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PubMed2002

Midline thalamic region: widespread excitatory input to the entorhinal cortex and amygdala.

The midline thalamus has a role in memory formation and has well described projections to multiple limbic sites including the hippocampus, amygdala, and entorhinal cortex. Stimulation of this region evokes excitatory responses in the CA1 region of the hippocampus, but nothing is known about the nature of thalamic influence on other limbic sites such as the entorhinal cortex and the amygdala. In this study we electrically stimulated the midline thalamus in anesthetized rats to determine whether responses could be evoked in the amygdala or entorhinal cortex. In addition we examined the distribution of the responses within the target regions as well as the effect of short interval paired or high-frequency tetanizing stimulation. We found reproducible responses in the entorhinal cortex and the amygdala with a distribution of responses that matched the described synaptic input from the thalamus. In addition, high-frequency stimulation induced a consistent long-term potentiation in the two sites. Paired stimulation resulted in depression of the test response in the amygdala, but a facilitation in the entorhinal cortex. These findings indicate that the midline has a significant monosynaptic excitatory influence in the amygdala and the entorhinal cortex. Combined with the previous work in the hippocampus, this study suggests that the midline thalamus plays a significant role in limbic physiology and may serve to synchronize activity in this system.

Action Potentials↗
PubMed1997

Species differences in the distribution of the glutamate receptor subunit, GluR1, in the rat and monkey entorhinal cortex.

The distribution of the DL-alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor subunits GluR1 and GluR2/3 were studied by immunocytochemistry in the rat and monkey temporal neocortex and entorhinal cortex. The monkey neocortex was similar to the rat neo- and entorhinal cortex, in that non-pyramidal neurons were densely labelled for GluR1, while pyramidal neurons were lightly labelled. The monkey entorhinal cortex was very different, in that dense GluR1 labelling was present in the pyramidal neurons of layer V. Although many GluR2/3-positive pyramidal neurons were also present in layers II, III, V and VI of the monkey entorhinal cortex, the neuropilar staining in layer V was less intense for GluR2/3, than for GluR1. This suggests that there were fewer GluR2 or GluR3 subunits in that layer compared with GluR1, and it is possible that many of the GluR1 subunits exist as homomers. Since GluR1 homomeric channels are permeable to calcium ions and are inwardly rectifying, the high GluR1 content of the layer V pyramidal neurons could render these cells particularly susceptible to calcium influx, and consequently, calcium-mediated neuronal injury. This could therefore be one of the reasons why the entorhinal cortex shows some of the earliest and most severe pathological alterations in Alzheimer's disease.

Animals↗
PubMed2006

Dopamine has bidirectional effects on synaptic responses to cortical inputs in layer II of the lateral entorhinal cortex.

Dopaminergic modulation of neuronal function has been extensively studied in the prefrontal cortex, but much less is known about its effects on glutamate-mediated synaptic transmission in the entorhinal cortex. The mesocortical dopamine system innervates the superficial layers of the lateral entorhinal cortex and may therefore modulate sensory inputs to this area. In awake rats, systemic administration of the dopamine reuptake inhibitor GBR12909 (10 mg/kg, ip) enhanced extracellular dopamine levels in the entorhinal cortex and significantly facilitated field excitatory postsynaptic potentials (fEPSPs) in layer II evoked by piriform cortex stimulation. An analysis of the receptor subtypes involved in the facilitation of evoked fEPSPs was conducted using horizontal slices of lateral entorhinal cortex in vitro. The effects of 15-min bath application of dopamine on synaptic responses were bidirectional and concentration dependent. Synaptic responses were enhanced by 10 microM dopamine and suppressed by concentrations of 50 and 100 microM. The D(1)-receptor antagonist SCH23390 (50 microM) blocked the significant facilitation of synaptic responses induced by 10 microM dopamine and the D(2)-receptor antagonist sulpiride (50 microM) prevented the suppression of fEPSPs observed with higher concentrations of dopamine. We propose here that dopamine release in the lateral entorhinal cortex, acting through D(1) receptors, can lead to an enhancement of the salience of sensory representations carried to this region from adjacent sensory cortices.

Animals↗
PubMed1984

Sparing and recovery of spatial alternation performance after entorhinal cortex lesions in rats.

Groups of adult rats were first trained on a spatial alternation task and then subjected to unilateral entorhinal cortex lesions, unilateral entorhinal cortex lesions followed by dorsal psalterium transections, or bilateral entorhinal cortex lesions. After this surgery, the rats were then tested for retention of spatial alternation. Neither unilateral lesions alone nor unilateral lesions followed by dorsal psalterium transections resulted in long-term spatial performance deficits; however, animals with bilateral lesions exhibited severe impairments from which they eventually recovered. The results from animals with bilateral entorhinal damage indicate that extensive postoperative training may facilitate the recovery of spatial alternation performance. Histological analyses indicated that the crossed entorhinal projection proliferated in the dentate gyrus after unilateral entorhinal lesions and such anomalous growth occurred independently of any changes in alternation performance.

Animals↗
PubMed1994

Extrinsic modulation of theta field activity in the entorhinal cortex of the anesthetized rat.

Field recordings of the entorhinal cortex (EC) were studied and compared to those recorded concomitantly in the dentate region of the hippocampal formation (HPC) in the urethane anesthetized rat. The EC, like the HPC, showed two main variations of spontaneous field activity: a desynchronized, large amplitude irregular activity and a synchronized, rhythmic, slow frequency field activity (RSA or theta). Corroborating previous research, a phase reversal was seen across layer II of the EC and when recorded superficial to this layer, EC theta was phase-locked to that recorded from the HPC (dentate). Entorhinal cortex (and HPC) theta could be evoked by the application of moderate tail pinches (sensory stimulation), by pharmacological treatments enhancing cholinergic transmission, and by electrical stimulation of the posterior hypothalamus. Spectral analysis revealed that in all cases, theta was produced coherently across the two limbic structures. Entorhinal cortex (and HPC) production of theta could be abolished by pharmacological treatments disrupting cholinergic transmission, and by reversible procaine inactivation of the medial septal region. Therefore, it was concluded that limbic theta is modulated spontaneously, and with sensory and hypothalamic stimulation through the activity of cells in the medial septal region via muscarinic neurotransmission. It was also hypothesized that the activation of cells in the posterior hypothalamus linearly codes the frequency, and to a lesser extent the power, of EC and HPC theta. Given these findings and the coincidence and coherence of the occurrence of theta across the EC and HPC, it was postulated that it occurs via a parallel mechanism in the two areas.

Anesthesia↗
PubMed1995

Input-output relations in the entorhinal-hippocampal-entorhinal loop: entorhinal cortex and dentate gyrus.

The pattern of impulse transfer along the entorhinal-hippocampal-entorhinal loop has been analyzed in the guinea pig by field potential analysis. The loop was driven by impulse volleys conducted by presubicular commissural fibers, directly stimulated in the dorsal psalterium, which monosynaptically activated perforant path neurons in the medial entorhinal cortex. Perforant path volleys activated in sequence the dentate gyrus, field CA3, field CA1, subiculum, and entorhinal cortex. Input-output curves were reconstructed from responses simultaneously recorded from different stations along the loop. The entorhinal response to the presubicular volley was found to increase gradually with respect to its input. The population excitatory postsynaptic potential (EPSP) of the dentate gyrus granule cells had a similar behavior. By contrast, the input-output relation between the granule cell population spike and population EPSP was described by a very sleep sigmoid curve. The population spike of CA3 and CA1 pyramidal neurons as well as the response evoked in the entorhinal cortex by the hippocampal output had slightly higher threshold than the granule cell population spike and, like the latter, abruptly reached maximum amplitude. These findings show that the entorhinal-hippocampal-entorhinal loop transforms a linear input in a non-linear, almost all-or-none output and that the dentate gyrus is the critical site where the transformation occurs. Beyond the dentate gyrus, the loop appears very permeant to impulse traffic.

Afferent Pathways↗
PubMed2003

Comparison of commissural sprouting in the mouse and rat fascia dentata after entorhinal cortex lesion.

Reactive axonal sprouting occurs in the fascia dentata after entorhinal cortex lesion. This sprouting process has been described extensively in the rat, and plasticity-associated molecules have been identified that might be involved in its regulation. To demonstrate causal relationships between these candidate molecules and the axonal reorganization process, it is reasonable to analyze knockout and transgenic animals after entorhinal cortex lesion, and because gene knockouts are primarily generated in mice, it is necessary to characterize the sprouting response after entorhinal cortex lesion in this species. In the present study, Phaseolus vulgaris-leucoagglutinin (PHAL) tracing was used to analyze the commissural projection to the inner molecular layer in mice with longstanding entorhinal lesions. Because the commissural projection to the fascia dentata is neurochemically heterogeneous, PHAL tracing was combined with immunocytochemistry for calretinin, a marker for commissural/associational mossy cell axons. Using both techniques singly as well as in combination (double-immunofluorescence) at the light or electron microscopic level, it could be shown that in response to entorhinal lesion mossy cell axons leave the main commissural fiber plexus, invade the denervated middle molecular layer, and form asymmetric synapses within the denervated zone. Thus, the commissural sprouting response in mice has a considerable translaminar component. This is in contrast to the layer-specific commissural sprouting observed in rats, in which the overwhelming majority of mossy cell axons remain within their home territory. These data demonstrate an important species difference in the commissural/associational sprouting response between rats and mice that needs to be taken into account in future studies.

Animals↗
PubMed2006

Expression of a familial Alzheimer's disease-linked presenilin-1 variant enhances perforant pathway lesion-induced neuronal loss in the entorhinal cortex.

Alzheimer's disease (AD) is characterized by neuronal loss in the hippocampus and entorhinal cortex that is manifested by progressive memory impairment and cognitive decline. Autosomal-dominant, familial forms of AD (FAD) are caused by mutations in genes encoding amyloid precursor protein, presenilin-1 (PS1), and presenilin 2. Although it is established that expression of mutant PS1 variants leads to increased production of highly fibrillogenic amyloidbeta42 (Abeta42) peptides that deposit in the brains of patients with AD, the mechanism(s) by which Abeta deposition and expression of mutant genes induce lamina- and region-specific vulnerability of neuronal populations is not known. We have examined the hypothesis that expression of transgene-encoded FAD-linked mutant PS1 variants in entorhinal cortex neurons exacerbates the vulnerability of these cells to lesion-induced neuronal loss. To test this notion, we transected the perforant pathway (PP) of transgenic mice harboring either wild-type human PS1 (PS1HWT) or the FAD-linked mutant PS1DeltaE9 variant and examined neuronal survival in layer II of the entorhinal cortex (ECL2). Remarkably, PP transections lead to marked reductions in the numbers of ECL2 neurons in the ECL2 of mice expressing mutant PS1, compared with ECL2 neurons in PP-lesioned PS1HWT mice. Finally, and in contrast to studies in nontransgenic mice and in mice expressing PS1HWT, ECL2 neurons that express mutant PS1 and the calcium binding protein calbindin-D28k in ECL2 are also susceptible to lesion-induced neuronal loss. We conclude that expression of FAD-linked mutant PS1 variants enhances the vulnerability of neurons in the entorhinal cortex to PP lesion-induced cytotoxicity.

Alzheimer Disease↗
PubMed2000

Hyperpolarization-activated cation currents in stellate and pyramidal neurons of rat entorhinal cortex.

Properties of hyperpolarization-activated cation currents (I(h)) were investigated in neurons of juvenile rat entorhinal cortex using the patch-clamp technique. A rat brain slice preparation containing the entorhinal cortex was used for whole-cell recordings of I(h) in pyramidal cells from layer IV and in stellate cells from layer II of the entorhinal cortex. In both stellate and pyramidal cells, I(h) activated at potentials more negative than -60 mV and did not show any time-dependent inactivation. Half-maximal activation of I(h) was achieved at -95.3 mV in pyramidal cells and at -95.0 mV in stellate cells. The channels were permeable for sodium and potassium ions. I(h) of pyramidal and stellate neurons was reduced by about 50% in the presence of 100 microM ZD7288. Extracellularly applied 1 mM Cs(+) decreased I(h) of pyramidal cells by 92%, whereas I(h) of stellate cells was only reduced by 70%. In both pyramidal and stellate neurons, I(h) was not significantly changed during the application of 1 mM Ba(2+). 8-Bromo-c-AMP increased amplitudes of I(h) in stellate cells, while I(h) of pyramidal cells remained unchanged. It is suggested that different types of hyperpolarization-activated cation channels are expressed in pyramidal and stellate cells of the entorhinal cortex.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Modelling cognitive dysfunctions with bilateral injections of ibotenic acid into the rat entorhinal cortex.

Neurodegenerative diseases, traumatic brain injury and stroke are likely to result in cognitive dysfunctioning. Animal models are needed in which these deficits and recovery of the affected functions can be investigated. In the present study, the entorhinal area was chosen as the target for lesioning and for assessing the lesion-induced deficits in the Morris water maze. The entorhinal cortex is regarded as an interface between the hippocampus and neocortex. Deafferentiating the hippocampus through entorhinal lesions impairs spatial learning. The effects of lesions, induced by either electrocoagulation (experiment 1) or ibotenate excitotoxicity (experiment 2), on spatial orientation behaviour were investigated. Water maze performance after unilateral or bilateral ibotenate injections into the entorhinal cortex was studied in the third experiment. In an additional study, the replicability of the spatial learning deficit after lesions induced by bilateral injections of ibotenic acid into the entorhinal cortex was assessed by comparing the results of nine experiments. We found that spatial learning was impaired after bilateral lesions aimed at the entorhinal cortex. The electrolytic lesion technique produced a relatively large sham effect, whereas the excitotoxic lesioning method did not. Unilateral injections of ibotenic acid into the entorhinal cortex did not affect spatial navigation. The ibotenate-induced lesions replicably produced deficits in the Morris tasks. The degree of the induced spatial learning impairments and the effects on the rate of acquisition during training, however, differed between experiments. This result suggests that the fundamental biological diversity between shipments of rats can account for variation in the effects of parahippocampal damage on spatial learning even in highly standardized experimental set-ups. Rats lesioned by bilateral injections of ibotenic acid into the entorhinal cortex provide an interesting and reliable model for investigating cognitive dysfunctions in neurodegenerative diseases, stroke or traumatic brain injury.

Brain Injuries↗
PubMed1997

The entorhinal cortex: an examination of cyto- and myeloarchitectonic organization in humans.

The entorhinal cortex (ERC) has been implicated in the pathophysiology of Alzheimer's disease, schizophrenia and other disorders affecting cognitive functions. While powerful anatomical and histochemical methods (immunohistochemistry, in situ hybridization, etc.) may be applied (although with limitations) to postmortem human brain, each analysis should utilize a cytoarchitectonic approach to provide appropriate comparisons within the subdivisions of the ERC. Accordingly, we describe here the normal cyto- and myeloarchitecture of the human ERC as a prerequisite for the accompanying study of this region in schizophrenia. Our parcellation of this cortex differs from previous treatments in three ways. First, we adopted specific criteria of inclusion to define each subdivision of the region. Although distinctive ERC features are most prominent in the intermediate portion of this region, at least one of these features was considered the minimum necessary criterion to include adjacent tissue in the entorhinal area. Second, we used morphometric measurements (neuronal size and density as well as subdivisional volume and laminar thickness) to support our qualitative evaluation. Third, we have applied to the human ERC the conventional cytoarchitectonic nomenclature of the entorhinal cortex used previously in studies of non-human primates. This allows a more accurate extrapolation of the available numerous experimental anatomical, physiological and psychological data on this region to the human. As in the monkey, the five main subareas were recognized in the human (prorhinal, lateral, intermediate, sulcal and medial) but three required further subdivision (intermediate, sulcal and medial). The morphometric results obtained suggested a progression of the human entorhinal cortex from the peripheral to the central subareas, with the intermediate subarea (281) as the most complete entorhinal subdivision. Compared with non-human primates, the human ERC not only retains the basic periallocortical organization but also demonstrates further evolution. Taken together with available experimental data on the connectivity of this brain region, these results provide an anatomical basis for evaluating the ERC in human behavior.

Adult↗
PubMed2000

Functional connections and epileptic spread between hippocampus, entorhinal cortex and amygdala in a modified horizontal slice preparation of the rat brain.

The hippocampus, the entorhinal cortex and the amygdala are interconnected structures of the limbic system that are implicated in memory and emotional behaviour. They demonstrate synaptic plasticity and are susceptible to development of temporal lobe epilepsy, which may lead to emotional and psychological disturbances. Their relative anatomical disposition has limited the study of neurotransmission and epileptic spread between these three regions in previous in vitro preparations. Here we describe a novel, modified-horizontal slice preparation that includes in the same plane the hippocampus, entorhinal cortex and amygdala. We found that, following application of bicuculline, each region in our preparation could generate spontaneous bursts that resembled epileptic interictal spikes. This spontaneous activity initiated in the hippocampal CA3/2 region, from where it propagated and controlled the activity in the entorhinal cortex and the amygdala. We found that this spontaneous bursting activity could spread via two different pathways. The first pathway comprises the well-known subiculum-entorhinal cortex-perirhinal cortex-amygdala route. The second pathway consists of a direct connection between the CA1 region and perirhinal cortex, through which the hippocampal bursting activity can spread to the amygdala while bypassing the entorhinal cortex. Thus, our experiments provide a new in vitro model of initiation and spread of epileptic-like activity in the ventral part of the limbic system, which includes a novel, fast and functional connection between the CA1 region and perirhinal cortex.

Action Potentials↗
PubMed1986

Neurophysiology of limbic system pathways in the rat: projections from the subicular complex and hippocampus to the entorhinal cortex.

We studied the responses of rat entorhinal neurons to electrical stimulation of the dentate gyrus, hippocampus and subicular complex. Three main results were obtained. Excitatory postsynaptic potentials were recorded in entorhinal neurons in response to electrical stimulation. Cell in layers II, III and V of the entorhinal cortex were responsive. Frequency potentiation of excitatory responses was observed when 10/s stimulation was used. Excitatory responses were followed by inhibitory postsynaptic potentials. The results provide evidence for an excitatory projection from the hippocampus and subiculum to the entorhinal cortex, and are consistent with the existence of feed-forward inhibition of entorhinal principal neurons.

Animals↗
PubMed1996

Coexistence of parvalbumin and GABA in nonpyramidal neurons of the rat entorhinal cortex.

The possible coexistence of the calcium-binding protein, parvalbumin, with the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), and its synthesizing enzyme, glutamate decarboxylase (GAD), was studied in nonpyramidal cells of the rat medial and lateral entorhinal cortex. The material was analyzed by two different methods, the first of which was a mirror techniques where the possible coexistence of two different antigens was analyzed from cells cut in half at the surface of the adjacent section. The other method consisted of analyzing double immunofluorescent-stained sections with a confocal microscope. The colocalization analysis revealed that all parvalbumin-immunoreactive neurons (mirror technique n = 688 and confocal microscopy n = 644) in all layers of the medial and lateral entorhinal cortex were also immunopositive for GABA or GAD. Parvalbumin-cells made up 52% of the GABA cells in most of the layers in the medial and lateral entorhinal cortex. In layer III of the entorhinal cortex, the proportion was about 40%. Thus, parvalbumin-containing neurons in the entorhinal cortex represent a large GABAergic cell population, which is likely to play an important role in controlling both the input and the output of the entorhinal cortex.

Animals↗
PubMed1997

Lesions of the entorhinal cortex disrupt behavioral and neuronal responses to context change during extinction of discriminative avoidance behavior.

Rabbits given either electrolytic lesions of the entorhinal cortex or sham-lesions were trained to prevent a foot-shock by stepping in an activity wheel after one tone, a positive conditioned stimulus (CS+), and to ignore a different tone, a negative conditioned stimulus (CS-). Neuronal activity was recorded simultaneously in the basolateral nucleus of the amygdala, the CA1 cell field of hippocampus, anterior cingulate cortical area 24b and posterior cingulate cortical area 29c/d. The activity of neurons in the entorhinal cortex was recorded in the controls. Acquisition of conditioned avoidance responses (CRs) was not affected by lesions of the entorhinal cortex. Discriminative neuronal activity (greater neuronal responses to the CS+ than to the CS-) during CR acquisition was significantly enhanced in hippocampal area CA1 and attenuated in the basolateral amygdala in rabbits with lesions. Following acquisition to a criterion, two counterbalanced extinction tests were administered, one in the original context and the other in the presence of novel contextual stimuli. CR frequency was significantly reduced in controls but not in rabbits with lesions, during extinction with novel contextual stimuli, relative to performance in the original context. The rabbits with lesions also showed fewer inter-trial responses than controls during extinction in the original context but intertrial response frequency in rabbits with lesions did not differ from the frequency in controls during extinction in the novel context. Neurons in the basolateral amygdala in controls showed discriminative activity during extinction in the original context but not in the novel context. Amygdalar neurons in the rabbits with lesions did not show discriminative activity during extinction in either context. Posterior cingulate cortical neurons in control rabbits did not show discriminative activity during extinction in the original context but these neurons exhibited robust discriminative activity in the novel context. Posterior cingulate cortical neurons in rabbits with lesions showed discriminative activity in both extinction sessions. The results indicated that the entorhinal cortex does not play a significant role in the acquisition of discriminative avoidance behavior, under the employed conditions of training. However, the interactions of neurons in the entorhinal cortex, amygdala and cingulate cortex are essential for contextual modulation of CRs during extinction.

Amygdala↗
PubMed1997

Topographical organization of projections from the entorhinal cortex to the striatum of the rat.

The efferent projections of the entorhinal cortex to the striatum were studied with retrograde (horseradish peroxidase wheat germ agglutinin) and anterograde (biocytin and biotinylated dextran amine) tracing methods. The bulk of the entorhinal cortical fibres were found to project to the nucleus accumbens in the ventral striatum, but the caudate putamen is only sparsely and diffusely innervated, rostrally, along its dorsal and medial borders. Fibres arising from neurons in the lateral entorhinal cortex project throughout the rostrocaudal extent of the nucleus accumbens but are most abundant in the core and lateral shell of that nucleus. The rostral neurons of the medial entorhinal cortex were found to project sparsely to the striatum, whereas caudal neurons provide a dense input to the rostral one-third of the nucleus accumbens, especially to the rostral pole, where they concentrate more in the core than in the shell. Contralateral entorhinal projections, which are very sparse, were found in the same parts of the nucleus accumbens and the caudate-putamen as the ipsilateral terminal fields. The present observations that entorhinal inputs to the nucleus accumbens are regionally aligned suggest that disruption of these connections could produce site-specific deficits with, presumably, specific behavioural consequences.

Animals↗
PubMed1997

Basal expression, subcellular distribution, and up-regulation of the proto-oncogene c-JUN in the rat dentate gyrus after unilateral entorhinal cortex lesion.

The expression of the transcription factor c-JUN was investigated in the rat fascia dentata under normal conditions and after entorhinal cortex lesion. As shown by immunocytochemistry and in situ hybridization histochemistry c-JUN and its messenger RNA are present in the principal cell layers of the dentate gyrus and Ammon's horn (except hippocampal region CA2). Pre-embedding immunogold electron microscopy revealed an almost exclusive nuclear localization of c-JUN, where it is associated with chromatin. In addition, double immunolabelling for c-JUN and parvalbumin demonstrated that c-JUN immunoreactivity is primarily found in principal neurons since GABAergic parvalbumin-positive interneurons did not express c-JUN. After unilateral electrolytic lesion of the entorhinal cortex c-JUN was strongly up-regulated in the ipsilateral dentate gyrus within 2 h postlesion. This up-regulation was also present in the contralateral fascia dentata 12 h after entorhinal cortex lesion and returned to control levels on both sides 24 h postlesion. The cellular distribution of c-JUN did not change after entorhinal cortex lesion: parvalbumin-positive interneurons never contained c-JUN. These results point to a specific role of c-JUN in the granule cells of the fascia dentata in the normal animal and in rats with entorhinal cortex lesions. The selective induction of c-JUN after entorhinal lesion could be one of the first molecular steps that regulate transneuronal changes within granule cells after their denervation. A different mechanism has to be assumed for GABAergic interneurons known to receive an entorhinal innervation as well.

Animals↗
PubMed2007

Cholinergic suppression of excitatory synaptic responses in layer II of the medial entorhinal cortex.

Theta-frequency (4-12 Hz) electroencephalographic activity is thought to play a role in mechanisms mediating sensory and mnemonic processing in the entorhinal cortex and hippocampus, but the effects of acetylcholine on excitatory synaptic inputs to the entorhinal cortex are not well understood. Field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the piriform (olfactory) cortex were recorded in the medial entorhinal cortex during behaviors associated with theta activity (active mobility) and were compared with those recorded during nontheta behaviors (awake immobility and slow wave sleep). Synaptic responses were smaller during behavioral activity than during awake immobility and sleep, and responses recorded during movement were largest during the negative phase of the theta rhythm. Systemic administration of cholinergic agonists reduced the amplitude of fEPSPs, and the muscarinic receptor blocker scopolamine strongly enhanced fEPSPs, suggesting that the theta-related suppression of fEPSPs is mediated in part by cholinergic inputs. The reduction in fEPSPs was investigated using in vitro intracellular recordings of EPSPs in Layer II neurons evoked by stimulation of Layer I afferents. Constant bath application of the muscarinic agonist carbachol depolarized membrane potential and suppressed EPSP amplitude in Layer II neurons. The suppression of EPSPs was not associated with a substantial change in input resistance, and could not be accounted for by a depolarization-induced reduction in driving force on the EPSP. The GABA(A) receptor-blocker bicuculline (50 microM) did not prevent the cholinergic suppression of EPSPs, suggesting that the suppression is not dependent on inhibitory mechanisms. Paired-pulse facilitation of field and intracellular EPSPs were enhanced by carbachol, indicating that the suppression is likely due to inhibition of presynaptic glutamate release. These results indicate that, in addition to well known effects on postsynaptic conductances that increase cellular excitability, cholinergic activation in the entorhinal cortex results in a strong reduction in strength of excitatory synaptic inputs from the piriform cortex.

Animals↗