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Decreased ability of rat temporal hippocampal CA1 region to produce long-term potentiation
Neuroscience Letters 279 (2000) 177±180 www.elsevier.com/locate/neulet
Decreased ability of rat temporal hippocampal CA1 region to produce long-term potentiation Costas Papatheodoropoulos, George Kostopoulos* Department of Physiology, University of Patras, Medical School, Patras 261 10, Greece Received 2 December 1999; received in revised form 15 December 1999; accepted 15 December 1999
Abstract Tetanic stimulation of Schaffer collaterals in the CA1 region of transverse slices, taken from the septal (dorsal) part of young rat hippocampus, produced N-Methyl-D-aspartate-dependent long-term potentiation (LTP) of the rising slope of excitatory postsynaptic potential (mean 38%). Under identical conditions of stimulation (100 Hz, 1 s) slices taken from the temporal (ventral) third of hippocampus presented a substantially reduced ability for LTP (mean 5%). The defect appeared to lie with the induction rather than the maintenance phase of LTP. These results suggest that a signi®cant functional differentiation at the local synaptic plasticity level occurs between the two poles of hippocampus, which together with the substantial differences in their extrinsic connections, may help explain the reported differential participation of neurons in these parts of hippocampus during animal memory tests. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Septotemporal; Ventral hippocampus; Long-term potentiation; Synaptic plasticity; Memory
The well established role, that the hippocampus plays in information processing associated to memory, is apparently broad and of great importance across species [14,25]. In the framework of this role, experimental evidence suggests a functional dissociation between the septal (SH or dorsal) and temporal (TH or ventral) parts of hippocampus [16,23]. Lesion and recording studies in rats show a more critical role of SH compared to TH in spatial memory [11,15]; while TH may be more critical for information processing related to internal states [8]. Explanations for this difference have been sought in the substantially differing external anatomical connections of the two parts of hippocampus [20]. We wondered whether functional differences exist also at the local circuit level and particularly in the ability of circuits in the respective parts of hippocampus to show long-term potentiation (LTP), which is the most outstanding model connecting memory phenomena with synaptic function [9,21,24]. Finding such differences might help us better understand hippocampal functions and provide an experimental tool to further explore LTP and neuronal mechanisms underlying learning and memory. Hippocampal slices were prepared from 14 male Wistar * Corresponding author. Tel.: 130-61-997825/997667; fax: 130-61-997215. E-mail address: [email protected] (G. Kostopoulos)
rats aged 28±38 days. The animals were deeply anaesthetized with ether and decapitated immediately after they stopped breathing. The brain was submerged in chilled (2±48C) arti®cial cerebrospinal ¯uid (ACSF) and the two hippocampi were excised free. Only the extreme, septal and temporal, parts of the structure were used. Speci®cally, using a McIlwain tissue chopper, 500 mm thick transverse slices were cut from the region extending more than 1 and less than 3.5 mm from the septal or temporal end of the hippocampus (Fig. 1). In order to cut both regions perpendicularly to the long axis of hippocampus a turn of the plate supporting the structure was needed. Every experiment included slices from both parts of hippocampus and at all stages of preparation and recording, we meticulously tried to treat the slices of both groups in identical way. The slices were immediately transferred to an interface type chamber, where they were kept at a constant temperature of 32 ^ 0.28C for at least 1.5 h before recording. They were continuously humidi®ed with mixed gas 95% O2 and 5% CO2 and perfused with arti®cial cerebrospinal ¯uid containing (in mM): 124 NaCl; 4 KCl; 2 MgSO4; 2 CaCl2; 1.25 NaH2PO4; 26 NaHCO3; 10 glucose; at pH 7.4, equilibrated with 95% O2 and 5% CO2. In all the experiments, one recording electrode made of single carbon ®ber (diameter 7 mm) was used and placed in CA1 stratum radiatum for recording ®eld excitatory postsy-
0304-3940/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 9 9) 01 00 2- 2
178
C. Papatheodoropoulos, G. Kostopoulos / Neuroscience Letters 279 (2000) 177±180
Fig. 1. Method used to cut slices from the two poles of hippocampus. Left: photograph of a left hippocampus with T and S indicating its temporal and septal pole, respectively. Right: tracing of the photograph showing the regions of hippocampus used in this study (solid lines with arrows) and the slicing direction (solid lines perpendicular to the long axis, dotted line).
naptic potentials (EPSPs). Twisted insulated steel wires (50 mm diameter) placed in the same region were used for bipolar stimulation of Schaffer collaterals. Synaptic responses were evoked by constant current pulses (0.1 ms, 0.3±0.9 mA) at a frequency of 0.05 Hz. The stimulation for baseline responses was adjusted to evoke a half-maximal EPSP amplitude based on input±output curves. Only slices with stable response for at least 20 min were selected for further experimentation. In order to induce LTP a single train at 100 Hz for 1 s was used at the same pulse intensity as for test pulses. The EPSP was quanti®ed by the slope of its rising phase. The slices were segregated into two groups according to the region they were taken from (SH and TH). The value of EPSP slope percent increase at 30 min after tetanus over that in baseline responses was taken as the degree of LTP and was statistically compared for slices within each group (paired t-test) and between the two groups (independent t-test). The two groups of slices (20 from SH and 30 from TH) had baseline ®eld EPSP responses of comparable amplitude (2.65 ^ 0.15 and 2.70 ^ 0.17 mV, respectively). The ability of slices in the two groups to yield a long-term enhancement of the ®eld EPSP slope (i.e. the LTP) in response to a single high frequency stimulation train (HFS) was tested and compared. Our results with SH slices (representative example in Fig. 2B) were in full agreement with reports using identical experimental conditions [10]. In several experiments we took note of the distance from the septal and the temporal pole of hippocampus from which slices were taken. We did not observe any obvious correlation between this position and LTP in 14 septal or 20 temporal slices. Most of the SH slices (12/20) showed LTP greater than 30% and only one failed to show any LTP (mean LTP in all SH slices 38.3 ^ 6.5%, circles in Fig. 3). This LTP was found to last at least 1 h after induction (examples shown in Fig. 2B,C) and to depend on N-Methyl-d-aspartate (NMDA) receptors, since its induction was blocked when the NMDA receptors antagonist d-2-amino-5-phosphonovaleric acid (AP5) was added to the perfusion medium (Fig. 2C). The reverse was observed in TH slices (representative example
in Fig. 2A). In the majority of TH slices (17/30) HFS was unable to induce LTP and only four TH slices presented sustained increase of the EPSP slope similar to one observed in SH slices and in literature (greater than 20%). In these few TH slices LTP was kept stable for at least 60 min after HFS. The four TH slices, which showed signi®cant LTP, were obtained from four different animals and did not consistently differ from the majority of TH slices not showing LTP in terms of their position on the septotemporal axis, their gross morphology or their baseline EPSP amplitude or slope (1.64 ^ 0.3 vs. 1.6 ^ 0.14 mV/ms). The mean LTP of all 30 TH slices was statistically signi®cant but small (5.5 ^ 3%, t 2:26, P 0:031, triangles in Fig. 3). Expectedly, the difference between the mean LTP values of SH and TH slices was statistically highly signi®cant (t 5:3, P , 0.001). It is well established, primarily from in vitro studies, that a train of HFS readily produces a long-term increase in the ®eld potential recorded from the CA1 region of young rats hippocampus [7,10] and that this kind of LTP is dependent
Fig. 2. Representative data from slices taken from temporal (A) and septal (B) parts of hippocampus showing their relative ability to produce LTP after a single train of high frequency stimulation (HFS, arrows, 100 pulses at 100 Hz). Very conspicuous is the inability of the TH slice to produce LTP. (C) Example of a SH slice in which HFS was incapable to produce LTP when delivered under the presence of 100 mM AP5 (thick line) given 17 min before HFS and lasting for 20 min. A stimulation train delivered after washing out the drug produces LTP. The EPSP traces in each graph represent single sweeps obtained 5 min before (dashed line) and 30 min after (solid line) HFS. Calibration bars: 1 mV, 5 ms in all cases.
C. Papatheodoropoulos, G. Kostopoulos / Neuroscience Letters 279 (2000) 177±180
Fig. 3. Comparison of LTP (the effect of HFS on the EPSP slope), in the two groups of hippocampal slices taken, respectively, from the septal (circles) and temporal (triangles) region. Means ^ SEM of the percent increase of EPSP slope are shown. While in SH slices HFS produces a robust increase of EPSP slope (38.4 ^ 6.5%), in temporal slices only a small change (5.5 ^ 3%) was detected. Numbers in parenthesis represent numbers of slices.
upon the activation of NMDA receptors [2,7] (Fig. 2C). However, all these studies have been done in the septal part, which comprises the two thirds of hippocampus. We are not aware of any study comparing the ability for LTP along the septotemporal axis. In the present study, we demonstrate that most of the slices taken from the temporal third of hippocampus are unable to produce LTP in response to HFS and as a group they show a de®nite, substantial and signi®cant defect relative to those in SH. The fact that four TH slices could keep LTP without decrement suggests that the de®cit may be related to the induction or expression phase of this phenomenon rather than the maintenance. Recently, a signi®cant decrease of NMDA receptors in CA1 stratum radiatum along the septotemporal axis of hippocampus has been shown [13]. Taking into account the dependence of tetanus-induced LTP on NMDA receptors, this `de®cit' in NMDA receptors in TH may obviously provide the ®rst, at least partial, explanation of the substantially weaker ability for LTP induction reported here for the TH. In addition, TH is relatively to SH richer in aminergic and peptidergic innervation and poorer in adenosine A1 and muscarinic receptors [12,17,22]. Several of these differences may play a role in the observed TH defect of LTP. Previous studies have shown that slices from TH are less susceptible to ischemia [1] and more sensitive to epileptogenic provocations [3,6] compared to slices from SH. The latter difference is particularly interesting in association to our ®ndings in view of the proposal that epileptogenesis and LTP may share some common mechanisms [19]. The signi®cance of our ®ndings is twofold. First they provide a convenient new tool for exploring the neuronal mechanisms underlying LTP, i.e. by identifying the critical LTP induction factor, which is missing in TH. To our knowledge no other brain area has been shown to present
179
substantial regional differences in LTP. Second, our results reinforce the idea of segmentation of hippocampus along its longitudinal axis. This idea is based on well-established anatomical [5], biochemical [13] and behavioral [4] differences between SH and TH in animals, and has important implications for the proposed different roles of posterior and anterior parts of human hippocampus [18,23]. In conclusion, by comparison to the SH part, CA1 neurons from the TH part of rat hippocampus are relatively unable to show LTP with the classical paradigm of HFS in vitro. Functional segregation along the septotemporal axis may, therefore, be due not only to differences in respective external connections, but also to differences in properties of neuronal circuits intrinsic to the septal and temporal parts of hippocampus. [1] Ashton, D., Reempts, J.V., Haseldonckx, M. and Willems, R., Dorsal-ventral gradient in vulnerability of CA1 hippocampus to ischemia: a combined histological and electrophysiological study. Brain Res., 487 (1989) 368±372. [2] Bashir, Z.I., Berretta, N., Bortolotto, Z.A., Clark, K., Davies, C.H., Frenguelli, B.G., Harvey, J., Potier, B. and Collingridge, G.L., NMDA receptors and long-term potentiation in the hippocampus. In G.L. Collingridge and J.C. Watkins (Eds.), The NMDA Receptor, Oxford University Press, Oxford, 1994, pp. 295±312. [3] Bragdon, A.C., Taylor, D.M. and Wilson, W.A., Potassiuminduced epileptiform activity in area CA3 varies markedly along the septotemporal axis of the hippocampus. Brain Res., 378 (1986) 169±173. [4] Colombo, M., Fernandez, T., Nakamura, K. and Gross, C.G., Functional differentiation along the anterior-posterior axis of the hippocampus in monkeys. J. Neurophysiol., 80 (1998) 1002±1005. [5] Dolorfo, C.L. and Amaral, D.G., Entorhinal cortex of the rat: topographic organization of the cells of origin of the perforant path projection to the dentate gyrus. J. Comp. Neurol., 398 (1998) 25±48. [6] Gilbert, M., Racine, R.J. and Smith, G.K., Epileptiform burst responses in ventral vs. dorsal hippocampal slices. Brain Res., 361 (1985) 389±391. [7] Harris, K.M. and Teyler, T.J., Developmental onset of longterm potentiation in area CA1 of the rat hippocampus. J. Physiol. (Lond.), 346 (1984) 27±48. [8] Hock Jr, B.J. and Bunsey, M.D., Differential effects of dorsal and ventral hippocampal lesions. J. Neurosci., 18 (1998) 7027±7032. [9] Holscher, C., Synaptic plasticity and learning and memory: LTP and beyond. J. Neurosci. Res., 58 (1999) 62±75. [10] Izumi, Y. and Zorumski, C.F., Developmental changes in long-term potentiation in CA1 of rat hippocampal slices. Synapse, 20 (1995) 19±23. [11] Jung, M.W., Wiener, S.I. and McNaughton, B.L., Comparison of spatial ®ring characteristics of units in dorsal and ventral hippocampus of the rat. J. Neurosci., 14 (1994) 7347±7356. [12] Lee, P.H., Xie, C.W., Lewis, D.V., Wilson, W.A., Mitchell, C.L. and Hong, J.S., Opioid-induced epileptiform bursting in hippocampal slices: higher susceptibility in ventral than dorsal hippocampus. J. Pharmacol. Exp. Ther., 253 (1990) 545±551. [13] Martens, U., Capito, B. and Wree, A., Septotemporal distribution of [3H]MK-801, [3H]AMPA and [3H]Kainate binding
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[16] [17]
[18] [19]
C. Papatheodoropoulos, G. Kostopoulos / Neuroscience Letters 279 (2000) 177±180 sites in the rat hippocampus. Anat. Embryol. (Berl.), 198 (1998) 195±204. Mishkin, M., Vargha-Khadem, F. and Gadian, D.G., Amnesia and the organization of the hippocampal system. Hippocampus, 8 (1998) 212±216. Moser, E., Moser, M.B. and Andersen, P., Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions. J. Neurosci., 13 (1993) 3916±3925. Moser, M.B. and Moser, E.I., Functional differentiation in the hippocampus. Hippocampus, 8 (1998) 608±619. Onodera, H., Sato, G. and Kogure, K., Quantitative autoradiographic analysis of muscarinic cholinergic and adenosine A1 binding sites after transient forebrain ischemia in the gerbil. Brain Res., 415 (1987) 309±322. Quigg, M., Bertram, E.H. and Jackson, T., Longitudinal distribution of hippocampal atrophy in mesial temporal lobe epilepsy. Epilepsy Res., 27 (1997) 101±110. Reid, I.C. and Stewart, C.A., Seizures, memory and synaptic plasticity. Seizure, 6 (1997) 351±359.
[20] Risold, P.Y. and Swanson, L.W., Structural evidence for functional domains in the rat hippocampus. Science, 272 (1996) 1484±1486. [21] Shors, T.J. and Matzel, L.D., Long-term potentiation: what's learning got to do with it? Behav. Brain Sci., 20 (1997) 597± 614. [22] Storm-Mathisen, J., Localization of transmitter candidates in the brain: the hippocampal formation as a model. Prog. Neurobiol., 8 (1977) 119±181. [23] Strange, B.A., Fletcher, P.C., Henson, R.N., Friston, K.J. and Dolan, R.J., Segregating the functions of human hippocampus. Proc. Natl. Acad. Sci. USA, 96 (1999) 4034±4039. [24] Teyler, T.J., Cavus, I., Davies, C.H., DiScenna, P., Grover, L., Lee, Y. and Little, Z., Advances in understanding the mechanisms underlying synaptic plasticity. In A. Schurr and B.M. Rigor (Eds.), Brain Slices in Basic and Clinical Research., CRC Press, Boca Raton, 1995, pp. 1±25. [25] Wood, E.R., Dudchenko, P.A. and Eichenbaum, H., The global record of memory in hippocampal neuronal activity. Nature, 397 (1999) 613±616.
Decreased ability of rat temporal hippocampal CA1 region to produce long-term potentiation Costas Papatheodoropoulos, George Kostopoulos* Department of Physiology, University of Patras, Medical School, Patras 261 10, Greece Received 2 December 1999; received in revised form 15 December 1999; accepted 15 December 1999
Abstract Tetanic stimulation of Schaffer collaterals in the CA1 region of transverse slices, taken from the septal (dorsal) part of young rat hippocampus, produced N-Methyl-D-aspartate-dependent long-term potentiation (LTP) of the rising slope of excitatory postsynaptic potential (mean 38%). Under identical conditions of stimulation (100 Hz, 1 s) slices taken from the temporal (ventral) third of hippocampus presented a substantially reduced ability for LTP (mean 5%). The defect appeared to lie with the induction rather than the maintenance phase of LTP. These results suggest that a signi®cant functional differentiation at the local synaptic plasticity level occurs between the two poles of hippocampus, which together with the substantial differences in their extrinsic connections, may help explain the reported differential participation of neurons in these parts of hippocampus during animal memory tests. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Septotemporal; Ventral hippocampus; Long-term potentiation; Synaptic plasticity; Memory
The well established role, that the hippocampus plays in information processing associated to memory, is apparently broad and of great importance across species [14,25]. In the framework of this role, experimental evidence suggests a functional dissociation between the septal (SH or dorsal) and temporal (TH or ventral) parts of hippocampus [16,23]. Lesion and recording studies in rats show a more critical role of SH compared to TH in spatial memory [11,15]; while TH may be more critical for information processing related to internal states [8]. Explanations for this difference have been sought in the substantially differing external anatomical connections of the two parts of hippocampus [20]. We wondered whether functional differences exist also at the local circuit level and particularly in the ability of circuits in the respective parts of hippocampus to show long-term potentiation (LTP), which is the most outstanding model connecting memory phenomena with synaptic function [9,21,24]. Finding such differences might help us better understand hippocampal functions and provide an experimental tool to further explore LTP and neuronal mechanisms underlying learning and memory. Hippocampal slices were prepared from 14 male Wistar * Corresponding author. Tel.: 130-61-997825/997667; fax: 130-61-997215. E-mail address: [email protected] (G. Kostopoulos)
rats aged 28±38 days. The animals were deeply anaesthetized with ether and decapitated immediately after they stopped breathing. The brain was submerged in chilled (2±48C) arti®cial cerebrospinal ¯uid (ACSF) and the two hippocampi were excised free. Only the extreme, septal and temporal, parts of the structure were used. Speci®cally, using a McIlwain tissue chopper, 500 mm thick transverse slices were cut from the region extending more than 1 and less than 3.5 mm from the septal or temporal end of the hippocampus (Fig. 1). In order to cut both regions perpendicularly to the long axis of hippocampus a turn of the plate supporting the structure was needed. Every experiment included slices from both parts of hippocampus and at all stages of preparation and recording, we meticulously tried to treat the slices of both groups in identical way. The slices were immediately transferred to an interface type chamber, where they were kept at a constant temperature of 32 ^ 0.28C for at least 1.5 h before recording. They were continuously humidi®ed with mixed gas 95% O2 and 5% CO2 and perfused with arti®cial cerebrospinal ¯uid containing (in mM): 124 NaCl; 4 KCl; 2 MgSO4; 2 CaCl2; 1.25 NaH2PO4; 26 NaHCO3; 10 glucose; at pH 7.4, equilibrated with 95% O2 and 5% CO2. In all the experiments, one recording electrode made of single carbon ®ber (diameter 7 mm) was used and placed in CA1 stratum radiatum for recording ®eld excitatory postsy-
0304-3940/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 9 9) 01 00 2- 2
178
C. Papatheodoropoulos, G. Kostopoulos / Neuroscience Letters 279 (2000) 177±180
Fig. 1. Method used to cut slices from the two poles of hippocampus. Left: photograph of a left hippocampus with T and S indicating its temporal and septal pole, respectively. Right: tracing of the photograph showing the regions of hippocampus used in this study (solid lines with arrows) and the slicing direction (solid lines perpendicular to the long axis, dotted line).
naptic potentials (EPSPs). Twisted insulated steel wires (50 mm diameter) placed in the same region were used for bipolar stimulation of Schaffer collaterals. Synaptic responses were evoked by constant current pulses (0.1 ms, 0.3±0.9 mA) at a frequency of 0.05 Hz. The stimulation for baseline responses was adjusted to evoke a half-maximal EPSP amplitude based on input±output curves. Only slices with stable response for at least 20 min were selected for further experimentation. In order to induce LTP a single train at 100 Hz for 1 s was used at the same pulse intensity as for test pulses. The EPSP was quanti®ed by the slope of its rising phase. The slices were segregated into two groups according to the region they were taken from (SH and TH). The value of EPSP slope percent increase at 30 min after tetanus over that in baseline responses was taken as the degree of LTP and was statistically compared for slices within each group (paired t-test) and between the two groups (independent t-test). The two groups of slices (20 from SH and 30 from TH) had baseline ®eld EPSP responses of comparable amplitude (2.65 ^ 0.15 and 2.70 ^ 0.17 mV, respectively). The ability of slices in the two groups to yield a long-term enhancement of the ®eld EPSP slope (i.e. the LTP) in response to a single high frequency stimulation train (HFS) was tested and compared. Our results with SH slices (representative example in Fig. 2B) were in full agreement with reports using identical experimental conditions [10]. In several experiments we took note of the distance from the septal and the temporal pole of hippocampus from which slices were taken. We did not observe any obvious correlation between this position and LTP in 14 septal or 20 temporal slices. Most of the SH slices (12/20) showed LTP greater than 30% and only one failed to show any LTP (mean LTP in all SH slices 38.3 ^ 6.5%, circles in Fig. 3). This LTP was found to last at least 1 h after induction (examples shown in Fig. 2B,C) and to depend on N-Methyl-d-aspartate (NMDA) receptors, since its induction was blocked when the NMDA receptors antagonist d-2-amino-5-phosphonovaleric acid (AP5) was added to the perfusion medium (Fig. 2C). The reverse was observed in TH slices (representative example
in Fig. 2A). In the majority of TH slices (17/30) HFS was unable to induce LTP and only four TH slices presented sustained increase of the EPSP slope similar to one observed in SH slices and in literature (greater than 20%). In these few TH slices LTP was kept stable for at least 60 min after HFS. The four TH slices, which showed signi®cant LTP, were obtained from four different animals and did not consistently differ from the majority of TH slices not showing LTP in terms of their position on the septotemporal axis, their gross morphology or their baseline EPSP amplitude or slope (1.64 ^ 0.3 vs. 1.6 ^ 0.14 mV/ms). The mean LTP of all 30 TH slices was statistically signi®cant but small (5.5 ^ 3%, t 2:26, P 0:031, triangles in Fig. 3). Expectedly, the difference between the mean LTP values of SH and TH slices was statistically highly signi®cant (t 5:3, P , 0.001). It is well established, primarily from in vitro studies, that a train of HFS readily produces a long-term increase in the ®eld potential recorded from the CA1 region of young rats hippocampus [7,10] and that this kind of LTP is dependent
Fig. 2. Representative data from slices taken from temporal (A) and septal (B) parts of hippocampus showing their relative ability to produce LTP after a single train of high frequency stimulation (HFS, arrows, 100 pulses at 100 Hz). Very conspicuous is the inability of the TH slice to produce LTP. (C) Example of a SH slice in which HFS was incapable to produce LTP when delivered under the presence of 100 mM AP5 (thick line) given 17 min before HFS and lasting for 20 min. A stimulation train delivered after washing out the drug produces LTP. The EPSP traces in each graph represent single sweeps obtained 5 min before (dashed line) and 30 min after (solid line) HFS. Calibration bars: 1 mV, 5 ms in all cases.
C. Papatheodoropoulos, G. Kostopoulos / Neuroscience Letters 279 (2000) 177±180
Fig. 3. Comparison of LTP (the effect of HFS on the EPSP slope), in the two groups of hippocampal slices taken, respectively, from the septal (circles) and temporal (triangles) region. Means ^ SEM of the percent increase of EPSP slope are shown. While in SH slices HFS produces a robust increase of EPSP slope (38.4 ^ 6.5%), in temporal slices only a small change (5.5 ^ 3%) was detected. Numbers in parenthesis represent numbers of slices.
upon the activation of NMDA receptors [2,7] (Fig. 2C). However, all these studies have been done in the septal part, which comprises the two thirds of hippocampus. We are not aware of any study comparing the ability for LTP along the septotemporal axis. In the present study, we demonstrate that most of the slices taken from the temporal third of hippocampus are unable to produce LTP in response to HFS and as a group they show a de®nite, substantial and signi®cant defect relative to those in SH. The fact that four TH slices could keep LTP without decrement suggests that the de®cit may be related to the induction or expression phase of this phenomenon rather than the maintenance. Recently, a signi®cant decrease of NMDA receptors in CA1 stratum radiatum along the septotemporal axis of hippocampus has been shown [13]. Taking into account the dependence of tetanus-induced LTP on NMDA receptors, this `de®cit' in NMDA receptors in TH may obviously provide the ®rst, at least partial, explanation of the substantially weaker ability for LTP induction reported here for the TH. In addition, TH is relatively to SH richer in aminergic and peptidergic innervation and poorer in adenosine A1 and muscarinic receptors [12,17,22]. Several of these differences may play a role in the observed TH defect of LTP. Previous studies have shown that slices from TH are less susceptible to ischemia [1] and more sensitive to epileptogenic provocations [3,6] compared to slices from SH. The latter difference is particularly interesting in association to our ®ndings in view of the proposal that epileptogenesis and LTP may share some common mechanisms [19]. The signi®cance of our ®ndings is twofold. First they provide a convenient new tool for exploring the neuronal mechanisms underlying LTP, i.e. by identifying the critical LTP induction factor, which is missing in TH. To our knowledge no other brain area has been shown to present
179
substantial regional differences in LTP. Second, our results reinforce the idea of segmentation of hippocampus along its longitudinal axis. This idea is based on well-established anatomical [5], biochemical [13] and behavioral [4] differences between SH and TH in animals, and has important implications for the proposed different roles of posterior and anterior parts of human hippocampus [18,23]. In conclusion, by comparison to the SH part, CA1 neurons from the TH part of rat hippocampus are relatively unable to show LTP with the classical paradigm of HFS in vitro. Functional segregation along the septotemporal axis may, therefore, be due not only to differences in respective external connections, but also to differences in properties of neuronal circuits intrinsic to the septal and temporal parts of hippocampus. [1] Ashton, D., Reempts, J.V., Haseldonckx, M. and Willems, R., Dorsal-ventral gradient in vulnerability of CA1 hippocampus to ischemia: a combined histological and electrophysiological study. Brain Res., 487 (1989) 368±372. [2] Bashir, Z.I., Berretta, N., Bortolotto, Z.A., Clark, K., Davies, C.H., Frenguelli, B.G., Harvey, J., Potier, B. and Collingridge, G.L., NMDA receptors and long-term potentiation in the hippocampus. In G.L. Collingridge and J.C. Watkins (Eds.), The NMDA Receptor, Oxford University Press, Oxford, 1994, pp. 295±312. [3] Bragdon, A.C., Taylor, D.M. and Wilson, W.A., Potassiuminduced epileptiform activity in area CA3 varies markedly along the septotemporal axis of the hippocampus. Brain Res., 378 (1986) 169±173. [4] Colombo, M., Fernandez, T., Nakamura, K. and Gross, C.G., Functional differentiation along the anterior-posterior axis of the hippocampus in monkeys. J. Neurophysiol., 80 (1998) 1002±1005. [5] Dolorfo, C.L. and Amaral, D.G., Entorhinal cortex of the rat: topographic organization of the cells of origin of the perforant path projection to the dentate gyrus. J. Comp. Neurol., 398 (1998) 25±48. [6] Gilbert, M., Racine, R.J. and Smith, G.K., Epileptiform burst responses in ventral vs. dorsal hippocampal slices. Brain Res., 361 (1985) 389±391. [7] Harris, K.M. and Teyler, T.J., Developmental onset of longterm potentiation in area CA1 of the rat hippocampus. J. Physiol. (Lond.), 346 (1984) 27±48. [8] Hock Jr, B.J. and Bunsey, M.D., Differential effects of dorsal and ventral hippocampal lesions. J. Neurosci., 18 (1998) 7027±7032. [9] Holscher, C., Synaptic plasticity and learning and memory: LTP and beyond. J. Neurosci. Res., 58 (1999) 62±75. [10] Izumi, Y. and Zorumski, C.F., Developmental changes in long-term potentiation in CA1 of rat hippocampal slices. Synapse, 20 (1995) 19±23. [11] Jung, M.W., Wiener, S.I. and McNaughton, B.L., Comparison of spatial ®ring characteristics of units in dorsal and ventral hippocampus of the rat. J. Neurosci., 14 (1994) 7347±7356. [12] Lee, P.H., Xie, C.W., Lewis, D.V., Wilson, W.A., Mitchell, C.L. and Hong, J.S., Opioid-induced epileptiform bursting in hippocampal slices: higher susceptibility in ventral than dorsal hippocampus. J. Pharmacol. Exp. Ther., 253 (1990) 545±551. [13] Martens, U., Capito, B. and Wree, A., Septotemporal distribution of [3H]MK-801, [3H]AMPA and [3H]Kainate binding
180
[14] [15]
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