Frequency-Dependent Information Flow From the Entorhinal Cortex to the Hippocampus
Tengis Gloveli,
Dietmar Schmitz,
Ruth M. Empson, and
Uwe Heinemann
Department of Neurophysiology, Institute of Physiology at the Charité, Humboldt University Berlin, 10117 Berlin, Germany
 |
ABSTRACT |
Gloveli, Tengis, Dietmar Schmitz, Ruth M. Empson, and Uwe Heinemann. Frequency-dependent information flow from the entorhinal cortex to the hippocampus. J. Neurophysiol. 78: 3444-3449, 1997. Storage and retrieval of information in the hippocampus is dependent on information transfer from the entorhinal cortex (EC). We studied how the separate pathways from layer II and III of the EC to the hippocampus are selected for information transfer during repetitive synaptic stimulation. Intracellular recordings were made from EC layer II and III projection cells in horizontal combined EC-hippocampal slices. Synaptic responses to stimulation of deep layers or the lateral EC with stimulus intensities ~70% of that required to elicit an action potential were analyzed during short trains of repetitive stimulation. The threshold intensities for induction of action potentials were in layer II cells 8.2 ± 3.8 (SE) V, significantly larger than 4.4 ± 1.5 V in type 1, and 5.2 ± 3.3 V in type 2 layer III cells, respectively. During repetitive subthreshold stimulation with frequencies below 5 Hz the pathway from the EC layer II remained quiet and was preferentially activated with stimulation frequencies above 5 Hz. In contrast the EC layer III cells responded preferentially to low stimulus frequencies (<10 Hz) and became strongly inhibited when synaptically stimulated with frequencies above 10 Hz. Interestingly during stimulus frequencies between 5 and 10 Hz the likelihood that both layer II and III cells fire was large. Thus a frequency switch operates in the entrohinal cortex regulating output of layer II and III cells to the hippocampus. We suggest that such frequency dependent regulation of information flow presents a new principle of neuronal information processing.
 |
INTRODUCTION |
In the hippocampus storage of information is thought to be promoted during periods where rhythmical activity is generated (Huerta and Lisman 1993
; Mitchell et al. 1982
). The major cortical input to the hippocampus, the perforant path, arrives from the entorhinal cortex (EC) layers II and III. Layer II cells project to the dentate gyrus from where the trisynaptic loop via area CA3, CA1, and the subiculum are activated (Tamamaki and Nojyo 1993
). A parallel projection directly to area CA1 and the subiculum arises from layer III cells (Hjorth-Simonsen and Jeune 1972
; Steward and Scoville 1976
; Witter et al. 1988
). The layer III to CA1 pathway can mediate activation of hippocampal place cells, which fire only when the animal is located at a specific location in a complex environment (Muller and Kubie 1989
). Additionally it was shown that place cell activation is independent of the pathway through the dentate gyrus (McNaughton et al. 1989
) and frequently occurs at a relative low background EEG activity (O'Keefe and Recce 1993
). However in vivo experiments have shown that layer II cells are rhythmically active during exploratory behavior in the theta rhythm range (Mitchell and Ranck 1980
). The hippocampus also exhibits rhythmic oscillatory field potentials at theta frequency during exploratory behavior. Moreover stimulus induced activation of hippocampal pathways in this frequency range readily induces long-term potentiation (LTP) (Staubli and Lynch 1987
). These findings may suggest that the information flow from the entorhinal cortex to the hippocampus is regulated in a frequency dependent manner. To test this hypothesis we performed intracellular recordings of layer II and III projection cells and studied their behavior during synaptic activation in different frequency ranges.
 |
METHODS |
Projection cells were impaled in the superficial layers of the medial EC in 400 µm thick horizontal slices from adult Wistar rats (200-250 g) containing the hippocampus and entorhinal, perirhinal, and temporal cortices as previously reported (Gloveli et al. 1997a
). Slices were considered acceptable if stimulation of the lateral EC evoked negative-going complex field potentials >1.5 mV in layer III. Intracellular recording electrodes contained 3 M K-acetate and 2% biocytin (resistances 50-120 M
). Recordings in bridge mode were made with a Neurodata IR 183 (Neurodata Instruments, New York) or a SEC10L amplifier (NPI Instruments, Tamm, Germany). Resting membrane potentials were estimated by subtraction of the tip potential after withdrawal from the cell and were more negative than
50 mV. Potential changes were filtered at 3 kHz and then stored on an IBM compatible PC after sampling at 8-10 kHz by a CED 1401 (Cambridge Electronic Design, Cambridge, UK) or TIDA A/D converter. Stimulation of afferent input to layer II and III projection cells was either performed in layer II/III of the lateral EC or layer V of the medial EC (mEC). Trains of 20 or 30 stimuli (0.05 ms) with frequencies ranging from 1 to 40 Hz usually subthreshold for induction of action potentials were delivered. P values of significance were determined with the use of Student's t-test. Data are reported as mean ± SE.
The following drugs were used: DL-2-amino-5-phosphonovaleric acid (DL-AP5; 30-40 µM; Research Biochemicals, Natick, MA); 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2-3-dione (NBQX; 5-10 µM; Novo Nordisk, Denmark); bicuculline methiodide (5µM; Sigma, Deisenhofen, Germany); 3-N-[1-(s)-(3,4-dichlorophenyl)ethyl]amino-2-(s)-hydroxypropyl-P-benzyl-phosphinic acid(CGP55845A; 2-5 µM; CIBA-GEIGY, Basel); and atropine sulfate (1-5 µM, Research Biochemicals).
 |
RESULTS |
We identified layer II and III projection cells by their electrophysiological and morphological properties. Previous studies have shown that spiny stellate neurons are the main projection cells in layer II of the EC (Alonso and Klink 1993
; Jones 1994
; Lingenhöhl and Finch 1991
; Tamamaki and Nojyo 1993
). Layer II stellate cells in the mEC were identified (n = 32) according to their electrophysiological (Alonso and Klink 1993
; Jones 1994
) and morphological properties (n = 5). All these cells displayed characteristic "sags" during subthreshold depolarizing or hyperpolarizing current injection as well as a rebound depolarization after hyperpolarizing current injection (Fig. 1Aa). The mean resting membrane potential of stellate neurons was
68.6 ± 0.8 mV. Mean input resistance and time constant were 37.2 ± 3.5 M
and 8.0 ± 0.5 ms, respectively. They responded to synaptic stimulation with a fast EPSP followed by a fast and slow IPSP (see also Jones 1994
; Jones and Heinemann 1991
), which were interrupted by a depolarizing component (Fig. 1Ab). Mean values of amplitudes and latencies of peaks for EPSPs in layer II cells were 5.3 ± 0.6 mV and 5.6 ± 0.5 ms, respectively. Fast and slow IPSPs peaked at 15.5 ± 1.5 ms and 108.2 ± 6 ms after the stimulus artifact and had a mean value of
3.0 ± 0.5 mV and -1.6 ± 0.3 mV, respectively. The different synaptic components could be pharmacologically identified by their sensitivity to
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA,n = 5) and N-methyl-D-aspartate (NMDA, n = 4) receptor antagonists, as well as to
-aminobutyric acid-A (GABAA, n = 4) and
-aminobutyric acid-B (GABAB, n = 9) receptor blockers (see also Jones 1994
; Jones and Heinemann 1991
). In most of the stellate cells a small depolarizing component was still present when glutamate receptor anatagonists were applied together with GABAA and GABAB receptor antagonists (n = 9) (see also Pralong and Jones 1993
). This component did not respond to the metabotropic glutamate receptor antagonist, (R, S)-
-methyl-4-carboxyphenylglycine (MCPG), nor to the muscarinic antagonist, atropine (D. Schmitz, R. Hetka, T. Gloveli, Y. Behr, and U. Heinemann, in preparation).

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| FIG. 1.
Electrophysiology and morphology of projection cells of EC layer II and III. Typical responses of a layer II stellate cell (Aa) and type 1 (Ba) and type 2 (Ca) layer III cells to hyperpolarizing and depolarizing current injections. Calibrations in Ca also apply to records in Aa and Ba. Layer II cells responded typically to single synaptic stimulation from lateral entorhinal cortex (EC), with an EPSP followed by a fast and slow IPSP (Ab). Type 1 layer III cells responded on single electrical stimulation with a strong, long-lasting EPSP (Bb). In type 2 layer III cells single stimulation evoked a fast EPSP followed by a fast and slow IPSP (Cb). Calibrations in Cb also apply to records in Ab and Bb. Morphological methods easily distinguished layer II spiny stellate cells (Ac) from type 1 (Bc) and type 2 (Cc) layer III pyramidal cells. Note large differences in cell body shape, but similar extent of apical dendrites reaching cortical surface. Note highly directional main axons in layer II and III cells ( ). Calibrations in Cc also apply to records in Ac and Bc.
|
|
Projection cells in layer III have distinctly different properties. In a preceding paper (Gloveli et al. 1997a
) we identified two types of projection cells in this layer. Both cell types could antidromically be activated from the deep layers of the EC. Mean resting membrane potential in type 1 neurons (n = 94) was
71.2 ± 0.5 mV. Mean input resistance and time constant were 69.1 ± 2.8 M
and 19.3 ± 0.7 ms, respectively. Layer III type 2 projection cells (n = 65) had an average membrane potential of
70.3 ± 0.6 mV. Mean input resistance and time constant were 30.0 ± 2.0 M
and 8.1 ± 0.6 ms, respectively. The two types of projection cells differently responded to single stimulation of the lateral EC. Type 1 cells present a rather long-lasting EPSP (Fig. 1Bb) consisting of an AMPA and NMDA receptor mediated response followed in some cells by a small GABAB receptor mediated IPSP (Gloveli et al. 1997a
). Type 2 cells responded to synaptic stimulation with a fast EPSP, followed by a fast and slow IPSP (Fig. 1Cb; Gloveli et al. 1997a
). However in contrast to layer II cells, all layer III projection cells responded with a long-lasting inhibitory potential to high-frequency synaptic stimulation (Gloveli et al. 1997b
). Because the firing behaviors during repetitive stimulation in type 1 and type 2 cells were similar we subsequently pooled the data of these layer III projection cells.
In Fig. 1 we show a spiny stellate cell (Ac) and a type 1 (Bc) and type 2 (Cc) projection cell of layer III. Layer III cells were pyramidal cells with dendrites reaching layer I and II and axons that could be followed at least into the deep layers of the EC (Fig. 1, Bc and Cc). Following single electrical stimulation input-output curves for both types of cells were rather steep (not shown) and even merely doubling the threshold intensity for induction of an EPSP often brought these cells above firing threshold. This is in contrast to layer II stellate cells where the inhibition often was sufficiently strong to make the triggering of action potentials difficult (see also Finch et al. 1986
, 1988
; Jones 1994
). Consequently input-output curves were rather flat (not shown). Thus stimulation intensity to evoke EPSPs had to be multiplied by a factor between 4 and 5 to elicit an action potential. This difference in the three cell types is also evident from the mean stimulus intensities required to elicit action potentials. Action potentials were synaptically evoked in stellate neurons with a stimulus intensity of 8.2 ± 3.8 V (n = 12) from the lateral EC whereas at the same stimulation site only 4.4 ± 1.5 V (n = 16, P < 0.05) and 5.2 ± 3.3 V (n = 16, P < 0.05) were required for triggering of action potentials in type 1 and type 2 layer III cells, respectively.
As all recorded layer III projection cells displayed a prolonged IPSP after trains of high-frequency stimulation and none of the stellate cells did, we became interested in the behavior of these cells during repetitive stimulation. For the purpose of this experiment usually only one cell in a given slice was studied. The cells were stimulated with 5-10 trains of 20 or 30 stimuli and frequencies between 1 and 40 Hz from lateral EC and in some cells also from deep layers (n = 23) of the mEC. However the synaptic responses were independent of the stimulation site. The intensity was usually set to ~70% of that required for induction of action potentials. Long-lasting aftereffects of high-frequency stimulation were not studied. However if major changes in single stimulus-induced synaptic potentials were noted, further stimulus trains were not analyzed.
Layer II cells, when stimulated with frequencies below 5 Hz, did not produce any action potentials at all during the stimulus train (Fig. 2Aa). EPSPs and IPSPs fluctuated around resting membrane potentials and showed some waxing and waning during the train. Stellate cells displayed a net hyperpolarization when stimulated with frequencies >10 Hz and action potentials appeared late during the stimulus train (Fig. 2, Ac-d). We determined whether the EPSPs or remaining depolarizing component of a stimulus-evoked synaptic potential triggered the action potential and found that it was almost always the fast EPSP that induced firing (Fig. 2Ab-d). Interestingly during the late phase of the stimulus train, action potentials were evoked by synaptic activation at potentials between
72 and
62 mV (mean value
64.4 ± 1.2 mV). In contrast firing threshold during depolarizing current injection was found to range between
59 and
50 mV (mean value
57.2 ± 0.6 mV). This difference was statistically significant (P < 0.001, n = 9). Thus with subthreshold repetitive stimulation, firing of cells can be induced often from a net hyperpolarized membrane potential at lower thresholds than observed during depolarizing current injection. Because it was reported that acetylcholine can modulate intrinsic conductances and that the EC receives a strong cholinergic input from the septum, we tested whether or not the changes in action potential threshold during repetitive stimulation depends on cholinergic transmission. However the frequency dependent induction of action potentials was not affected by the muscarinic antagonist atropine and the firing threshold during repetitive stimulation was not changed (control,
62.3 ± 0.4 mV; atropine,
62.1 ± 0.4 mV, n = 3, data not shown).

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| FIG. 2.
Different synaptic responses of layer II and III cells on repetitive stimulation. A: On low-frequency ( 5 Hz) subthreshold stimulation layer II cell did not produce any action potentials at all during simulus train (a). However when stimulation frequencies were increased (>10 Hz) fast EPSPs often induced action potentials during trains of stimulation, even when cells were net hyperpolarized (b-d). Note that action potentials appeared fairly late in train (c and d). B: in contrast to layer II cells, EPSPs in type 1 layer III cells summated and generated action potentials on low-frequency ( 10 Hz) subthreshold stimulation (a and b). During high-frequency repetitive stimulation (>10 Hz) EPSPs amplitude started to summate but than declined and a slow hyperpolarization became appearent (c and d). Note that only one action potential could be elicited during high-frequency stimulation (c and d). C: like type 1 cells, type 2 layer III projection cells fired action potentials during low-frequency ( 10 Hz) stimulation (a and b). In responce to higher frequencies this cell generated only one action potential early during a stimulus train and after stimulation a prolonged hyperpolarization was noted (c and d). A-C: single traces are shown and action potentials are truncated. Calibration in Ad, Bd, and Cd also applies to records in Aa-c, Ba-c, and Ca-c, respectively. D-F: average number of action potentials (in percent of applied stimuli) induced by 20 stimuli of lateral EC with indicated frequencies in layer II cells (D) and in type 1 (E) and type 2 (F) layer III cells. Stimulus intensity was 70% of that required to evoke an action potential in layer II and III cells. Data are from 7, 6, and 8 cells, respectively.
|
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In contrast to layer II cells, on low-frequency stimulation (1-10 Hz) type 1 and type 2 layer III cells always responded with generation of action potentials after 4-6 stimuli (Fig. 2, Ba and Ca). When high-frequency stimulus trains (>10 Hz) were applied, layer III cells initially fired but then rapidly ceased to generate action potentials (Fig. 2, Bc-d, Cc-d, E, and F). Thus on high-frequency activation there was only a short firing period of these neurons early during a stimulus train at a time where layer II cells usually did not fire yet action potentials. Ceasing of firing during the train was associated with a strong repolarization in type 1 cells and sometimes a net hyperpolarization in type 2 cells, followed in both cases by prolonged hyperpolarization (Figs. 2, Bc-d and Cc-d, and 3Bc).

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| FIG. 3.
Responses of layer II and III cells on repetitive suprathreshold stimulation with different frequencies. A: with stimulation intensities slightly above threshold in layer II cell induction of action potentials was only slightly affected by different stimulation frequencies (a-c). Note that on high-frequency stimulation more action potentials appeared late during a stimulus train (c). B: low-frequency ( 10 Hz) repetitive stimulation with a stimulus intensity just above threshold was successful in induction of action potentials in a layer III cell during a prolonged train of stimuli (a, b). In contrast on high-frequency repetitive stimulation (20-40 Hz) only 1st 3-4 stimuli were able to evoke an action potential (c). Aa-c and Ba-c: action potentials are truncated. Calibration in Aa and Ba also applies to records in Ab-c and Bb-c. C: graphic representation of average number of action potentials (in percent of applied 20 stimuli) plotted against stimulation frequencies in layer II cells. Stimulus intensity was slightly above threshold for induction of an action potential. During different frequencies probability of induction of action potentials was between 44 and 57%. Data are from 9 cells. D: average number of action potentials (in percent of applied stimuli) induced by 20 stimuli with indicated frequencies in layer III cells. Stimulus intensity was suprathreshold for generation of an action potential. Graph illustrates that with low-frequency stimulation (0.1-10 Hz) probability of generation of action potentials was much higher than with high-frequency stimulation (20-40 Hz). Data are from 8 cells.
|
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During stimulation with frequencies between 5 and 10 Hz the probability for cell firing is large in all cell types of both layers and time periods where layer II and III cells elicited action potentials were overlapping (Fig. 2, Ab, Bb, Cb,and D-F).
With stimulation intensities slightly above threshold for induction of action potentials firing behavior of layer II cells was only little affected by different stimulation frequencies (Fig. 3Aa-c). Stimuli (44-57%) were successful in eliciting action potentials in nine cells tested with frequencies between 1 and 40 Hz (Fig. 3C). In contrast, type 1 and type 2 layer III cells were able to fire action potentials during a prolonged train of suprathreshold stimuli applied with low frequencies (5 Hz or less, Fig. 3Ba), although at higher frequencies (>10 Hz) the cells only fired initially during a stimulus train (Fig. 3, Bc and D). With stimulation intensities far above threshold for induction of action potentials all stimuli in a train were successful in generation of action potentials in both layer II and III cells independently from the stimulation frequency (not shown).
 |
DISCUSSION |
Here we report that a frequency switch operates in the entorhinal cortex regulating output of layer II and III to the hippocampus. During single- and low-frequency stimulation layer III cells were much more likely to fire action potentials. Thus under these circumstances the layer III to CA1 and subiculum pathway was probably activated while the hippocampal trisynaptic loop remained quiet. In contrast higher frequency synaptic activation of the EC seems capable of switching on the hippocampal trisynaptic loop as the layer II cells became more responsive. Firing threshold in stellate cells during repetitive synaptic stimulation was found to be significantly lower than firing threshold during depolarizing current injection. Because it is known that the mEC receives a strong cholinergic innervation (Alonso and Köhler 1984
) and that acetylcholine can modulate intrinsic cation conductances (Cantrell et al. 1996
; Yan and Surmeier 1996
), we tested whether or not acetylcholine was responsible for the changes in firing threshold. However the muscarinic receptor antagonist, atropine, did not change the firing behavior of stellate cells during high-frequency repetitive stimulation. Thus the activation of layer II cells in response to higher-frequency stimulation is not supported by the cholinergic input from the septum. However one can speculate that down regulation of K+ currents in response to synaptic input and/or removal of inactivation of sodium channels because of the net hyperpolarization induced by repetitive stimulation may be factors that lower the threshold for action potential induction during repetitive stimulation. Indeed it was shown that layer II cells possess K+ channels that are under strong metabolic control and quickly rundown in amplitude (Eder et al. 1991
).
One might argue that the observed differences in firing behavior of layer II and III cells are simply the result of their inhomogenous intrinsic properties. However, although the passive membrane properties of stellate cells and layer III type 2 neurons are on the parameters of resting membrane potentials and input resistances and time constants very similar, their firing behavior during repetitive stimulation is contrary. Moreover type 2 and type 1 cells are significantly different in their intrinsic properties (input resistance, time constant, Gloveli et al. 1997a
), but responded similarly to repetitive stimulation.
Layer II projection cells not only fired during high-frequency stimulation but the subsequent hyperpolarization was only ~200-500 ms (Figs. 2Ac-d and 3Ac). This suggests that the layer II cells were capable and ready to fire shortly after a response to high-frequency stimulation. In contrast, the prolonged inhibition (Figs. 2 and 3) lasting between 2 and 20 s (Gloveli et al. 1997b
) will impair synaptic activation of layer III projection cells after a burst of high-frequency synaptic stimulation.
Interestingly there is a frequency range of stimulation between 5 and 10 Hz (see Figs. 2 and 3) where there is a large likelihood that all cell types fire. These frequencies are in the range of theta rhythm, which is particularly suited for the induction of LTP (de Curtis and Llinas 1993
; Larson et al. 1986
). This suggests that both pathways to the hippocampus are activated for information transfer over this special frequency range. Outside this range the perforant path inputs to either CA1 or the dentate gyrus are selected by the properties of the projection cells.
Although the situation in vivo might be different, some of the present results agree well with those from in vivo studies. It was consistently shown that layer II cells of the EC in vivo display prominent inhibition to afferent stimulation, independent of the stimulation site (Finch and Babb 1980
; Finch et al. 1986
, 1988
). A net hyperpolarization of stellate cells in response to high-frequency afferent stimulation in vivo was also previously noted (Finch et al. 1986
) again similarly to the situation in our in vitro experiments. Previous studies have indicated that most dentate granule cells in vivo are probably silent or discharge at very low rates (McNaughton et al. 1991
) and that their intrinsic properties confer a high-threshold for synaptic excitation (see Lambert and Jones 1990
). Thus high-frequency discharges of layer II cells, noted in the present study during high-frequency stimulation, could be required to pass information via the trisynaptic loop. In contrast the inhibition of the layer III projection cells during high-frequency input could relieve the direct inhibitory influence on many cells in area CA1 (Empson and Heinemann 1995
). Although there is some controversy regarding the direct entorhinal activation of CA1 pyramidal cells (see Soltesz and Jones 1995
), most in vitro and in vivo experiments support the view that the EC recruits in most of the cells a feed-forward inhibition and in only some of them a small excitation (Buzsáki 1984
; Empson and Heinemann 1995
; Soltesz 1995
).
In conclusion, our data support the idea that under conditions of high-frequency activation large amounts of sensory information can enter the hippocampus, where they are processed by the appropriate memory mechanisms (O'Keefe and Nadel 1978
).
 |
ACKNOWLEDGEMENTS |
We thank M. J. Gutnick and J.G.R. Jefferys for comments on earlier versions of this paper. We thank A. Düerkop and T. Dugladze for the technical assistance. NBQX is a gift from Novo Nordisk, Denmark.
 |
FOOTNOTES |
Present address of R. M. Empson: Dept. of Pharmacology, University of Oxford, Mansfield Rd., Oxford OX1 3QT, United Kingdom.
Address reprint requests to T. Gloveli.
Received 5 May 1997; accepted in final form 4 September 1997.
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