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INNOVATIVE METHODOLOGY
1Max Planck Institute for Biochemistry, Department of Membrane and Neurophysics, Martinsried/Munich, Germany; and 2Infineon Technologies, Corporate Research, Munich, Germany
Submitted 4 April 2006; accepted in final form 8 May 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Egert et al. 1998; Gholmieh et al. 2001; Heuschkel et al. 2002; Jahnsen et al. 1999; Jobling et al. 1981; Meister et al. 1991; Novak and Wheeler 1988; Oka et al. 1999; Segev et al. 2004; Stoppini et al. 1997; Thiebaud et al. 1999; Van Bergen et al. 2003). Their spatial resolution, however, is rather low or else restricted to a small area. Moreover, the records of extracellular potentials are distinctly smaller than measured with conventional micropipette electrodes. Another approach is optical recording with voltage-sensitive dyes in brain slices (Bonhoeffer et al. 1989; Grinvald and Hildesheim 2004; Grinvald et al. 1982; Mann et al. 2005; Matsukawa et al. 2003; Nakagami et al. 1997). There, toxicity and unstable staining limit the duration of recording.
To overcome the problems, electrolyte-oxide-semiconductor (EOS) transistors have been introduced with cultured slices of rat hippocampus (Besl and Fromherz 2002; Fromherz 2005; Hutzler and Fromherz 2004). The EOS transistor signals matched micropipette recordings of field potentials. However, a high-resolution of 5 µm was achieved only in one dimension. Recently, high-density two-dimensional multitransistor arrays (MTAs) were implemented by an extended complementary metal oxide semiconductor (CMOS) technology and tested with snail neurons (Eversmann et al. 2003; Lambacher et al. 2004).
In this study, we show how MTA recording can be applied to cultured brain slices to yield time-resolved images of electrical field potentials at a spatial resolution of 7.8 µm on an area of 1 mm2. The total array is read out at a frequency of 2 kHz. Higher frequencies are attained by reading out part of the array. The principle of recording is shown in Fig. 1. Brain tissue is in contact to an insulating and inert layer of TiO2 that covers the silicon chip (Hutzler and Fromherz 2004; Wallrapp and Fromherz 2006). Integrated transistors are built in an electrolyte-oxide-metal-oxide-semiconductor (EOMOS) configuration: a local change of the electrical field potential is capacitively coupled through the insulating TiO2 layer to the gate of a field-effect transistor. There it gives rise to a modulation of the source-drain current that is calibrated in terms of the field potential. The surface of a chip is shown in Fig. 2: through the insulating TiO2, we can see the 16,384 contacts with a diameter of 4.5 µm and a pitch of 7.8 µm. Figure 3A shows that the MTA is able to cover a large part of a hippocampal slice where cornu ammonis and gyrus dentatus can be identified by comparison with the classical anatomical drawing in Fig. 3B (Ramón y Cajal 1911).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The silicon chips had a size of 5.4 x 6.5 mm. Details of their design are described in previous publications (Eversmann et al. 2003; Lambacher et al. 2004). The chips were wire bonded to standard ceramic packages. A chamber of perspex was attached to shield the bond contacts and to expose the transistor array to culture medium (Besl and Fromherz 2002; Lambacher et al. 2004). The chips were cleaned twice with detergent (BM flüssig, 104101, Biomed Labordiagnostik, Oberschleissheim, Germany), wiped with cotton swabs, and rinsed with Milli-Q water. After drying and sterilization with UV light (30 min), we applied 400 µl of a solution of poly-L-lysine (P6516, Sigma, Deisenhofen, Germany) at 1 mg/ml in 0.13 M Tris/HCl buffer (pH 8.4) for 48 h, rinsed the chips with Milli-Q water, and dried them. No change of chip quality was observed after five cleaning-culture-measurement cycles.
Hippocampal slice culture
Organotypic slices from rat hippocampus on silicon chips were prepared following established procedures (Besl and Fromherz 2002; Debanne et al. 1999; Gähwiler 1981). In short, the hippocampi of 5- to 7-day-old Wistar rats were excised after decapitation and cut into 400-µm-thick transverse slices using a McIlwain tissue chopper. They were transferred to 3 µl of chicken plasma (30-0390L, Cocalico Biologicals, Reamstown, PA) spread on the chip. The slice was gently placed onto the transistor array, using a pipette. Precise positioning was difficult because of capillary attraction of the plasma-immersed slice to the walls of the narrow chamber. Coagulation was started by adding 3 µl of thrombin solution (112374, Merck, 140 U/ml) that immobilized the slice on the chip. After 4 min, 1 ml of culture medium was added, consisting of 50% BME (21090–022, Invitrogen), 25% Hanks' balanced salt solution (24020–091, Invitrogen), and 25% horse serum (16050–122, Invitrogen) with 1 mM L-glutamine (25030–032, Invitrogen) and 25 mM D-glucose. The chamber was closed with the lid of a falcon dish (Falcon 3001, Becton Dickinson Labware Europe, Le Pont De Claix, France) using seal and clip (Besl and Fromherz 2002), placed in an incubator (Incudrive-S, Schütt Labortechnik, Göttingen, Germany) at 34°C, and rotated at 10 rev/h. Three days after preparation, mitose inhibitors (uridine, U-3750, cytosine-
-D-arabino-furanoside, C-6645, 5-fluoro-2'-deoxyuridine, F-0503, Sigma) were added to a concentration of 10 µM. The culture medium was exchanged 1 day after the addition of the inhibitors and again 1 wk later. The slices were cultured for 7–10 days.
A chip with slice was placed into the socket of the electronic set-up that was able to dissipate the heat created by the chip. The slice was perfused with recording medium at about 32°C with a rate of 1 ml/min. The recording medium (Debanne et al. 1999) contained (in mM) 149 Na+, 149 Cl–, 2.7 K+, 2.8 Ca2+, 2.0 Mg2+, 11.6 HCO3–, 0.4 H2PO4–, and 5.6 glucose and was adjusted to pH 7.4 by titration with HCl. Excitatory synaptic transmission was blocked in some experiments by D-(–)-2-amino-5-phosphonopentanoic acid (D-AP5, 106–10, BioTrend GmbH, Köln, Germany) and 6,7-dinitroquinoxaline-2,3-dione (DNQX; D-0540, Sigma, from DMSO stock solution), both at a concentration of 50 µM (Davies and Watkins 1982; Honore et al. 1988).
Electrophysiology
For stimulation, we used monopolar tungsten microelectrodes (AMS 5753, Science Products, Hofheim, Germany). A stimulus isolation unit (A360D, World Precision Instruments, Berlin, Germany) generated 200-µs negative current pulses of 50–70 µA. The bath electrolyte was held at a constant electrical potential with a Ag/AgCl pellet electrode (E-206, Science Products). Local electrical field potentials were measured with micropipette electrodes. The micropipettes (tip diameter of 
2 µm, resistance of 10 M
) were made from borosilicate glass (1403547, Hilgenberg, Germany), filled with 3 M NaCl and contacted with a chlorinated silver wire. They were connected to an amplifier (BA-1S, NPI electronic, Tamm, Germany). The signals were band-pass filtered between 1 Hz and 1 kHz and sampled at 10 kHz. Tungsten electrode and micropipette were positioned with micromanipulators (Narishige, Tokyo, Japan).
MTA recording
Slices were stimulated with a tungsten microelectrode positioned in the pyramidal layer of the CA3 area. The electrical response was measured with 16,384 sensor transistors. In some cases, we first performed an imaging experiment with standard recording medium, and subsequently with a medium containing the toxins DNQX (50 µM) and AP5 (50 µM) to block AMPA and N-methyl-D-aspartate (NMDA) channels and to observe presynaptic activity alone. Reversibility of toxin effects was confirmed by washout.
During a recording experiment, the columns of the transistor array were sequentially connected to 128-line amplifiers. After a settling time of 1.92 µs, the output of these line amplifiers was multiplexed during another 1.92 µs into 16-output channels. The read-out time of the whole chip therefore was 492 µs. It could be shortened by restricting the read-out to a fraction of the array. The read-out scheme created a time gradient along the sensor area, as only 16 sensor transistors were read out at exactly the same time. We obtained isochronic images by interpolating the signals linearly between the two frames before and after the chosen time at each position.
The multiplexing scheme required a maximum on-chip bandwith of 32 MHz, far larger than allowed by the sampling theorem at the read-out frequency of 2 kHz. From the resulting aliasing together with the intrinsic noise of the sensor transistors (gate area 11 µm2), we expected a minimal noise around 50 µV rms. We observed a total noise of about 250 µV rms because of imperfections of chip design and set-up. In some experiments, the signal-to-noise ratio was improved by spatial Gaussian filtering.
Because of the small size of the sensor transistors, there is a statistical variation of the threshold voltage with an SD of 4.2 mV that is large compared with extracellular neuronal signals. A reset circuit is implemented on the chip that assigns individual bias voltages to the gates to maintain a common baseline (Eversmann et al. 2003; Lambacher et al. 2004). Reset cycles are applied until the start of a measurement. There is a minor drift of the working point within the duration of a measurement (590 ms). It is eliminated by fitting the transistor record before and after the interval of the evoked neuronal signals (40 ms) by a polynomial function that is subtracted from the complete record.
EOMOS transistors are calibrated by applying rectangular voltage pulses of 70 Hz and 5 mV peak-to-peak to the bath electrode. The calibration is performed for the same duration as the measurement to check for a drift of sensitivity. The voltage pulses give rise to a change of the electrical potential at the surface of the chip. The local change of electrical potential couples through the insulating electrolyte/chip interface to the top metal contact and to the gate of the transistor (Fig. 1) and proportionally modulates the source-drain current.
In a measurement, the excited brain slice gives rise to a electrical field potential, i.e., to changes of the local extracellular voltage with respect to the bath electrode on ground potential. The local field potential at the surface of the chip couples through the insulating electrolyte/chip interface to the gate and proportionally modulates the source-drain current as in the situation of calibration. Because of the design of the CMOS chip, there is no cross-talk of transistor signals on the chip. The response of a transistor is solely determined by the local field potential above the insulating TiO2 averaged over the diameter of 4.5 µm of the top contact.
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RESULTS |
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At first we consider a typical measurement by a single EOMOS transistor. Figure 4 shows a selected transistor record of an evoked field potential in stratum pyramidale in an area where the transistor records were almost invariant within a range of 20 µm. The slice is stimulated by a tungsten microelectrode in the pyramidal layer of CA3 with a negative current pulse of 55 µA and 200 µs in a region that was 1.2 mm apart from the site of recording along the arch of cornu ammonis. By reading out only part of the MTA, the transistor signals were recorded at an enhanced sampling rate of 8 kHz. To improve the signal-to-noise ratio, we applied a Bessel filtering between 1 Hz and 1 kHz and a two-dimensional spatial Gaussian filtering with 
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2 pixel (11 µm). Five milliseconds after the stimulation artifact, the transistor measured a positive voltage transient with an amplitude of 3 mV and a duration of about 20 ms.
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). It is caused by the activation of excitatory synapses [population excitatory postsynaptic potential (pEPSP)] in stratum radiatum. In all regions of s. pyramidale and s. radiatum that are probed by the MTA (Fig. 5), we find a similar shape and a similar amplitude of the EOMOS transistor signals and of common micropipette recordings in brain slices (Duport et al. 1999; Richardson et al. 1987). Thus the EOMOS transistors are able to record local field potentials.
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20 µm. The micropipette signal that is simultaneously recorded with the EOMOS transistor signals is also plotted in Fig. 4. It has a very similar shape with an amplitude of 2 mV. The lower amplitude can be assigned to the different vertical position of the two probes: because of current flow from neuronal sources in the slice to the bath, there is a drop of the field potential across the slice such that a micropipette records a lower signal than the transistor (Fromherz 2002). Functional imaging
We consider one data set for time-resolved imaging of electrical activity in a cultured hippocampal slice with the slice-chip system depicted in Fig. 3A. We used all 16,384 sensor transistors that were read out at 2 kHz. A movie of the complete measurement can be downloaded from the website of the journal. The results were reproducible for repeated stimulations of the same slice. Similar results of spatiotemporal dynamics were obtained in 12 further slice-chip systems with different positions of the cultured slice on the transistor array.
PRESYNAPTIC IMAGING. We considered first an imaging experiment in which toxins block the synaptic transmission mediated by NMDA/AMPA type channels. Reversibility of the toxin effects was confirmed by washout. The left column of Fig. 5 displays eight frames between 1 and 20 ms after stimulation with a tungsten microelectrode (negative current pulse of 70 µA and 200 µs) that was placed in the pyramidal layer of CA3 as shown in Fig. 3A. In the frames recorded at 1, 1.5, and 2 ms after stimulation, we observed distinct negative transients that propagated from the site of stimulation along cornu ammonis in two directions. At later phases (Fig. 5, 5 ms), no field potentials were detected. Therefore we excluded a significant contribution of postsynaptic signals caused by GABA-type channels that were not blocked.
We replotted a blow-up of a selected MTA record at 1.5 ms after stimulation in Fig. 6A. A gray line marks the border between s. pyramidale and s. radiatum as it is derived from the functional image of postsynaptic activity without toxins in Fig. 6B. The picture shows that the fast wave of presynaptic activity is localized near s. pyramidale. That localization indicates that the wave reflects action potentials that propagate along the mossy fibers that were stimulated by the tungsten microelectrode en passant (Amaral and Witter 1989; Andersen et al. 1971; Ishizuka et al. 1990). Accordingly, the orthodrome propagation terminates in a region of cornu ammonis where the border of CA3 and CA1 is located, and the antidrome propagation terminates near gyrus dentatus (Fig. 5, left). From the frames at 1, 1.5, and 2 ms, we evaluate a velocity of 0.25 m/s, a typical value for the unmyelinated mossy fibers (Andersen et al. 1971).
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With applied toxins, we were not able to see presynaptic activity that propagated from CA3 to CA1 along s. radiatum where the Schaffer collaterals are localized in acute and cultured slices (Amaral and Witter 1989; Andersen et al. 1971; Caesar and Aertsen 1991; Ishizuka et al. 1990). The number of stimulated collaterals may have been too low in our experiment to give rise to a fiber volley with sufficiently high amplitude to be recorded by the MTA.
POSTSYNAPTIC IMAGING.
Eight time fr1 ames of an MTA record without toxins are depicted in the right column of Fig. 5. In the frames at 1 and 1.5 ms after stimulation, we see again negative transients that spread in two directions as in the experiment with toxins. However, now, 2 ms after stimulation, additional negative and positive signals arise along cornu ammonis. The spread of the negative and positive wing is not perfectly synchronous. The signals fade away beyond 20 ms after stimulation. We assign these evoked field potentials to excitatory synaptic inwards currents in s. radiatum and compensating outward currents in s. pyramidale (Johnston and Amaral 1998).
We replotted a blow-up of a selected MTA record at 5 ms after stimulation without toxin in Fig. 6B. Because of their long duration, the postsynaptic signals are still visible near the stimulation site when their front reaches the boundaries of CA3. We marked the border between the positive and negative wing of the signals with a gray curve. For orientation, that line is also drawn in the micrograph of Fig. 3A. It follows the structure of cornu ammonis. The MTA record at 5 ms after stimulation provides a perfect functional image of the hippocampal slice in terms of its postsynaptic activity.
We observed weak postsynaptic signals downward along cornu ammonis in the CA1 region with a negative amplitude in s. radiatum and positive amplitude in s. pyramidale (Fig. 5, right, frames 5 and 10 ms). These signals may arise from an activation of CA3-CA1 synapses by Schaffer collaterals with an excitation that was too low to be recorded by the MTA.
Selected MTA recordings
FIELD POTENTIAL ACROSS THE LAYERS.
From the full set of data in Fig. 5, we evaluated a linear profile of the field potential without toxins across the strata of CA3 as marked in Fig. 6B at 5 ms after stimulation. The result is plotted in Fig. 7. There is a wide trough in s. radiatum and a narrower ridge in s. pyramidale. For comparison, the profile with toxins 2.5 ms after stimulation at the same position is also shown in Fig. 7. Only a shallow trough is observed in s. pyramidale. Qualitatively, the profile without toxin reflects the inward current through glutamate receptors in the dendrites and compensating outward currents in the somata (Johnston and Amaral 1998; Richardson et al. 1987).
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). The two-dimensional representation of the field potential in Fig. 5 (right, 5 ms) indicates, however, that the postsynaptic signal is not homogeneous along s. pyramidale of CA3, but that there is a distinct positive peak near its border to CA1. For illustration, we replotted the frame at 5 ms after stimulation in Fig. 8 as a three-dimensional profile that shows an increase of the pEPSP along CA3 by a factor of two.
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= 2 pixel. The transients are plotted in Fig. 9. The signal in CA3 (Fig. 9A) shows a pEPSP with an amplitude of 4 mV in s. pyramidale. The pEPSP in CA1 (Fig. 9B) is by a factor of two smaller with an amplitude of 2 mV in s. pyramidale. There is a distinct population spike in CA1 that reflects the firing of pyramidal neurons, but not in CA3, with its higher pEPSP. The experiment reveals a different functionality of pyramidal neurons in two different areas as induced by the same stimulus. The biological implications of this effect need to be studied.
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DISCUSSION |
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An individual EOMOS transistor records the local electrical field potential in a cultured hippocampus slice at the surface of the substrate, averaged over the area of 16 µm2 (diameter, 4.5 µm) of the insulated gate contact. Shape and amplitude of the pEPSP records are similar to signals measured with conventional micropipette electrodes. The fact that EOMOS transistors probe the true field potential is a physical consequence 1) of the direct coupling of the electrical potential from the extracellular space across the insulating electrolyte/chip interface to the transistor gate with an induced change of the source-drain current and 2) of the proper calibration of the source-drain current by an external modulation of the bath potential (Fromherz 2005). The nature of the measuring process with an EOMOS transistor is analogous to recording with simple EOS transistors where shape and amplitude of field potentials in cultured hippocampus slices resembled micropipette recordings (Besl and Fromherz 2002).
Field potentials in hippocampus slices have been probed by planar metallic multielectrode arrays (MEAs) with an electrode diameter of 20–50 µm (area, 300–2,000 µm2) and a spacing of 100–200 µm. When we compare the results with MTA recordings, we must consider the same kind of signals. An inspection of reports that refer to pEPSPs in the CA1 or CA3 region of cultured hippocampal slices (Duport et al. 1999; Egert et al. 1998; Gholmieh et al. 2001; Jahnsen et al. 1999; Stoppini et al. 1997; Van Bergen et al. 2003) shows that the signal amplitudes were in a range of 400 µV or below. The signal amplitudes in acute slices (Heuschkel et al. 2002; Jobling et al. 1981; Novak and Wheeler 1988; Oka et al. 1999; Thiebaud et al. 1999) were around 200 µV or below. Thus the voltages recorded by planar metal electrodes do not correspond to the field potentials that are measured by micropipette electrodes (Jahnsen et al. 1999). Aspects that may play a role in that discrepancy of MEA recording and that play no role in MTA recording are 1) the chemical inhomogeneity of the substrate (electrodes surrounded by insulator) that may affect the tissue–substrate interaction, 2) the large size of the metal electrodes that leads to an averaging of the signals, and 3) capacitive shunting of the signals in the extended connection lanes to the amplifier.
Functional imaging in terms of field potentials
MTA recording provides a functional image of slice activity in terms of the field potential on an area of 1 mm2 at a spatial resolution of 7.8 µm. The high resolution on a large area is important for two kinds of physiological studies.
Field potentials are used to reconstruct the underlying current source density in slices by evaluating the second spatial derivative from discrete sampling (Mitzdorf 1985). However, that procedure is valid only if the sampling accounts for the highest spatial frequencies in the signal. The linear profile of Fig. 7, which is recorded with full spatial resolution, shows that the field potential significantly changes over short distances, within 20 µm by 1 mV or 25% of its amplitude. Thus the high spatial resolution of MTA recording is crucial if a quantitative current-source density (CSD) analysis is attempted. A CSD analysis on the basis of a sampling of field potentials at intervals of 100–200 µm—as provided by common planar multielectrode arrays—is not adequate.
Neuronal wiring in a hippocampus slice may give rise to inhomogeneous neuronal activities that change over rather short distances and to correlations of neuronal activity over large distances. Such effects can only be studied if the activities can be probed at arbitrary positions over a large area. Examples in this report are the modulation of activity along cornu ammonis at the border of CA3 as shown in Fig. 8 and the striking difference of postsynaptic signals that are simultaneously recorded at different positions in Fig. 9. Such features of spatiotemporal dynamics are difficult to achieve by micropipette electrodes or by coarse sampling with a multielectrode array.
Compared with planar MEAs, we have to pay for the high spatial resolution on a large area by a lower performance in time resolution of 2 kHz and in noise of 250 µV rms at a full resolution of 7.8 µm and a full recording area of 1,000 x 1,000 µm. Nonetheless, the signal-to-noise ratio is fairly high because the signals are larger by an order of magnitude compared with MEA recording. However, depending on the problem to be studied, the band width of MTA recording can be enhanced by lowering the number of pixels that are read out, e.g., with 8 kHz on an area of 500 x 500 µm at full spatial resolution, and subsequent software filtering or/and a spatial averaging over adjacent pixels can be applied, sacrificing spatial resolution. Ongoing improvements of chip design and amplifiers will lead to a significant progress in that respect.
In summary, in this study, we implemented a novel neuroelectronic system consisting of a cultured brain slice and a silicon chip with a high-density MTA. By direct electrical interfacing of brain slice and chip, we achieved a complete functional image in terms of the field potential on an area of 1 mm2 at a resolution of 7.8 µm in space and 0.5 ms in time without signal averaging. The test experiments confirm known features of signaling in cultured hippocampal slices. The high density of recording sites and the large area of recording provide time-resolved images of presynaptic and postsynaptic activity that are almost continuous in space. Profiles of field potentials can be evaluated along arbitrary directions. The dynamics of neuronal activity can be correlated over large distances.
Crucial for MTA recording of field potentials is the combination of 1) transistor recording with local probing and calibration of extracellular voltage (Besl and Fromherz 2002), 2) CMOS technology with a close packing of sensor transistors in two dimensions (Lambacher et al. 2004), and 3) an inert and homogeneous surface of the silicon chips made of titanium dioxide (Hutzler and Fromherz 2004; Wallrapp and Fromherz 2006). Important for a practical application of MTA recording as a universal electrophysiological tool will be the availability of a chip and a setup that are controlled by a common PC and also a combination of MTA recording with a multicapacitor array stimulation. These developments are in progress.
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 A movie of functional imaging for a cultured hippocampal slice by MTA recording as depicted in Fig. 5 is available on the website of the journal. At an enhanced resolution, it can be downloaded from the homepage of the Department of Membrane and Neurophysics (www.biochem.mpg.de/mnphys)
Address for reprint requests and other correspondence: P. Fromherz, Dept. of Membrane and Neurophysics Max Planck Inst. for Biochemistry, Martinsried/Munich 82152, Germany (E-mail: fromherz{at}biochem.mpg.de)
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