat lateral amygdala

Intracellular and field potential recordings were taken from the lateral nucleus of the amygdala in a rat horizontal brain slice preparation that included hippocampal formation. Pyramidal cells comprised the majority of labeled cells (77%). Electrophysiological classification based on hyperpolarizing or depolarizing afterpotentials subdivided both the pyramidal and non-pyramidal cell classes, although pyramidal cells tended to have hyperpolarizing afterpotentials (70%) and non-pyramidal cells tended to have depolarizing afterpotentials (63%). Synchronous population bursts were triggered with single extracellular stimuli in the deep layers of entorhinal cortex. These events propagated from deep layers of entorhinal cortex into the lateral nucleus of the amygdala. Latencies were consistent with a direct entorhinal to amygdala projection. Individual lateral nucleus neurons exhibited responses ranging from a long burst response that included an initial period of 200 Hz firing and a tail of gamma frequency firing lasting over 100 ms (grade 1) to an epsp with no firing (grade 4). Half of pyramidal cells responding to events initiated in entorhinal cortex were found to receive epsps strong enough to trigger firing. Only one stellate neuron fired in response to entorhinal stimulation. Excitatory postsynaptic responses included NMDA and non-NMDA receptor mediated components. We demonstrate that synchronous population events can propagate from entorhinal cortex to the lateral nucleus of the amygdala and that pyramidal neurons of the lateral nucleus are more common targets than stellate neurons. We conclude that other synchronous events such as sharp waves and interictal spikes can spread from entorhinal cortex to amygdala in the same manner.

The laminar pattern of connections between prefrontal and anterior temporal cortices in the Rhesus monkey is related to cortical structure and function.

The laminar pattern of axonal termination from prefrontal (caudal orbitofrontal, rostral orbitofrontal and lateral areas) to anterior temporal areas (entorhinal cortex, perirhinal cortex and area TE) and from temporal to prefrontal areas was investigated with the aid of anterograde tracers. Both regions are characterized by structural heterogeneity, and include agranular, dysgranular and granular cortical types, denoting, respectively, the absence, incipience and presence of granular layer 4. In addition, both the prefrontal and anterior temporal cortices are composed of areas that have related though specialized functions. The pattern of cortical axonal termination was associated with both the structural type of the cortex of origin and the structure of the destination cortex. Thus, efferent fibers from a single origin in either prefrontal or anterior temporal cortex terminated in different patterns depending on their target area. Conversely, axons terminated in different patterns in a single target area, prefrontal or anterior temporal, depending on their area of origin. Projections from agranular or dysgranular type cortices (e.g. medial temporal areas and caudal orbitofrontal areas) terminated mostly in the upper layers of granular cortices (e.g. area TE and lateral prefrontal areas), and projections from granular cortices terminated mostly in the deep layers of agranular or dys- granular cortices. A robust projection from dysgranular orbitofrontal areas terminated in the deep layers of the agranular entorhinal cortex. Projections from prefrontal areas to area TE terminated in the upper layers, and may facilitate focused attention on behaviorally relevant stimuli processed through reciprocal pathways between prefrontal and temporal cortices.