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Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites
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Wei Fan a,∗ , Ting Fu b a b
Leibniz Institute for Neurobiology, Magdeburg, Germany Institute of Molecular Biology and Medical Chemistry, Otto-von-Guericke-University, Magdeburg, Germany
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We studied the role of somatostatin in the modulation of LTP in CA1 hippocampus. Somatostatin system enhanced late-LTP in apical dendrites. Somatostatin system was not activated during early-LTP in apical dendrites. Somatostatin system was not activated with strong tetanization in basal dendrites. Somatostatin system was activated with theta burst stimulation in basal dendrites.
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Article history: Received 14 September 2013 Received in revised form 4 December 2013 Accepted 16 December 2013
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Keywords: Hippocampus Long-term potentiation Somatostatin Apical dendrite Basal dendrite Rat
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1. Introduction
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The cyclic neuropeptide, somatostatin, is widely expressed in mammalian brain and modulates hormone secretion and neurotransmission. The long-term potentiation (LTP) at Schaffer collateral synapses onto hippocampal CA1 pyramidal neurons has been intensively studied as a cellular model of learning and memory. The apical (stratum radiatum) and basal dendrites (stratum oriens) of CA1 pyramidal neurons differ in LTP induction and maintenance. Here the role of somatostatin in the modulation of LTP was investigated in rat hippocampus. Our results show that somatostatin enhances LTP in apical and basal dendrites. However, the activation conditions of the somatostatin system are different in these two compartments. © 2013 Elsevier Ireland Ltd. All rights reserved.
Somatostatin is a cyclic peptide which has two molecular forms, a 14-residue form (SST-14) and an N-terminally extended 28-residue form (SST-28). Five G protein-coupled somatostatin receptors (SSTR1-5) have been cloned and all bind SST-14 and SST28 with low nanomolar affinity [28,31]. Somatostatin is widely distributed in mammalian brain [19] and is involved in modulation of hormone secretion and neurotransmission [42]. In rodent hippocampus, somatostatin is expressed in dentate gyrus, CA3, and CA1 regions [8] and modulates synaptic plasticity [12]. LTP [7] in hippocampus has been intensively studied as a cellular mechanism that underlies learning and memory [5,6]. LTP consists of distinct temporal phases, i.e., a protein synthesis-independent
∗ Corresponding author at: Leibniz Institute for Neurobiology, Brenneckestrasse 6, 39118 Magdeburg, Germany. Tel.: +49 17699949261. E-mail address: [email protected] (W. Fan).
early phase (early-LTP, 4 h) [21,41]. LTP at Schaffer collateral synapses onto CA1 pyramidal neurons differs between apical and basal dendrites, in magnitude [2], induction [27,34], maintenance [27] and consolidation [22]. Here we investigated the role of the somatostatin system in the modulation of LTP at apical and basal dendrites. We showed that somatostatin enhances LTP in both dendritic compartments. However, the activation conditions of the somatostatin system in apical and basal dendrites are different.
2. Materials and methods Transversal slices (400 m) of the dorsal hippocampus were prepared from male Wistar rats aged 7–8 weeks [13], in accordance with directive 2010/63/EU of the European parliament and of the council of 22 September 2010. Ethical approval was obtained from the governmental animal subjects review board. Slices were incubated in an interface chamber (volume 1.4 ml) at 32 ◦ C and the high oxygen tension was maintained by bubbling 95% O2 and
0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.12.025
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Fig. 1. The somatostatin system enhanced late-LTP in apical dendrites. (A) Location of electrodes. The analog trace shows an example of recorded fEPSP. (B) Late-LTP induced by STET (n = 12). The insets represent typical fEPSP traces recorded at 30 min before (dotted line), 30 min after (broken line), and 6 h after (full line) LTP induction. (C) Somatostatin (1 M) did not affect late-LTP (n = 10). (D) CYN 154806 (1 M) reduced late-LTP (n = 9). (E) Saline injection did not affect late-LTP (n = 8). (F) Cysteamine injection (200 mg/kg) reduced late-LTP (n = 9). (G) and (H) Summary histogram of B–E, representing the fEPSP slope 30 and 360 min after LTP induction. *p < 0.05. **p < 0.01. Filled boxes represent drug application, −30 to 30 min.
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5% CO2 (40 l/h). Slices were perfused at 0.7 ml/min with artificial cerebrospinal fluid (ACSF) containing (in mM) 124 NaCl, 4.9 KCl, 1.2 KH2 PO4 , 2.0 MgSO4 , 2.0 CaCl2 , 24.6 NaHCO3 , 10.0 d-glucose (saturated with 95% O2 and 5% CO2 , pH 7.4, ∼305 mOsm). Slices were allowed to recover for 2.5 h after preparation. Then the monopolar lacquer-coated stainless steel electrodes (571000, A-M Systems), used for recording and stimulating, were positioned in the CA1 region, as shown in Figs. 1A and 3A, for different experiments. The field EPSP (fEPSP) slope was recorded with a Model 1700 differential AC amplifier (A-M Systems) and Power 1401 analog-to-digital converter (Cambridge Electronic Design),
and monitored on-line with the custom-made software, PWIN. The test stimulation strength was determined for each input to elicit a fEPSP of 40% of its maximal slope for the control and LTP inducing inputs. Baseline recording was started at least 4 h after preparation, using test stimuli consisting of four biphasic constant current pulses (0.2 Hz; pulse duration: 0.1 ms/polarity) per time point, every 15 min for at least 1 h. In Figs. 1 and 3, late-LTP was induced with a strong tetanization (STET) protocol consisting three stimulus trains (100 pulses per train; 100 Hz; pulse duration: 0.2 ms/polarity; inter-train interval: 10 min). In Fig. 4, late-LTP was induced with a theta-burst stimulation (TBS)
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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protocol consisting three stimulus trains (ten bursts of four pulses at 100 Hz; pulse duration: 0.2 ms/polarity; inter-burst interval: 200 ms; inter-train interval: 10 min). In Fig. 2, early-LTP was induced with a weak tetanization (WTET) protocol consisting one stimulus train (19 pulses; 100 Hz; pulse duration: 0.2 ms/polarity), as described [16]. For late-LTP experiments, test stimuli were delivered 1, 3, 5, 11, 15, 21, 25, 30 min after the first tetanization or TBS train and then every 15 min up to 6 h. For early-LTP experiments, test stimuli were delivered 1, 3, 5, 10, 15, 20, 25, 30 min after the tetanization train and then every 15 min up to 2 h. Somatostatin (1 M, Tocris) [25] or CYN 154806 (1 M, Tocris) [9,25] was applied 30 min before the first tetanization train and for a total duration of 1 h or 40 min in late-LTP or early-LTP experiments, respectively. Saline (1 ml) or cysteamine (200 mg/kg, Sigma–Aldrich, dissolved in 1 ml saline, pH 7.0) was subcutaneously injected to rats 13 h prior to decapitation, as described [26,32]. Values were presented as mean ± SEM and were analyzed using the Wilcoxon signed-rank test when compared within one group, or the Mann–Whitney-U test when compared between groups.
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3. Results
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3.1. The somatostatin system enhanced late-LTP in apical dendrites First, we studied the role of the somatostatin system in the modulation of late-LTP in apical dendrites. One electrode was positioned in the CA1 apical dendritic layer to record the fEPSP. Two electrodes were placed in stratum radiatum to stimulate two independent synaptic inputs (Fig. 1A). STET induced late-LTP in “stimulation 1” pathway (Fig. 1B, 143.8 ± 4.9% of baseline at 6 h, Wilcoxon signedrank test, n = 12, P < 0.001; compared with the control pathway “stimulation 2”, Mann–Whitney-U test, P < 0.0001). Somatostatin (0.1–1 M) perfused before and during tetanic stimulation (33 Hz for 5 s) augments the mossy fiber-CA3 LTP in guinea pig hippocampus but has no significant effect on Schaffer collateral-CA1 LTP [25]. Consistent with this report, we found that somatostatin (1 M) did not significantly change the induction or maintenance of late-LTP (Fig. 1C, n = 10; compared with untreated slices: 145.0 ± 6.6% vs 152.3 ± 5.5% at 30 min, P = 0.41, Fig. 1G; 146.3 ± 9.6% vs 143.8 ± 4.9% at 6 h, P = 0.94, Fig. 1H). Depletion of somatostain with cysteamine treatment or genetic invalidation reduces Schaffer collateral-CA1 LTP in rat and mouse hippocampus [20,26,32]. We found that cysteamine (200 mg/kg) impaired the maintenance of late-LTP (compared with the saline group: Fig. 1E, n = 8; Fig. 1F, n = 9; P < 0.05 from 135 to 360 min; 114.4 ± 4.9% vs 148.9 ± 9.0% at 6 h, P < 0.01, Fig. 1H). Saline injection did not significantly affect lateLTP (P = 0.83 at 30 min, Fig. 1G; P = 0.69 at 6 h, Fig. 1H). Among the five somatostatin receptors, SSTR2, SSTR3 and SSTR5 were found in hippocampus. Because SSTR3 is expressed in the membrane of neuronal cilia [10,38,42], SSTR2 and SSTR4 are likely to play a role in the modulation of neurotransmission. SSTR2 is the most abundant somatostatin receptor in rodent hippocampus [11,35,36] and a selective SSTR2 antagonist, CYN 154806, has been reported [9,14]. We found that CYN 154806 (1 M) impaired late-LTP (Fig. 1D, n = 9; LTP lasted until 330 min, compared with “stimulation 2”; compared with untreated slices: 129.1 ± 5.6% vs 152.3 ± 5.5% at 30 min, P < 0.05, Fig. 1G; 113.2 ± 6.4% vs 143.8 ± 4.9% at 6 h, P < 0.01, Fig. 1H). These results are consistent with that the release of somatostatincontaining dense-core vesicles requires high frequency activity [4,18]. The lack of effect of application of somatostatin may due to the saturation of somatostatin receptors, in the condition of STET
Fig. 2. The somatostatin system was not activated during early-LTP in apical dendrites. (A) Early-LTP induced by WTET (n = 9). The insets represent typical fEPSP traces recorded at 30 min before (dotted line) and 60 min after (full line) LTP induction. (B) Somatostatin (1 M) enhanced early-LTP (n = 9). (C) CYN 154806 (1 M) did not affect late-LTP (n = 9). Filled boxes represent drug application, −30 to 10 min.
protocol. The role of SSTR4 was not studied due to the lack of a selective SSTR4 antagonist. Then, we studied the role of somatostatin system in the modulation of early-LTP in apical dendrites. WTET induced early-LTP with a duration of no less than 120 min (Fig. 2A, 113.8 ± 2.7% of baseline at 120 min, n = 9, P < 0.05; compared with “stimulation 2”, P < 0.01). We found that somatostatin (1 M) enhanced early-LTP (Fig. 2B, n = 8; compared with untreated slices: P < 0.05 from 25 to 60 min; 124.6 ± 3.4% vs 113.7 ± 2.0% at 60 min), whereas CYN 154806 (1 M) had no significant effect on early-LTP (Fig. 2C, n = 10; compared with untreated slices: 115.0 ± 3.0% vs 114.4 ± 1.8% at 30 min, P = 0.69; 114.7 ± 3.0% vs 113.7 ± 2.0% at 60 min, P = 0.64; 111.4 ± 2.4% vs 113.8 ± 2.7% at 120 min, P = 0.50). These results suggest that a short train of high frequency stimulation (19 pulses, 100 Hz) is not strong enough to release somatostatin.
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Fig. 3. The somatostatin system was not activated with STET in basal dendrites. (A) Location of two recording electrodes in stratum oriens and stratum radiatum, and their corresponding stimulating electrodes. (B) Late-LTP induced by STET (n = 12). (C) Somatostatin (1 M) enhanced late-LTP (n = 11). (D) CYN 154806 (1 M) did not affect late-LTP (n = 8). (E) Saline injection did not affect late-LTP (n = 8). (F) Cysteamine injection (200 mg/kg) did not affect late-LTP (n = 9). (G) and (H) Summary histogram of B-E. Insets and boxes as in Fig. 1.
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3.2. The somatostatin system was activated with theta-burst stimulation in basal dendrites, but not with strong tetanization Finally, we studied the role of the somatostatin system in the modulation of late-LTP in basal dendrites. In CA1 stratum oriens, tetanic stimulation could induce a slowly developing potentiation in the untetanized control pathway [29]. To avoid this interference, we employed the synaptic response evoked in stratum radiatum as the control pathway. Two electrodes were positioned in the CA1 apical and basal dendritic layer, respectively, to record the fEPSP. Two stimulating electrodes were placed in stratum oriens and stratum radiatum (Fig. 3A). STET induced late-LTP in “stimulation oriens” pathway (Fig. 3B, 196.6 ± 12.6% of baseline at 6 h, n = 12,
P < 0.001; compared with the control pathway “stimulation radiatum”, P < 0.0001). Different from apical dendrites, somatostatin (1 M) enhanced late-LTP (Fig. 3C, n = 11; compared with untreated slices: 283.4 ± 11.2% vs 211.4 ± 11.8% at 30 min, P < 0.01, Fig. 3G; 260.4 ± 10.4% vs 196.6 ± 12.6% at 6 h, P < 0.01, Fig. 3H), whereas cysteamine injection (200 mg/kg) did not significantly modulate late-LTP (compared with saline group: Fig. 3E, n = 8; Fig. 3F, n = 9; 218.5 ± 15.4% vs 212.0 ± 23.2% at 30 min, P = 0.80, Fig. 3G; 193.8 ± 16.2% vs 184.8 ± 17.1% at 6 h, P = 0.80, Fig. 3H). Saline injection did not significantly affect late-LTP (P = 0.86 at 30 min, Fig. 1G; P = 0.51 at 6 h, Fig. 1H). Consistent with the effect of cysteamine, CYN 154806 (1 M) had no significant effect on late-LTP (Fig. 3D, n = 8; compared with untreated slices: 220.4 ± 21.6% vs 211.4 ± 11.8%
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Fig. 4. The somatostatin system was activated with TBS in basal dendrites. (A) Late-LTP induced by TBS (n = 10). (B) Cysteamine injection (200 mg/kg) reduced late-LTP (n = 10). (C) and (D) Summary histogram of A to B. Insets and boxes as in Fig. 1.
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at 30 min, P = 0.81, Fig. 3G; 196.4 ± 17.0% vs 196.6 ± 12.6% at 6 h, P = 0.95, Fig. 3H). These data imply that the somatostatin system is not activated with STET in basal dendrites. Theta-burst stimulation is another commonly used paradigm to induce LTP [1,23]. TBS induced a late-LTP of greater magnitude in basal dendrites (Fig. 4A, 239.0 ± 15.7% of baseline at 6 h, n = 10, P < 0.01; compared with “stimulation radiatum”, P < 0.0001), in comparison with the late-LTP induced with STET (Fig. 4C, D, 290.0 ± 20.8% vs 212.0 ± 23.2% at 30 min, P < 0.05; 239.0 ± 15.7% vs 184.8 ± 17.1% at 6 h, P < 0.05). Cysteamine impaired the maintenance of late-LTP (compared with saline group: Fig. 4A, n = 10; Fig. 4B, n = 10; P < 0.05 from 300 to 360 min; 181.6 ± 12.1% vs 239.0 ± 15.7% at 6 h, P < 0.01, Fig. 4D). These data suggest that the somatostatin system is activated with TBS in basal dendrites.
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4. Discussion
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In this study, we show that in apical dendrites, application of somatostatin has no effect on late-LTP induced with STET; SSTR2 antagonist CYN 154806 or depletion of somatostatin with cysteamine reduces late-LTP induced with STET. Our results are consistent with the reports from guinea pig [25], rat [32] and mouse hippocampus [20]. On the contrary, in basal dendrites, we find that somatostatin enhances late-LTP induced with STET in basal dendrites; CYN 154806 or cysteamine has no effect on late-LTP induced with STET. Interestingly, we find that cysteamine impairs the lateLTP induced by TBS in basal dendrites. These findings indicate that somatostatin can enhance LTP in apical and basal dendrites. However, the activation conditions of the somatostatin system are different in these two dendritic compartments. The somatostatin system can be activated with STET in apical dendrites, but not in basal dendrites; and it can be activated with TBS in basal dendrites. What mechanism can account for this difference? SSTR2 has two splice variants SSTR2A and SSTR2B [10]. SSTR2A was found in both apical and basal dendrites [10,11]. The expression of SSTR2B was obvious in apical dendrites, but not in basal dendrites [36]. SSTR4 was reported to be more abundant in apical dendrites than in basal
dendrites [37–39]. Taken together, somatostatin receptors are less expressed in basal dendrites. In the CA1 region of hippocampus, the majority of somatostatin-immunoreactive cells are located in stratum oriens-alveus [8,19], which are oriens-lacunosum moleculare (O-LM) and oriens-bistratified (O-Bi) interneurons [15,42]. The O-LM cell represents the larger proportion and projects its axon to the distal apical dendrites of pyramidal neurons in stratum lacunosum-moleculare. The O-Bi cell projects its axon to both apical and basal dendrites in stratum radiatum and stratum oriens [24]. Like other neuropeptides, somatostatin binds to its receptors via extrasynaptic and long distance volume transmission [3,17]. Therefore, when O-LM and O-Bi cells are activated to release somatostatin, the concentration of somatostatin should be higher in stratum radiatum than that in stratum oriens. In summary, lower expression of somatostatin receptors in basal dendrites and lower concentration of released somatostatin in stratum oriens provide explanations for our results. Therefore, a stronger input may be required to activate somatostatin-mediated modulation of synaptic plasticity in basal dendrites. We show that TBS, which induces a late-LTP of greater magnitude, can activate the somatostatin system (Fig. 4). These data support our hypothesis. CA2 pyramidal neurons innervate both CA1 stratum radiatum and oriens, but with a preference for oriens [40]. The laminaspecific projection pattern is a valuable clue to investigate the mechanism of the difference between apical and basal dendrites. In rat dorsal hippocampus, CA1 stratum oriens receives more innervations from the contralateral CA3, whereas CA1 stratum radiatum receives more from the ipsilateral CA3 [40]. In our in vitro study, the innervations from the contralateral hippocampus were cut off, meaning that a larger proportion of inputs to stratum oriens were missing, in comparison to stratum radiatum. Therefore, it is interesting to study the role of the somatostatin system in the modulation of synaptic plasticity in vivo. The distal and proximal apical dendrites of a CA1 pyramidal neuron differ in plasticity thresholds [30,33]. It is interesting to compare the role of somatostatin in modulation of LTP and the activation condition of somatostatin system in these two compartments in further studies.
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites
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Wei Fan a,∗ , Ting Fu b a b
Leibniz Institute for Neurobiology, Magdeburg, Germany Institute of Molecular Biology and Medical Chemistry, Otto-von-Guericke-University, Magdeburg, Germany
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h i g h l i g h t s • • • • •
We studied the role of somatostatin in the modulation of LTP in CA1 hippocampus. Somatostatin system enhanced late-LTP in apical dendrites. Somatostatin system was not activated during early-LTP in apical dendrites. Somatostatin system was not activated with strong tetanization in basal dendrites. Somatostatin system was activated with theta burst stimulation in basal dendrites.
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Article history: Received 14 September 2013 Received in revised form 4 December 2013 Accepted 16 December 2013
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Keywords: Hippocampus Long-term potentiation Somatostatin Apical dendrite Basal dendrite Rat
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1. Introduction
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The cyclic neuropeptide, somatostatin, is widely expressed in mammalian brain and modulates hormone secretion and neurotransmission. The long-term potentiation (LTP) at Schaffer collateral synapses onto hippocampal CA1 pyramidal neurons has been intensively studied as a cellular model of learning and memory. The apical (stratum radiatum) and basal dendrites (stratum oriens) of CA1 pyramidal neurons differ in LTP induction and maintenance. Here the role of somatostatin in the modulation of LTP was investigated in rat hippocampus. Our results show that somatostatin enhances LTP in apical and basal dendrites. However, the activation conditions of the somatostatin system are different in these two compartments. © 2013 Elsevier Ireland Ltd. All rights reserved.
Somatostatin is a cyclic peptide which has two molecular forms, a 14-residue form (SST-14) and an N-terminally extended 28-residue form (SST-28). Five G protein-coupled somatostatin receptors (SSTR1-5) have been cloned and all bind SST-14 and SST28 with low nanomolar affinity [28,31]. Somatostatin is widely distributed in mammalian brain [19] and is involved in modulation of hormone secretion and neurotransmission [42]. In rodent hippocampus, somatostatin is expressed in dentate gyrus, CA3, and CA1 regions [8] and modulates synaptic plasticity [12]. LTP [7] in hippocampus has been intensively studied as a cellular mechanism that underlies learning and memory [5,6]. LTP consists of distinct temporal phases, i.e., a protein synthesis-independent
∗ Corresponding author at: Leibniz Institute for Neurobiology, Brenneckestrasse 6, 39118 Magdeburg, Germany. Tel.: +49 17699949261. E-mail address: [email protected] (W. Fan).
early phase (early-LTP, 4 h) [21,41]. LTP at Schaffer collateral synapses onto CA1 pyramidal neurons differs between apical and basal dendrites, in magnitude [2], induction [27,34], maintenance [27] and consolidation [22]. Here we investigated the role of the somatostatin system in the modulation of LTP at apical and basal dendrites. We showed that somatostatin enhances LTP in both dendritic compartments. However, the activation conditions of the somatostatin system in apical and basal dendrites are different.
2. Materials and methods Transversal slices (400 m) of the dorsal hippocampus were prepared from male Wistar rats aged 7–8 weeks [13], in accordance with directive 2010/63/EU of the European parliament and of the council of 22 September 2010. Ethical approval was obtained from the governmental animal subjects review board. Slices were incubated in an interface chamber (volume 1.4 ml) at 32 ◦ C and the high oxygen tension was maintained by bubbling 95% O2 and
0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.12.025
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Fig. 1. The somatostatin system enhanced late-LTP in apical dendrites. (A) Location of electrodes. The analog trace shows an example of recorded fEPSP. (B) Late-LTP induced by STET (n = 12). The insets represent typical fEPSP traces recorded at 30 min before (dotted line), 30 min after (broken line), and 6 h after (full line) LTP induction. (C) Somatostatin (1 M) did not affect late-LTP (n = 10). (D) CYN 154806 (1 M) reduced late-LTP (n = 9). (E) Saline injection did not affect late-LTP (n = 8). (F) Cysteamine injection (200 mg/kg) reduced late-LTP (n = 9). (G) and (H) Summary histogram of B–E, representing the fEPSP slope 30 and 360 min after LTP induction. *p < 0.05. **p < 0.01. Filled boxes represent drug application, −30 to 30 min.
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5% CO2 (40 l/h). Slices were perfused at 0.7 ml/min with artificial cerebrospinal fluid (ACSF) containing (in mM) 124 NaCl, 4.9 KCl, 1.2 KH2 PO4 , 2.0 MgSO4 , 2.0 CaCl2 , 24.6 NaHCO3 , 10.0 d-glucose (saturated with 95% O2 and 5% CO2 , pH 7.4, ∼305 mOsm). Slices were allowed to recover for 2.5 h after preparation. Then the monopolar lacquer-coated stainless steel electrodes (571000, A-M Systems), used for recording and stimulating, were positioned in the CA1 region, as shown in Figs. 1A and 3A, for different experiments. The field EPSP (fEPSP) slope was recorded with a Model 1700 differential AC amplifier (A-M Systems) and Power 1401 analog-to-digital converter (Cambridge Electronic Design),
and monitored on-line with the custom-made software, PWIN. The test stimulation strength was determined for each input to elicit a fEPSP of 40% of its maximal slope for the control and LTP inducing inputs. Baseline recording was started at least 4 h after preparation, using test stimuli consisting of four biphasic constant current pulses (0.2 Hz; pulse duration: 0.1 ms/polarity) per time point, every 15 min for at least 1 h. In Figs. 1 and 3, late-LTP was induced with a strong tetanization (STET) protocol consisting three stimulus trains (100 pulses per train; 100 Hz; pulse duration: 0.2 ms/polarity; inter-train interval: 10 min). In Fig. 4, late-LTP was induced with a theta-burst stimulation (TBS)
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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protocol consisting three stimulus trains (ten bursts of four pulses at 100 Hz; pulse duration: 0.2 ms/polarity; inter-burst interval: 200 ms; inter-train interval: 10 min). In Fig. 2, early-LTP was induced with a weak tetanization (WTET) protocol consisting one stimulus train (19 pulses; 100 Hz; pulse duration: 0.2 ms/polarity), as described [16]. For late-LTP experiments, test stimuli were delivered 1, 3, 5, 11, 15, 21, 25, 30 min after the first tetanization or TBS train and then every 15 min up to 6 h. For early-LTP experiments, test stimuli were delivered 1, 3, 5, 10, 15, 20, 25, 30 min after the tetanization train and then every 15 min up to 2 h. Somatostatin (1 M, Tocris) [25] or CYN 154806 (1 M, Tocris) [9,25] was applied 30 min before the first tetanization train and for a total duration of 1 h or 40 min in late-LTP or early-LTP experiments, respectively. Saline (1 ml) or cysteamine (200 mg/kg, Sigma–Aldrich, dissolved in 1 ml saline, pH 7.0) was subcutaneously injected to rats 13 h prior to decapitation, as described [26,32]. Values were presented as mean ± SEM and were analyzed using the Wilcoxon signed-rank test when compared within one group, or the Mann–Whitney-U test when compared between groups.
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3. Results
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3.1. The somatostatin system enhanced late-LTP in apical dendrites First, we studied the role of the somatostatin system in the modulation of late-LTP in apical dendrites. One electrode was positioned in the CA1 apical dendritic layer to record the fEPSP. Two electrodes were placed in stratum radiatum to stimulate two independent synaptic inputs (Fig. 1A). STET induced late-LTP in “stimulation 1” pathway (Fig. 1B, 143.8 ± 4.9% of baseline at 6 h, Wilcoxon signedrank test, n = 12, P < 0.001; compared with the control pathway “stimulation 2”, Mann–Whitney-U test, P < 0.0001). Somatostatin (0.1–1 M) perfused before and during tetanic stimulation (33 Hz for 5 s) augments the mossy fiber-CA3 LTP in guinea pig hippocampus but has no significant effect on Schaffer collateral-CA1 LTP [25]. Consistent with this report, we found that somatostatin (1 M) did not significantly change the induction or maintenance of late-LTP (Fig. 1C, n = 10; compared with untreated slices: 145.0 ± 6.6% vs 152.3 ± 5.5% at 30 min, P = 0.41, Fig. 1G; 146.3 ± 9.6% vs 143.8 ± 4.9% at 6 h, P = 0.94, Fig. 1H). Depletion of somatostain with cysteamine treatment or genetic invalidation reduces Schaffer collateral-CA1 LTP in rat and mouse hippocampus [20,26,32]. We found that cysteamine (200 mg/kg) impaired the maintenance of late-LTP (compared with the saline group: Fig. 1E, n = 8; Fig. 1F, n = 9; P < 0.05 from 135 to 360 min; 114.4 ± 4.9% vs 148.9 ± 9.0% at 6 h, P < 0.01, Fig. 1H). Saline injection did not significantly affect lateLTP (P = 0.83 at 30 min, Fig. 1G; P = 0.69 at 6 h, Fig. 1H). Among the five somatostatin receptors, SSTR2, SSTR3 and SSTR5 were found in hippocampus. Because SSTR3 is expressed in the membrane of neuronal cilia [10,38,42], SSTR2 and SSTR4 are likely to play a role in the modulation of neurotransmission. SSTR2 is the most abundant somatostatin receptor in rodent hippocampus [11,35,36] and a selective SSTR2 antagonist, CYN 154806, has been reported [9,14]. We found that CYN 154806 (1 M) impaired late-LTP (Fig. 1D, n = 9; LTP lasted until 330 min, compared with “stimulation 2”; compared with untreated slices: 129.1 ± 5.6% vs 152.3 ± 5.5% at 30 min, P < 0.05, Fig. 1G; 113.2 ± 6.4% vs 143.8 ± 4.9% at 6 h, P < 0.01, Fig. 1H). These results are consistent with that the release of somatostatincontaining dense-core vesicles requires high frequency activity [4,18]. The lack of effect of application of somatostatin may due to the saturation of somatostatin receptors, in the condition of STET
Fig. 2. The somatostatin system was not activated during early-LTP in apical dendrites. (A) Early-LTP induced by WTET (n = 9). The insets represent typical fEPSP traces recorded at 30 min before (dotted line) and 60 min after (full line) LTP induction. (B) Somatostatin (1 M) enhanced early-LTP (n = 9). (C) CYN 154806 (1 M) did not affect late-LTP (n = 9). Filled boxes represent drug application, −30 to 10 min.
protocol. The role of SSTR4 was not studied due to the lack of a selective SSTR4 antagonist. Then, we studied the role of somatostatin system in the modulation of early-LTP in apical dendrites. WTET induced early-LTP with a duration of no less than 120 min (Fig. 2A, 113.8 ± 2.7% of baseline at 120 min, n = 9, P < 0.05; compared with “stimulation 2”, P < 0.01). We found that somatostatin (1 M) enhanced early-LTP (Fig. 2B, n = 8; compared with untreated slices: P < 0.05 from 25 to 60 min; 124.6 ± 3.4% vs 113.7 ± 2.0% at 60 min), whereas CYN 154806 (1 M) had no significant effect on early-LTP (Fig. 2C, n = 10; compared with untreated slices: 115.0 ± 3.0% vs 114.4 ± 1.8% at 30 min, P = 0.69; 114.7 ± 3.0% vs 113.7 ± 2.0% at 60 min, P = 0.64; 111.4 ± 2.4% vs 113.8 ± 2.7% at 120 min, P = 0.50). These results suggest that a short train of high frequency stimulation (19 pulses, 100 Hz) is not strong enough to release somatostatin.
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Fig. 3. The somatostatin system was not activated with STET in basal dendrites. (A) Location of two recording electrodes in stratum oriens and stratum radiatum, and their corresponding stimulating electrodes. (B) Late-LTP induced by STET (n = 12). (C) Somatostatin (1 M) enhanced late-LTP (n = 11). (D) CYN 154806 (1 M) did not affect late-LTP (n = 8). (E) Saline injection did not affect late-LTP (n = 8). (F) Cysteamine injection (200 mg/kg) did not affect late-LTP (n = 9). (G) and (H) Summary histogram of B-E. Insets and boxes as in Fig. 1.
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3.2. The somatostatin system was activated with theta-burst stimulation in basal dendrites, but not with strong tetanization Finally, we studied the role of the somatostatin system in the modulation of late-LTP in basal dendrites. In CA1 stratum oriens, tetanic stimulation could induce a slowly developing potentiation in the untetanized control pathway [29]. To avoid this interference, we employed the synaptic response evoked in stratum radiatum as the control pathway. Two electrodes were positioned in the CA1 apical and basal dendritic layer, respectively, to record the fEPSP. Two stimulating electrodes were placed in stratum oriens and stratum radiatum (Fig. 3A). STET induced late-LTP in “stimulation oriens” pathway (Fig. 3B, 196.6 ± 12.6% of baseline at 6 h, n = 12,
P < 0.001; compared with the control pathway “stimulation radiatum”, P < 0.0001). Different from apical dendrites, somatostatin (1 M) enhanced late-LTP (Fig. 3C, n = 11; compared with untreated slices: 283.4 ± 11.2% vs 211.4 ± 11.8% at 30 min, P < 0.01, Fig. 3G; 260.4 ± 10.4% vs 196.6 ± 12.6% at 6 h, P < 0.01, Fig. 3H), whereas cysteamine injection (200 mg/kg) did not significantly modulate late-LTP (compared with saline group: Fig. 3E, n = 8; Fig. 3F, n = 9; 218.5 ± 15.4% vs 212.0 ± 23.2% at 30 min, P = 0.80, Fig. 3G; 193.8 ± 16.2% vs 184.8 ± 17.1% at 6 h, P = 0.80, Fig. 3H). Saline injection did not significantly affect late-LTP (P = 0.86 at 30 min, Fig. 1G; P = 0.51 at 6 h, Fig. 1H). Consistent with the effect of cysteamine, CYN 154806 (1 M) had no significant effect on late-LTP (Fig. 3D, n = 8; compared with untreated slices: 220.4 ± 21.6% vs 211.4 ± 11.8%
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Fig. 4. The somatostatin system was activated with TBS in basal dendrites. (A) Late-LTP induced by TBS (n = 10). (B) Cysteamine injection (200 mg/kg) reduced late-LTP (n = 10). (C) and (D) Summary histogram of A to B. Insets and boxes as in Fig. 1.
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at 30 min, P = 0.81, Fig. 3G; 196.4 ± 17.0% vs 196.6 ± 12.6% at 6 h, P = 0.95, Fig. 3H). These data imply that the somatostatin system is not activated with STET in basal dendrites. Theta-burst stimulation is another commonly used paradigm to induce LTP [1,23]. TBS induced a late-LTP of greater magnitude in basal dendrites (Fig. 4A, 239.0 ± 15.7% of baseline at 6 h, n = 10, P < 0.01; compared with “stimulation radiatum”, P < 0.0001), in comparison with the late-LTP induced with STET (Fig. 4C, D, 290.0 ± 20.8% vs 212.0 ± 23.2% at 30 min, P < 0.05; 239.0 ± 15.7% vs 184.8 ± 17.1% at 6 h, P < 0.05). Cysteamine impaired the maintenance of late-LTP (compared with saline group: Fig. 4A, n = 10; Fig. 4B, n = 10; P < 0.05 from 300 to 360 min; 181.6 ± 12.1% vs 239.0 ± 15.7% at 6 h, P < 0.01, Fig. 4D). These data suggest that the somatostatin system is activated with TBS in basal dendrites.
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4. Discussion
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In this study, we show that in apical dendrites, application of somatostatin has no effect on late-LTP induced with STET; SSTR2 antagonist CYN 154806 or depletion of somatostatin with cysteamine reduces late-LTP induced with STET. Our results are consistent with the reports from guinea pig [25], rat [32] and mouse hippocampus [20]. On the contrary, in basal dendrites, we find that somatostatin enhances late-LTP induced with STET in basal dendrites; CYN 154806 or cysteamine has no effect on late-LTP induced with STET. Interestingly, we find that cysteamine impairs the lateLTP induced by TBS in basal dendrites. These findings indicate that somatostatin can enhance LTP in apical and basal dendrites. However, the activation conditions of the somatostatin system are different in these two dendritic compartments. The somatostatin system can be activated with STET in apical dendrites, but not in basal dendrites; and it can be activated with TBS in basal dendrites. What mechanism can account for this difference? SSTR2 has two splice variants SSTR2A and SSTR2B [10]. SSTR2A was found in both apical and basal dendrites [10,11]. The expression of SSTR2B was obvious in apical dendrites, but not in basal dendrites [36]. SSTR4 was reported to be more abundant in apical dendrites than in basal
dendrites [37–39]. Taken together, somatostatin receptors are less expressed in basal dendrites. In the CA1 region of hippocampus, the majority of somatostatin-immunoreactive cells are located in stratum oriens-alveus [8,19], which are oriens-lacunosum moleculare (O-LM) and oriens-bistratified (O-Bi) interneurons [15,42]. The O-LM cell represents the larger proportion and projects its axon to the distal apical dendrites of pyramidal neurons in stratum lacunosum-moleculare. The O-Bi cell projects its axon to both apical and basal dendrites in stratum radiatum and stratum oriens [24]. Like other neuropeptides, somatostatin binds to its receptors via extrasynaptic and long distance volume transmission [3,17]. Therefore, when O-LM and O-Bi cells are activated to release somatostatin, the concentration of somatostatin should be higher in stratum radiatum than that in stratum oriens. In summary, lower expression of somatostatin receptors in basal dendrites and lower concentration of released somatostatin in stratum oriens provide explanations for our results. Therefore, a stronger input may be required to activate somatostatin-mediated modulation of synaptic plasticity in basal dendrites. We show that TBS, which induces a late-LTP of greater magnitude, can activate the somatostatin system (Fig. 4). These data support our hypothesis. CA2 pyramidal neurons innervate both CA1 stratum radiatum and oriens, but with a preference for oriens [40]. The laminaspecific projection pattern is a valuable clue to investigate the mechanism of the difference between apical and basal dendrites. In rat dorsal hippocampus, CA1 stratum oriens receives more innervations from the contralateral CA3, whereas CA1 stratum radiatum receives more from the ipsilateral CA3 [40]. In our in vitro study, the innervations from the contralateral hippocampus were cut off, meaning that a larger proportion of inputs to stratum oriens were missing, in comparison to stratum radiatum. Therefore, it is interesting to study the role of the somatostatin system in the modulation of synaptic plasticity in vivo. The distal and proximal apical dendrites of a CA1 pyramidal neuron differ in plasticity thresholds [30,33]. It is interesting to compare the role of somatostatin in modulation of LTP and the activation condition of somatostatin system in these two compartments in further studies.
Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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Please cite this article in press as: W. Fan, T. Fu, Somatostatin modulates LTP in hippocampal CA1 pyramidal neurons: Differential activation conditions in apical and basal dendrites, Neurosci. Lett. (2013), http://dx.doi.org/10.1016/j.neulet.2013.12.025
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