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1Department of Neuroscience, University of Rome "Tor Vergata"; 2Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello; and 3Institute of Neurobiology and Molecular Medicine, Rome, Italy
Submitted 29 April 2005; accepted in final form 2 June 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors from rat cerebellar granule cells in culture to assess the ability of these peptides to regulate the glutamatergic input. Both NKA and NKB, but not SP, produce a significant enhancement of ionic current through AMPA receptors activated by the agonist kainate in 53.5 and 46% of patched neurons, respectively. This effect was not observable in the presence of MEN 10,627 and Trp7
Ala8, NKA and NKB competitive antagonist receptors, respectively, indicating that the current modulations were mediated by the respective receptors. NKB also produces a significant enhancement of ionic current through the AMPA receptors activated directly by its agonist AMPA and cyclothiazide, an allosteric modulator that selectively suppresses desensitization of AMPA receptors. The presence of NK3 receptors was demonstrated in these neurons by RT-PCR amplification of total RNA extracted from cerebellar granule cells, using NK3-specific primer pairs. Immunocytochemistry experiments, using a specific polyclonal antibody directed against NK3, also confirmed the presence of NK3 receptors and their co-localization with the GLUR2 AMPA subunit in about 54% of cerebellar granule neurons. This study adds the tachykinins to the list of neuromodulators capable of exerting a excitatory action on cerebellar granule cells. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Severini et al. 2002) and display a relative specificity for three subtypes of heterotrimeric G-protein–linked receptors, neurokinin-1 (NK1), neurokinin-2 (NK2), and neurokinin-3 (NK3), respectively (Ingi et al. 1991; Maggi 1995; Regoli et al. 1994). Activation of these receptors induces multiple intracellular signaling mechanisms, including the inositol triphosphate (IP3) and cAMP-signaling pathways (Mitsuhashi et al. 1992; Nakajima et al. 1992). There is widespread acceptance that TKs have a variety of effects in physiological and pathological conditions (Longmore et al. 1997; Ogier and Raggenbass 2003; Yang et al. 2003) and that they have neuroprotective and neurodegenerative properties (Raffa 1998; Severini et al. 2002). Previous studies have demonstrated that the TKs can depolarize central neurons by their ability to modulate the activity of a wide range of ion channels. For example, within the locus coeruleus, substance P has been shown not only to activate a nonselective cation conductance but also to inhibit an inwardly rectifying K+ conductance (Shen and North 1992), to activate a nonselective Ca2+-mediated cation conductance in striatal cholinergic interneurons (Bell et al. 1998), and to inhibit hippocampal pyramidal neurons by exciting hippocampal interneurons, probably by a suppression of a resting K+ conductance (Ogier and Raggenbass 2003). In addition, it has been reported that activation of NK2 receptors enhances both L-type and N-type Ca2+ currents, whereas activation of NK3 receptors inhibits N-type Ca2+ currents in dissociated dorsal root ganglia neurons (Sculptoreanu and de Groat 2003). Moreover, it has been shown that agonists selective for TK receptor subtypes are able to modulate responses to excitatory amino acids both in vitro (Randic et al. 1990) and in vivo (Dougherty and Willis 1990), playing an important synergistic role in mediating neurotransmission. In fact, it has been reported that NK1 can result in increases in release of both 
-aminobutyric acid-A (GABA) and glutamate, suggesting a crucial modulatory role for NK1 receptors in the rat nucleus tractus solitarius (Bailey et al. 2004) and in rat entorhinal cortex (Maubach et al. 1998).
Growing evidence has indicated that glutamate receptor-mediating excitotoxicity is one of the crucial factors resulting in degenerative diseases or severe motor disturbances such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis disease in human beings (Beal 1992; Blandini et al. 1996; Raffa 1998). Tachykinins appear to be involved in several regulatory functions, often in synergy with glutamate excitatory transmission (Hill 2002; Quartara and Maggi 1998; Rupniak and Kramer 1999; Saria 1999). In fact, it has been recognized that TKs have a variety of effects in physiological and pathological conditions, suggesting intrinsic neuroprotective and neurodegenerative properties (Raffa 1998; Severini et al. 2002). For example, by regulating the activity of hippocampal interneurons (Ogier and Raggenbass 2003), endogenous tachykinins may potentially influence learning and memory formation and may play some role in epileptic seizures. In fact, facilitating the induction of status epilepticus, tachykinins have been implicated in epileptogenesis within temporal lobe structures such as the hip-pocampus and entorhinal cortex, as recently reported (Liu et al. 1999; Maubach et al. 1998; Schwarzer et al. 1995). In addition, a slow, persistent increase of NKB in the rat hippocampus after kainic acid–induced seizures, has been demonstrated (Marksteiner et al. 1992; Schwarzer et al. 1995). It is well known that both glutamate-driving excitatory neurotransmission and glutamate excitotoxicity are mainly mediated by N-methyl-D-aspartate (NMDA), -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainic acid (KA) glutamate receptors (Beal 1992; Hollmann and Heinemann 1994).
Although it has been shown that there are several excitatory systems in different cerebral areas that can be modulated by TKs, until now no direct evidence has been reported on their effects on the AMPA glutamate receptors. Previous work has shown that the TKs are present in rat cerebellum (Otsuka and Yoshioka 1993) and that the glutamate-mediated toxicity is increased by TKs in cultured cerebellar granule cells (Severini et al. 2002), although the presence of these receptors and their possible function in granule cells has not been reported to date.
To determine the possible modulatory effect of tachykinins on the excitability of rat cerebellum, and in particular on the glutamate receptors, we have examined the effect of SP, NKA, and NKB on AMPA receptors from cerebellar granule cells (CGCs) in culture. We have observed that NKA and NKB, but not SP, produce a significant enhancement of current through AMPA receptors, indicating their involvement in the control of the cerebellar excitability.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Cultures enriched in granule neurons were obtained from dissociated cerebella of 8-day-old Wistar rats as previously described by Levi et al. (1984). Cells were plated in basal Eagle’s medium (BME; Gibco, Milan, Italy) supplemented with 10% FCS (Gibco), 25 mM KCl, 2 mM glutamine (Gibco), and 100 µg/ml gentamycin (Gibco) in 12-well clusters (Costar, 4 cm2 growth area, 22.6 mm well diameter), previously coated with poly-L-lysine. Cells were plated at a constant density of 1.2 x 106 cells/well, in BME volumes of 2 ml.
Whole cell patch-clamp recordings
Whole cell patch-clamp recordings were made from CGCs 8–10 days old in culture. The recording electrodes were pulled from borosilicate glass with an outer diameter of 1.2 mm and had open tip resistances of 4–5 M
. To record the kainite- and AMPA-induced currents the internal solution for filling electrodes consisted of (in mM) 140 CsCl, 1 EGTA, 10 HEPES, and 6 D-glucose, pH 7.4 with CsOH. Our standard extracellular solution consisted of (in mM) 130 NaCl, 3 KCl, 2 MgCl2, 1.5 CaCl2, 10 HEPES, 6 D-glucose, and 10 tetraethyl-ammonium (TEA) Cl, pH 7.4 with NaOH. Recordings were obtained with an Axopatch-200B amplifier (Axon Instruments, Union City, CA). Experiments were performed at room temperature (22–24°C). After the establishment of a gigaseal, the pipette resistance and capacitance were compensated electronically. Current signals were digitized at 50 kHz and filtered at 10 kHz.
Statistical analyses were performed using SPSS 11.0.0 for Windows (SPSS, Chicago, IL). Average data are shown as means ± SE, with n the number of tested cells. The criterion we used to determine the patched cells in which the AMPA currents were increased in the presence of TKs was to choose those patches that have an increase in the mean current of more than half of the noise value (i.e., 5%). We considered as ineffective the action of the TKs in those neurons with an increase of the current amplitude equal to or less than this value (5%).
The significance of the effect was performed by one-way ANOVA followed by Bonferroni’s test for multiple comparisons when necessary or by paired Student’s t-test. The significance level was set to 0.05.
Chemical compounds
Substance P, NKA, NKB, and Trp7Ala8 were purchased from Bachem (Bubendorf, Switzerland). MEN 10,627 [cyclo(Met-Asp-Trp-Phe-Dap-Leu)-cyclo(2b-5b)] was a gift from Professor V. Erspamer, Rome. 1-(4-Aminophenil)-3-methylcarbamyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI53655) was a gift from Professor A. Guidotti, Chicago, IL. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) and cyclothiazide (CTZ) were from Tocris Cookson (Bristol, UK). Tetrodotoxin (TTX) was from Alomone (Jerusalem, Israel). Kainate and AMPA were dissolved in water. GYKI53655 and cyclothiazide were dissolved in dimethylsulfoxide (DMSO) before being diluted to their final concentration in standard extracellular bath solution immediately before use. Stock solutions of the peptides (1–5 mM) were made, according to their solubility, either in 80% DMSO or in ethanol, stored at 4°C, and then diluted in water just before use. Unless otherwise stated, the compounds to be tested were added to the perfusion solution. In a separate series of experiments we ensured that DMSO and ethanol concentrations had no effect on evoked responses. Tachykinin receptor agonists and antagonists were applied by multibarrel pipette gravity perfusion system controlled by electronic valves positioned near the soma of the recorded neuron using a fast perfusion system (SF-77B, Warner Instruments, Hamden, CT). The total solution exchange time constant was about 20 ms (Hatton et al. 2003).
RT-PCR studies
Total RNA was isolated from a 6-day-old culture of postnatal cerebellar granule neurons by the method of Comczynski and Sacchi (1987). RNA concentration was measured by spectrophotometry (
= 260/280 nm). One microgram of total RNA was reverse transcribed using reverse transcriptase, oligo-dT primers, and dNTP mix (Promega) for 1 h at 37°C. Two microliters of solution resulting from the RT reaction were used as template and added to 50 µl of PCR reaction mixture containing: 0.2 µM of forward (5'-GAG AGA TCC CAG GAG ACA-3') and reverse (5'-TGG GGT CAA ACA GCA CGG-3') specific primers for NK3 (Cintado et al. 2001) synthesized by Invitrogen (Life Technologies), 0.2 mM of each dNTP, 1.5 mM of MgCl2, and 0.5 µl of TaqPolymerase (Promega). After denaturation (94°C for 2 min), amplifications are carried out for 36 cycles of 94°C/15 s, 60°C/20 s, and 72°C/30 s. Ten microliters of each PCR product were estimated by comparison with the migration of a standard molecular weight marker series. Negative control was realized by omitting the enzyme in the reverse transcriptase reaction step.
Immunocytochemistry
CGCs were stained for 1 h at 4°C, using monoclonal antibody anti-GLUR2 1:500 (mab397, Chemicon; Abe et al. 2004) and rabbit polyclonal anti-NK3 1:400 (NB 300–102, Novus Biologicals; Howe et al. 2004; Yip et al. 2001), rinsed in phosphate-buffered saline (PBS) and fixed with 4% (wt/vol in PBS) paraformaldehyde for 30 min at room temperature. Fixed cells were washed in PBS, pH 7.4, and stained with rhodamine (TRITC) and fluorescein (FITC) conjugated secondary antibodies (Alexis) for 30 min at room temperature in a moist chamber. Nuclei were stained with Hoechst 33258 (0.5 mg/ml; Sigma) in PBS for 5 min. Neurons were then visualized by fluorescent microscopy (Zeiss, Oberkochen, Germany). Neurons were counted on immunofluorescence-labeled coverslips, using a 100x objective and a 10 x eye piece on an Olympus BX51 photomicroscope. CGCs were scored by counting 12 microscopic fields per coverslip in two coverslips from four experiments.
Controls to assess primary antibodies specificity were performed for the immunofluorescence procedure by including omission of the primary antibodies. In these samples no immunostaining was detected (data not shown).
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RESULTS |
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Whole cell recordings were obtained from CGCs 8–10 days old in culture. The neurons were voltage clamped and held at –60 mV. Bath application of kainate (200 µM) for 2–10 s induced inward currents in almost all tested neurons. Currents gated by kainate do not desensitize even with applications as long as 10 s but maintain their initial amplitude for the full duration of exposure to agonist. The current reached a plateau and returned to the baseline level after the removal of kainate (Fig. 1A). The kainate-evoked current was completely blocked by 20 µM CNQX, a competitive antagonist of AMPA/kainate receptors, indicating that kainate administration stimulated mainly non-NMDA receptors (Fig. 1B). The kainate-evoked response was mediated primarily through the activation of AMPA receptors with a negligible contribution from kainate receptors because bath application of 100 µM GYKI53655, a potent noncompetitive AMPA receptor antagonist, completely blocked the kainate-induced currents (Fig. 1C).
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; Vorobjev et al. 2000). NKB (200 nM) significantly increased (P < 0.05) the response to AMPA and CTZ in 46.6% of the patched cells (24.04 ± 6.14%; means ± SE, n = 7), whereas it was ineffective in the remaining cells (n = 8, Fig. 3). To assess the specificity of action of NK2 and NK3 receptor–preferring peptides, the use of selective antagonists was carried out. The NK2-selective competitive antagonist MEN 10,627 (1 µM; Maggi et al. 1993) and the NK3-selective competitive antagonist Trp7Ala8 (10 µM; Drapeau et al. 1990) produce an inhibition of NKA and NKB action on the kainate-activated currents, respectively. In these experiments, in all the patched cells, an increase of kainate-induced current was not observed (n = 13 for MEN 10,627 and n = 11 for Trp7Ala8), indicating that the increases of current were mediated by NK2 and NK3 receptors activation, respectively (Fig. 4).
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To demonstrate the presence of NK3 receptor in these neurons, amplification by RT-PCR using NK3-specific primer pairs on total RNA, extracted from CGCs 8 days old in culture, was used. The results obtained revealed PCR products of the predicted size (Fig. 5). No detectable amplification was observed using control samples.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Interaction between neurokinins and glutamate receptors has been found in the brain (Barker 1996; Kemel et al. 2002). Electrophysiological and pharmacological studies have shown that TKs affect neuronal activity and synaptic transmission of striatal and basal forebrain neurons, hippocampus, and spinal cord (Barker 1996; Bell et al. 1998; Chizh et al. 1995; Kouznetsova and Nistri 1998; Liu et al. 1999). Moreover, neurokinins may also play important roles in neurodegeneration or neurodegenerative diseases. It has been reported recently that TKs in the cerebral cortex exert a role in upmodulating glutamate activity (Stumm et al. 2001). NK1 receptor agonists can selectively modulate the communication between GABAergic interneurons (Kaneko et al. 1998), whereas NK2 and NK3 receptor agonists can influence the response to excitatory amino acids, increasing neuronal excitability with possible convulsive effects (Kaneko et al. 1998; Maubach et al. 1998), as demonstrated by the resistance to kainate-induced seizures and neuronal death in mice lacking the preprotachykinin A gene (Liu et al. 1999).
In vitro cultured rat CGCs represent one of the most widely used experimental models to study the physiological and toxic action of glutamate and the effects of substances that can modulate these processes (Balazs et al. 1988; Choi 1990; Eboli et al. 1993).
In this preparation, it has been recently shown that NKA and NKB exert a dose- and time-dependent upmodulating response to glutamate, whereas SP is ineffective (Severini et al. 2003). The action of these peptides in increasing glutamate response was confirmed by the inhibitory effect exerted by the NK2 and NK3 receptor antagonists, respectively.
Our reported electrophysiological data indicate a possible mechanism of action of the TKs in their growth of toxic glutamate effects. In fact, we observed in cultured CGCs a significant increase of the kainate-induced currents in the presence of NKA and NKB in 53.5 and 46% of patched cells, respectively. This effect was abolished with the respective receptor-competitive antagonists. In addition, a similar effect for NKB was observed when the AMPA glutamate receptors were activated directly by its agonist. AMPA receptors are glutamate-gated cation-selective channels that mediate most fast excitatory synaptic transmission in the mammalian brain. They are heteromeric complexes composed of various combinations of four subunits, GLUR1 to GLUR4 (Dingledine et al. 1999; Hollmann and Heinemann 1994). In particular, the GLUR2 subunit in the assembled AMPA receptors determines its Ca2+ permeability (Burnashev et al. 1992; Geiger et al. 1995). Because it is well known that activation of AMPA receptors is a possible pathway for neuronal toxicity (Liu et al. 2004; Vanderberghe et al. 2000; Weiss and Sensi 2000), it is reasonable to assume that the NKA and NKB cytotoxic action may be AMPA mediated, indicating a mechanism of action of these peptides in their growth of toxic glutamate effects in CGCs. The increase of the glutamate toxic action in the presence of NKA and NKB has been also reported in a previous paper that supposed a mode of action linked to generic glutamatergic functions (Severini et al. 2003).
Immunocytochemical studies have suggested that NK3 receptors are specifically localized to interneurons in cortex and hippocampus (Stumm et al. 2001). Cortical areas, including the entorhinal cortex, contain neurons immunoreactive for SP and NKB or their precursors, preprotachykinin A and preprotachykinin B (Kaneko et al. 1998; Seress and Leranth 1996). However, until now direct evidence for the localization of TK receptors in the rat CGC has never been reported. Our immunocytochemical studies are the first to show the presence of NK3 receptors on approximately 54% of CGCs and their co-localization with the GLUR2 subunit of the AMPA receptors. Interestingly, by electrophysiological experiments, we observed in a similar percentage of CGCs, an increase of the AMPA currents when the NK3 receptors were activated.
In conclusion, we reported that TKs are capable of exerting an excitatory action on cerebellar granule cells in culture and that this action is linked to modulation of the glutamatergic system, in particular of the ionotropic AMPA receptors. It remains to be demonstrated that the TKs can exert a similar physiological function in vivo.
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. Zona, Department of Neuroscience, University of Rome "Tor Vergata," Via Montpellier, 1, 00133 Rome, Italy (E-mail: zona{at}uniroma2.it)
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