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PubMed2005

Ripple activity in the dentate gyrus of dishinibited hippocampus-entorhinal cortex slices.

Fast oscillations at approximately 200 Hz, termed ripples, occur in the hippocampus and cortex of several species, including humans, and are thought to play a role in physiological (e.g., sensory information processing or memory consolidation) and pathological (e.g., seizures) processes. Blocking gamma-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition represents one of the most often used models of epileptiform discharge. Here we found that bath application of the GABA(A) receptor antagonist picrotoxin (50 microM) to mouse hippocampus-entorhinal cortex slices induced spontaneous epileptiform activity (duration 536.6 +/- 146.1 msec, mean +/- SD; interval of occurrence 14.8 +/- 3.3 sec, n = 12) with two distinct phases of discharge; the first was characterized, in the dentate gyrus only, by high-frequency, field oscillations (ripples) at 206.3 +/- 23.4 Hz (n = 12), whereas the second component corresponded to afterdischarges in the theta range frequency. Ripples, which were also recorded in "minislices" only of the dentate gyrus, were unaffected by application of the mu-opioid receptor agonist (D-Ala2-N-Me-Phe,Gly-ol)enkephalin (10 microM; n = 6) or the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxy-piperazine-4-yl)-propyl-l-phosphonate (10 microM; n = 5). In contrast, the non-NMDA glutamatergic receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (10 microM; n = 5) completely blocked all picrotoxin-induced activities. In addition, application of the GABA(B) receptor agonist baclofen (0.01-0.5 microM; n = 6) dose dependently and reversibly abolished all picrotoxin-induced activities. We also found that application of the gap-junction decouplers carbenoxolone (0.2-0.5 mM; n = 6) or octanol (0.2-0.5 mM; n = 3) blocked the second phase while leaving ripples unchanged. These findings demonstrate that the disinhibited dentate gyrus can generate ripple activity at approximately 200 Hz that is contributed by ionotropic glutamatergic mechanisms and is not dependent on either GABA(A) receptor-mediated or gap-junction mechanisms.

Analgesics, Opioid↗
PubMed1985

Lesion of the temporo-ammonic perforant path facilitates self-stimulation of the lateral entorhinal cortex in mice.

The effect of a lesion of the perforant path (PP) on self-stimulation (SS) of the lateral entorhinal cortex (LEC) was tested in mice between 8 and 21 days after surgery. The current intensities tested ranged between 0 and 80 microA (peak to peak 100 Hz sine-wave). The PP lesion led to a two-fold increase in SS rates at intensities above 30 microA without affecting the baseline SS rates (0 microA) and SS threshold (30 microA). The lesion also led to a significant increase in LEC after-discharge (AD) threshold and eliminated behavioral convulsions during SS testing. The suppression of AD by i.p. Na phenobarbital injection (10 mg/kg) led to a similar increase in SS rates in sham-lesioned mice; there was no difference in PP-lesioned animals. These results might be interpreted as evidence in favor of an independence of the neuronal processes mediating entorhinal and hippocampal reward-related behaviors.

Animals↗
PubMed2004

Dynamics of rat entorhinal cortex layer II and III cells: characteristics of membrane potential resonance at rest predict oscillation properties near threshold.

Neurones generate intrinsic subthreshold membrane potential oscillations (MPOs) under various physiological and behavioural conditions. These oscillations influence neural responses and coding properties on many levels. On the single-cell level, MPOs modulate the temporal precision of action potentials; they also have a pronounced impact on large-scale cortical activity. Recent studies have described a close association between the MPOs of a given neurone and its electrical resonance properties. Using intracellular sharp microelectrode recordings we examine both dynamical characteristics in layers II and III of the entorhinal cortex (EC). Our data from EC layer II stellate cells show strong membrane potential resonances and oscillations, both in the range of 5-15 Hz. At the resonance maximum, the membrane impedance can be more than twice as large as the input resistance. In EC layer III cells, MPOs could not be elicited, and frequency-resolved impedances decay monotonically with increasing frequency or has only a small peak followed by a subsequent decay. To quantify and compare the resonance and oscillation properties, we use a simple mathematical model that includes stochastic components to capture channel noise. Based on this model we demonstrate that electrical resonance is closely related though not equivalent to the occurrence of sag-potentials and MPOs. MPO frequencies can be predicted from the membrane impedance curve for stellate cells. The model also explains the broad-band nature of the observed MPOs. This underscores the importance of intrinsic noise sources for subthreshold phenomena and rules out a deterministic description of MPOs. In addition, our results show that the two identified cell classes in the superficial EC layers, which are known to target different areas in the hippocampus, also have different preferred frequency ranges and dynamic characteristics. Intrinsic cell properties may thus play a major role for the frequency-dependent information flow in the hippocampal formation.

Animals↗
PubMed1996

Unilateral neonatal hippocampal lesion alters septal innervation and trophism of the entorhinal cortex.

It is generally assumed that central nervous system injury sustained during development produces less severe behavioral deficits than damage in the adult, due to increased plasticity of the immature brain. However, developmental plasticity may also exacerbate deficits, presumably through formation of anomalous connections. Previous studies showed that after unilateral neonatal, but not adult, electrolytic hippocampal lesion spatial memory is severely impaired. To determine whether the memory deficit is correlated with anatomical changes in a major hippocampal afferent system, the septal input, the anterograde tracer Phaeseolus vulgaris leucoagglutinin was injected into the medial septum 2 months after unilateral neonatal hippocampal lesion. The density of septal fiber projections into the entorhinal cortex (EC) was found to be increased. Choline-acetyltransferase activity increased significantly in the EC 2 months postlesion, suggesting that septal cholinergic fibers are sprouting. Finally, nerve growth factor (NGF), which can mediate sprouting, was measured in the EC, NGF protein increased transiently 7 to 12 days postlesion in the ipsilateral EC, suggesting that increased trophic support is associated with growth of septal afferents into the EC. Thus, neonatal hippocampal lesion causes a reorganization of axonal connections associated with elevated NGF in the target region of the increased septal input. Moreover, since previous studies showed that the neonatal lesion is accompanied by a spatial memory deficit, this plasticity may compromise function of the remaining circuitry.

Animals↗
PubMed2001

Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion.

The apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for late-onset familial and sporadic Alzheimer's disease (AD) and is associated with a poor outcome after brain injury. Each apoE isoform is suggested to have differential effects on neuronal repair mechanisms within the CNS. In the present study, APOE genotype influence on the immediate response to injury and subsequent repair process was examined in a line of transgenic APOE mice possessing human APOE gene insertions (epsilon 3 and epsilon 4). Quantification of synaptophysin and GAP-43 immunoreactivity was used to measure the extent of degeneration and regeneration after entorhinal cortex lesion (ECL). Progressive neurodegenerative decline occurred in the ipsilateral dentate gyrus until day 28 post-ECL which was more severe in APOE epsilon 3 mice compared to APOE epsilon 4 mice. By day 90 post-ECL compensatory sprouting and reactive synaptogenesis had taken place in the dentate gyrus of APOE epsilon 3 mice such that GAP-43 and synaptophysin immunoreactivity had returned to prelesion levels. In contrast, APOE epsilon 4 mice displayed significant deficits in synaptophysin and GAP-43 immunostaining compared to the APOE epsilon 3 mice (P < 0.05). Expansion of the inner molecular layer (IML) was used as a measure of the sprouting index from the commissural-associational pathway and by day 90 post-ECL the IML width in APOE epsilon 3 mice had increased by 45% but only 20% in APOE epsilon 4 mice (P < 0.0001). ApoE immunoreactivity was increased within the neuropil and glia to the same extent in APOE epsilon 3 and APOE epsilon 4 mice post-ECL. There was no significant difference in the deposition and clearance of degeneration products between APOE epsilon 3 and epsilon 4 mice post-ECL. These results indicate that neuronal plasticity is impaired in transgenic mice possessing human APOE epsilon 4 alleles compared to APOE epsilon 3. These isoform-specific differences in plasticity may relate to the severity of AD and poor, long-term recovery after head injury in APOE epsilon 4 individuals.

Alzheimer Disease↗
PubMed1999

A relative energy failure is associated with low-Mg2+ but not with 4-aminopyridine induced seizure-like events in entorhinal cortex.

During seizure-like events (SLEs), intracellular Ca2+ concentration ([Ca2+]i) increases causing depolarization of the mitochondrial membrane and subsequent intramitochondrial accumulation of Ca2+. Mitochondrial depolarization results in an interruption of oxidative phosphorylation and increase in reactive oxygen species. Calcium activates enzymes of the citrate cycle. A characteristic feature of the low-Mg2+-induced SLEs is that they are transformed to a late activity refractory to anticonvulsant drugs, which may be regarded as a model system of difficult to treat status epilepticus. In contrast, 4-aminopyridine (4-AP)-induced activity rarely evolves to such late activity. The autofluorescence of NAD(P)H was used to monitor changes in cellular energy metabolism in the entorhinal cortex in two in vitro models of focal epilepsy. During repetitive 4-AP-induced SLEs there was a short decrease followed by a long-lasting overshoot of the NAD(P)H signal. This sequence remained unaltered during recurring SLEs. In contrast, during recurrent low-Mg2+-induced SLEs, the brief initial NADH signal reduction was unchanged but the following overshoot of NADH displayed a continuous decrease. This indicates a relative energy failure, which may contribute to the transformation to late activity in the low-Mg2+ model.

4-Aminopyridine↗
PubMed2004

Axonal connections from posterior paralaminar thalamic neurons to basomedial amygdaloid projection neurons to the lateral entorhinal cortex in rats.

Stimulation of amygdaloid nuclei and emotionally relevant stimuli are known to influence the induction and maintenance of long-term potentiation in the hippocampal formation and the formation of long-term declarative memories. Because the thalamic projection from the posterior paralaminar thalamic nuclei is an important sensory afferent projection to amygdaloid nuclei mediating the fast acquisition of fear-potentiated behavior, we were interested in verifying whether this projection establishes synaptic contacts on amygdala neurons that project to the hippocampal formation. Thalamic afferents were labeled with the anterograde tracer Phaseolus vulgaris leucoagglutinin and amygdalo-hippocampal neurons were identified by injection of the retrograde tracer Fluorogold into the lateral entorhinal cortex. A massive overlap of both projection systems was observed especially in the anterior basomedial nucleus of the amygdala. Light microscopic examination revealed that single anterogradely labeled boutons were in close apposition to retrogradely labeled neurons suggesting synaptic contacts. The occurrence of such synaptic contacts was confirmed with electron microscopy. However, despite the massive overlap of anterogradely labeled axons and retrogradely labeled neurons observed at the light microscopic level, electron microscopy revealed that only 10% of all labeled profiles make direct contacts on each other; anterogradely labeled boutons predominantly contacted unlabeled profiles but synapses with direct contact between labeled profiles were rare. Altogether the findings demonstrate that the thalamic connection with the basomedial nucleus of the amygdala may represent an anatomical substrate for modulating amygdala output to the hippocampal formation.

Amygdala↗
PubMed2000

Evidence for spatial modules mediated by temporal synchronization of carbachol-induced gamma rhythm in medial entorhinal cortex.

Fast (gamma) oscillations in the cortex underlie the rapid temporal coordination of large-scale neuronal assemblies in the processing of sensory stimuli. Cortical gamma rhythm is modulated in vivo by cholinergic innervation from the basal forebrain and can be generated in vitro after exogenous cholinergic stimulation. Using the isolated guinea pig brain, an in vitro preparation that allows for the study of an intact cerebrum, we studied the spatial features of gamma activity evoked by the cholinomimetic carbachol (CCh) in the medial entorhinal cortex (mEC). gamma activity induced by either arterial perfusion or intraparenchymal application of CCh showed a phase reversal across mEC layer II and was reduced or abolished in a spatially localized region by focal infusions of atropine, bicuculline, and CNQX. In addition, a spatially restricted zone of gamma activity could be induced by passive diffusion of CCh from a recording pipette. Finally, gamma oscillations recorded at multiple sites across the surface of the mEC using array electrodes during arterial perfusion of CCh demonstrated a decline in synchronization (coherence) as the interelectrode distance increased. This effect was independent of the signal amplitude and was specific for gamma as opposed to theta-like activity induced by CCh in the same experiments. These results suggest that CCh-induced gamma oscillations in the mEC are mediated through direct muscarinic excitation of a highly localized reciprocal inhibitory-excitatory network located in superficial layers. We propose that functional cortical modules of highly synchronous gamma oscillations may organize incoming (cortical) and outgoing (hippocampal) information in the mEC.

Animals↗
PubMed1980

Decline in reactive fiber growth in the dentate gyrus of aged rats compared to young adult rats following entorhinal cortex removal.

The reaction of septal and commissural-associational afferents in the dentate gyrus was examined at various times following a unilateral entorhinal lesion in 2- and 3-month-old, 12- to 18-month-old and 25--30-month-old rats. The response of septo-hippocampal fibers was examined histochemically by staining for acetylcholinesterase (AChE) activity; and that of commissural-associational fibers by the Holmes' fiber stain. In 2- and 3-month-old rats, AChE staining fibers, which project to the outer three-fourths of the molecular layer of the dentate gyrus, increased their staining intensity within 5--6 days following lesion of the entorhinal cortex. The rate of the response and the eventual magnitude declined progressively with the age of the subject. In 2- and 3-month-old rats, the commissural-associational fiber plexus appeared to expand partially into the entorhinal zone within 6 days following the lesion. This response also decreased progressively in rate and magnitude with age. Animals in the oldest age group showed at 12 days after the lesion a greater variability in the expansion of the commissural-associational fiber plexus than all younger groups. Astrocytes in the dentate molecular layer appeared to become more abundant and more hypertrophied in unoperated animals with age. The appearance of astrocytes in 25- to 30-month-old rats was similar to that seen in 2- and 3-month-old animals following an entorhinal lesion. An entorhinal lesion in the aged animals did not appear to cause a marked change in the appearance of astrocytes.

Aging↗
PubMed2006

Calcium binding protein containing neurons in the gliotic mouse hippocampus with special reference to their afferents from the medial septum and the entorhinal cortex.

In CA1 area and the hilus of the dentate gyrus of the mouse hippocampus, drastic reduction of NeuN, calbindin, calretinin, or parvalbumin immunopositive neurons was shown at 3, 7 and 60 days after pilocarpine-induced status epilepticus. In gliotic CA1 area at 60 days, few dendritic branches of calcium binding protein immunopositive neurons could be found suggesting reorganization of the afferents of surviving calcium binding protein immunopositive neurons. Calbindin, calretinin, or parvalbumin and 5-bromo-2'-deoxyuridine (BrdU) double labeling showed that calcium binding protein immunopositive neurons in gliotic CA1 area at 60 days were surviving instead of newly generated neurons. Iontophoretic injection of Phaseolus vulgaris leucoagglutinin into the medial septum and the nucleus of the diagonal band of Broca or the lateral entorhinal cortex showed contacts between Phaseolus vulgaris leucoagglutinin immunopositive en passant and terminal boutons and surviving calcium binding protein immunopositive neurons in the hippocampus. The presence in the gliotic hippocampus of enlarged and/or aggregated bouton-like structures 60 days after pilocarpine-induced status epilepticus is indicative for the reorganization of connections between the hippocampal afferents and surviving hippocampal neurons. This reconstruction could be a factor in the ongoing epileptic activity in this model of mesial temporal lobe epilepsy.

Afferent Pathways↗
PubMed1999

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Age Factors↗
PubMed1992

Carbachol-induced theta-like activity in entorhinal cortex slices.

The present study was conducted for two purposes: the first was to evaluate whether activation of cholinergic receptors of the entorhinal cortex in vitro (complete deafferentation) with carbachol (100 microM) was capable of producing theta (theta)-like slow activity. The second purpose was to determine whether carbachol-induced slow waveforms were mediated by muscarinic or nicotinic receptors. We demonstrated that carbachol was capable of producing theta-like slow activity. This activity was not altered by nicotinic antagonists, (+)-tubocurarine and hexametonium. Atropine and scopolamine, in contrast, completely blocked in vitro induced slow waves, indicating entorhinal muscarinic receptors to be actively involved in the mechanism generating cholinergic theta rhythm.

Animals↗
PubMed2000

Distribution of the receptor-anchoring protein gephyrin in the rat dentate gyrus and changes following entorhinal cortex lesion.

We analyzed the distribution of the receptor-anchoring protein gephyrin in the normal and deafferented rat dentate gyrus to investigate whether the expression of this postsynaptic protein is altered in response to the formation of new synaptic contacts. Confocal microscopy and digital image analysis revealed that in normal dentate gyrus immunolabeling was most prominent in the outer molecular layer and decreased successively in the direction of the granule cell layer. Simultaneous immunolabeling for gephyrin and cell-specific markers showed that granule cells and parvalbumin-positive interneurons express gephyrin. Large, intensely stained, gephyrin-positive clusters were distributed along distinct dendrites, and most of them were positive for parvalbumin. Calbindin-immunostained dendrites were associated with smaller, gephyrin-positive clusters. Lesion of the medial entorhinal cortex leads to deafferentiation of the middle molecular layer which resulted in an increased gephyrin immunoreactivity. These changes were due to a significantly increased concentration of the very small gephyrin-positive clusters. Parvalbumin-positive dendrites did not display any increase in co-localizing gephyrin-positive structures. The altered immunolabeling pattern persisted until 12 weeks after lesion, a time when the process of synaptic reorganization is complete. Our findings suggest that synaptogenesis following deafferentiation results in a cell-specific redistribution of gephyrin immunoreactivity at specific inhibitory synapses.

Age Factors↗
PubMed1987

Neuronal sources of theta rhythm in the entorhinal cortex of the rat. I. Laminar distribution of theta field potentials.

The laminar distribution of theta (theta) field potentials in the entorhinal cortex (EC) was investigated in paralysed and locally anesthetized rats injected with physostigmine in order to induce theta rhythm. Electrode penetrations through the medial, intermediate and lateral subdivisions of the EC showed in all cases: 1. the presence of theta rhythm from layer VI to layer III approximately in phase with CA1 theta rhythm; 2. an amplitude minimum between the outer third of layer III and the inner half of layer I; and 3. a phase-reversed theta rhythm in layers II-I with an amplitude maximum in the outer half of layer I. Results indicate the existence of neuronal sources of theta rhythm in the EC.

Action Potentials↗
PubMed1987

Synaptic organization of olfactory inputs and local circuits in the entorhinal cortex: a current source density analysis in the cat.

The distribution of the olfactory afferents within the ventrolateral part of the entorhinal cortex (EC) was studied by means of field potentials evoked by stimulation of the olfactory bulb (OB) and the olfactory cortex (PPC). Depth profiles of the field potentials evoked by OB or PPC stimulation were studied using current source density analysis. After OB or PPC stimulation an early superficial sink-deep source configuration was found, which some time later reversed into a superficial source-deep sink. Both OB and PPC activated mainly the superficial dendrites of the cells of layers II and III. In layers II and III evidence for strong recurrent inhibition was found, using double pulse stimulation. The results indicate that there exists a common basic design of the synaptic organization of the olfactory areas of the base of the brain extending to the EC.

Action Potentials↗
PubMed1984

Late post-learning effect of entorhinal cortex electrical stimulation persists despite destruction of the perforant path.

In an appetitive learning task in mice, stimulation of the lateral entorhinal cortex (LEC) 30 min after training produced an improvement in retention 24 h later, as well as faster extinction of conditioning. This effect persisted in animals with bilateral lesions of the perforant path. In addition, the threshold for hippocampal after-discharges produced by LEC stimulation was raised significantly in perforant-path lesioned animals. The results indicate a functional dissociation between hippocampal and cortical mechanisms involved in memory consolidation.

Animals↗
PubMed1986

Evidence implicating dentate granule cells in wet dog shakes produced by kindling stimulations of entorhinal cortex.

We studied the occurrence of wet dog shakes during the evolution of kindling induced by electrical stimulation of the lateral entorhinal cortex. Wet dog shakes occur with high incidence, particularly early in development of kindling. We also demonstrated that microinjection of colchicine into the hippocampus, but not into neocortex, produced a 95% suppression of wet dog shakes. We propose that the suppressive effect of colchicine is mediated by destruction of dentate granule cells. Together with evidence from other investigations, these data support the idea that activation of hippocampal neurons is essential for production of wet dog shakes induced by stimulation of the limbic system.

Animals↗
PubMed1986

Opioid-receptor blockade reduces nose-poke self-stimulation derived from medial entorhinal cortex.

Rats were trained to nose-poke for intracranial self-stimulation (SS) with electrodes unilaterally implanted in the medial entorhinal cortex. The acute effects of naloxone (NX; 0.1-10 mg/kg, IP) on a continuous reinforcement schedule were determined. Reductions in the self-stimulation rates occurred only at moderate doses (median of individual changes = -36% at 1 and 5 mg/kg), whereas the high dose (10 mg/kg) was ineffective. None of the doses influenced operant behavior. These results are consistent with the hypothesis that endogenous opioid-opiate receptor mechanisms play a modulatory role in SS reward. Considering that NX was administered systemically the action of the drug on reinforcement levels may be mediated by a site distinct from the locus of stimulation.

Animals↗