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1 Department of Experimental Neurophysiology, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit Amsterdam, de Boelelaan 1087, 1081 HV Amsterdam, The Netherlands
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(Received 27 May 2004;
accepted after revision 23 September 2004;
first published online 30 September 2004)
Corresponding author A. B. Brussaard: Department of Experimental Neurophysiology, CNCR, Vrije Universiteit Amsterdam, de Boelelaan 1087, 1081 HV Amsterdam, The Netherlands. Email: brssrd{at}cncr.vu.nl
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Introduction |
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The hypothalamic SON is a system that is well-suited to the study of heterosynaptic modulation of GABAergic transmission by glutamate as several mechanisms of synaptic modulation have been previously reported there. Spill-over of synaptic glutamate was shown to inhibit GABA synapses by activating presynaptic metabotropic glutamate receptors (mGluRs) (Oliet et al. 2001; Piet et al. 2003). In addition, the release of oxytocin acts as retrograde signal that modulates presynaptic secretion at GABA synapses (de Kock et al. 2003). The sensitivity of oxytocin neurones to GABA is also reduced by the activation of postsynaptic oxytocin receptors on SON neurones (Brussaard et al. 1996; Brussaard & Herbison, 2000). Vesicular oxytocin release from somatic and dendritic sites in the SON is calcium dependent; it can be induced by action potential firing and is modulated by calcium release from internal stores (Pow & Morris, 1989; Kombian et al. 1997; Ludwig et al. 2002; de Kock et al. 2003). It has been postulated that NMDAR activation in the SON may directly induce oxytocin release without electrical firing activity (Morris et al. 2000; Pak & Curras-Collazo, 2002; Ludwig & Pittman, 2003). This would be a novel mechanism in which glutamatergic synaptic activity could modulate GABA synapses at membrane potentials below the threshold of action potential firing. However, the experimental evidence for this hypothesis is thus far lacking. We addressed this issue by testing whether the glutamate input of these cells would directly induce the release of oxytocin in a calcium-dependent but action potential-independent manner.
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Methods |
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Wistar rats (lactating females, postparturition days 7–9, and virgin females, 6–8 weeks; Harlan CPB, Zeist, The Netherlands) were used. Non-anaesthetized rats were decapitated, and their brains quickly removed and placed in ice-cold artificial cerebrospinal fluid (ACSF, mM: 125 NaCl, 25 NaHCO3, 3 KCl, 1.2 NaH2PO4, 2.4 CaCl2, 1.3 MgSO4, 10 D(+)-glucose (carboxygenated with 5% CO2–95% O2, 304 mosmol l–1, pH 7.4)). This method was approved by the Animal Welfare Committee of the Vrije Universiteit Amsterdam, in accordance with Dutch law. Slice preparation has been previously described (Brussaard et al. 1999). Recordings were made from neurones located in regions of the SON in which the abundance of oxytocinergic neurones is high (Hou-Yu et al. 1986). The recording chamber was continuously perfused with ACSF, consisting of (mM): 125 NaCl, 3 KCl, 1.2 NaH2PO4, 2.4 CaCl2, 1.3 MgSO4, 25 NaHCO3, 10 glucose, carboxygenated in 5% CO2–95% O2, pH 7.4. Nucleated patches used for action current-induced capacitance changes (Fig. 1) were pulled using 3–5 M
electrodes containing (mM): 135 tetraethylammonium acetate, 10 dipotassium phosphocreatine, 4 MgATP, 0.3 GTP (acid free), 0.1 EGTA, 10 Hepes, pH 7.2 with TEA-OH. NMDA (100 µM)-induced capacitance changes (Figs 2–4) were studied using intracellular medium containing (mM): 145 CsCl, 2 MgCl2, 0.1 EGTA, 10 Hepes, 2 MgATP, 0.1 GTP (acid free), pH 7.4 with CsOH. During the latter experiments Mg2+-free ACSF was used supplemented with 10 µM glycine. The nucleated patches were positioned in front of a double-barrelled electrode attached to a piezo-element. The bath solution was heated to 33°C, whereas the double-barrelled solution was not heated. In the nucleated patch configuration, experiments in which series resistances were > 20 M were rejected.
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Whole-cell slice recordings
The recording chamber was continuously perfused with ACSF. 
-Amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors were blocked with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 µM; Sigma). The glutamate re-uptake inhibitor carboxycyclo-propylglycine (L-CGG-III, 10 µM; Tocris) was added to increase extracellular glutamate levels. The specific mGluRII/III antagonist (RS)--cyclopropyl-4-phosphonophenylglycine (CPPG, 30 nM, Tocris) was used to block mGluRs which are present on the GABAergic terminals in the SON (Piet et al. 2003). DL- 2-Amino-5-phosphonopentanoic acid (APV, 10 and 50 µM; Tocris) was used to block N-methyl-D-aspartate (NMDA) receptors. To study the retrograde action of oxytocin, the specific oxytocin antagonist [des-glycinamide9,d(CH2)5,O-Me-Tyr2,Thr4,Orn8]-vasotocin (d(CH2)5-OVT) was used (vasotocin, 1 µM; Bachum, Bubendorf, Switzerland). Whole-cell recordings were made using 2–3 M patch electrodes. Electrodes were filled with (mM): 154 potassium gluconate, 1 KCl, 0.1 EGTA, 10 Hepes, 10 glucose, 5 ATP, pH 7.4 with KOH. Series resistance was typically < 12 M. The spontaneous IPSC (sIPSC) data obtained were analysed off-line using the minianalysis software Synaptosoft (Decatur, GA, USA). The effect on sIPSC interval was calculated normalized to the first 10 s interval after depolarization to –30 mV. Experiments were performed at 33°C.
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Results |
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We recorded from dorsomedial SON neurones. These cells have previously been shown to express postsynaptic oxytocin receptors in 70% of recordings (Brussaard et al. 1996). To test whether calcium influx through NMDARs is sufficient to induce exocytosis, we performed capacitance measurements (de Kock et al. 2003). Due to morphological constraints, capacitance measurements can only be performed on spherical cells (Lindau & Neher, 1988) and not on neurones with extensive processes. Hence, to directly study release from somatic compartments of putative oxytocin neurones, we used nucleated giant outside-out membrane patches pulled from dorsal medial neurones in acute SON brain slices. This preparation is well-suited for studying ligand- and voltage-gated channels in combination with the fast application of agonists (Sather et al. 1992; Rozov et al. 1998; Bekkers, 2000). After establishing whole-cell configuration in the slice, a nucleated outside-out patch was pulled and lifted above the slice (Fig. 1A, lower panel). We first tested whether the activation of voltage-gated calcium channels (VGCCs) induces vesicular secretion in this preparation. To this end, action potential templates of single action potentials (APs), recorded from dorsomedial SON neurones in slices of previous experiments (de Kock et al. 2003), were used as stimulus templates in the nucleated patch recording while also monitoring the membrane capacitance. Templates of both single APs and trains of APs induced inward currents in nucleated patches. In addition, changes in corresponding membrane capacitance were observed (Fig. 1C and D). In response to a single action potential, capacitance changes (> 5 fF) were evoked in 2 out of 8 nucleated patches (Fig. 1C). In response to a train of four APs, similar capacitance changes were observed in 4 out of 8 nucleated patches (Fig. 1D). In one experiment, exocytosis was followed by rapid endocytosis (data not shown). Our results indicate that exocytosis of vesicles can be induced in nucleated patches in an action potential-dependent manner. We previously found that single APs and AP trains reliably induced secretory events in freshly cultured oxytocin neurones in vitro (de Kock et al. 2003). The reduced reliability of the induction of vesicular secretion in the nucleated patches shown here may result from the fact that the inward currents were reduced in nucleated patches in proportion to the reduction in membrane surface area compared to intact neurones (Fig. 1B–D) and/or the detection limits of the capacitance recording method. In addition, mechanical stress induced by the formation of the nucleated patch may have interfered with the vesicular release machinery.
NMDA-mediated responses from nucleated outside-out patches
To study putative NMDAR-mediated calcium influx and vesicular secretion, we applied NMDA to nucleated outside-out patches from animals that were lactating (days 7–9, L7–9). The patches were voltage clamped at –70 mV in magnesium-free bathing solution containing 5 mM extracellular calcium. NMDA (100 µM) applied repetitively onto a single nucleated patch produced reproducible inward current responses (Fig. 2A and B). Corresponding capacitance recordings showed that NMDAR activation induced changes in membrane capacitance with various amplitudes, although the NMDA currents were constant (see examples in Fig. 2B, same experiment as Fig. 2A). The overall average capacitance change in response to 77 NMDA applications to patches from N = 9 animals showed a clear increase during the first 10 ms (5.75 ± 0.89 fF; Fig. 2C). In order to test whether capacitance changes occurred in the absence of NMDA, we fitted two Gaussian distributions to pooled all-points histograms of capacitance measurements of 10 ms episodes taken with an interval of 80 ms during control recordings (Fig. 2D) and found a value of 0.33 ± 0.55 fF for the first 10 ms (not significantly different from zero; P = 0.51; t statistics) and –0.14 ± 0.53 fF during the second 10 ms episode (not significantly different from zero; P = 0.78; t statistics; and not significantly different from the first control episode; P = 0.45; Kolmogorov-Smirnov). In contrast, immediately after NMDA application there was a significant > 5 fF change in capacitance as compared to pre-NMDA values (Fig. 2E), i.e. when we fitted Gaussian distributions to pooled all-points histograms of capacitance measurements during the first 10 ms after NMDA application and compared this to the average capacitance during 100 ms before NMDA, the capacitance shifted from 0.12 ± 0.29 fF (not significantly different from zero; P = 0.69; Fig. 2E) to 5.75 ± 0.89 fF upon NMDA application (with P < 0.0001 for being different from zero; t statistics; Fig. 2E; and P < 0.00001 for being different from control; Kolmogorov-Smirnov). We conclude that NMDAR activation significantly increased the cell capacitance.
Next, we plotted the NMDA-induced capacitance changes in another way, making an amplitude distribution of the average membrane capacitance response during the first 10 ms after NMDA application upon individual applications. The distribution of the amplitudes of capacitance responses of all applications pooled from all experiments (77 NMDA applications from N = 9 animals) was scattered and skewed towards positive capacitance value levels (Fig. 2F). Since the overall average positive shift in response to NMDA was > 5 fF (Fig. 2C and E), we used this as a threshold separator in further classifications (see Figs 2–4). Capacitance responses between –5 fF and +5 fF occurred in each and every patch (for example see Fig. 2B) and were categorized as ‘failures’ (blue responses in Fig. 2B and F). Responses > +5 fF were categorized as ‘exocytosis-like’ responses (red responses in Fig. 2A, B and F). In addition, some responses were < –5 fF (green bins in Fig. 2F) and were categorized as putative ‘endocytosis (or retrieval)-like’ responses. Endocytosis-like responses occurred only in some of the patches and under particular conditions (described below). These results indicate that exocytosis and/or endocytosis of vesicles can be induced in nucleated patches in an NMDA-dependent but action potential-independent manner.
NMDAR-mediated vesicle secretion is calcium dependent
NMDAR-mediated capacitance responses in nucleated patches appeared to be calcium dependent. Evidence in favour of this idea was that, during recording in the presence of 2.4 instead of 5 mM extracellular calcium, the probability of observing exocytosis-like responses (> 5 fF) in individual recordings was reduced (Fig. 3A and B). When a > 5 fF response was observed, the amplitude of the NMDA current and the subsequent capacitance changes were not different between the two extracellular calcium conditions (Fig. 3A and B). In addition, endocytosis-like responses were observed (see Fig. 3C and D). When expressed as a percentage of the total number of observations (Fig. 3E) we found a significantly higher probability of observing an endocytosis-like response in 2.4 mM calcium, and a significantly lower exocytosis probability.
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The synapse physiology of the SON is under a strong neuroendocrine regulatory control during the female reproductive cycle (Brussaard & Herbison, 2000). We have previously shown that voltage-dependent calcium channel-induced exocytosis is up-regulated in lactating females with respect to virgin animals (de Kock et al. 2003). To test if the probability of observing NMDA-induced exocytosis-like responses is also up-regulated during the lactation stage, we compared nucleated patches of 6- to 8-week-old virgin animals and animals of L7–9 (both in 5 mM extracellular calcium). Also in virgin animals, NMDA activated inward currents in all nucleated patches tested (Fig. 4A). Corresponding capacitance recordings showed that NMDAR activation induced capacitance responses with a variable amplitude (Fig. 4A). Although the amplitude of the NMDA-induced currents and the size of the patches were not different between the two stages being recorded, the probability of seeing responses < 5 fF (i.e. failures and/or endocytosis-like responses (Fig. 4A) was largely increased at the virgin stage. Also in the pooled distribution of all capacitance responses from virgin versus lactating animals this was observed (Fig. 4C and D). This shift from relatively more endocytosis-like responses during the adult virgin stage to relatively more exocytosis-like responses during lactation was significant (Fig. 4B).
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To test to what extent endogenous release of glutamate is capable of triggering the retrograde, oxytocin-mediated signalling in the intact SON, whole-cell voltage-clamp recordings were made of dorsomedial SON neurones in brain slices. In these experiments spontaneous GABAergic transmission (IPSCs) was recorded under asymmetrical chloride conditions. AMPARs but not NMDARs were blocked by including CNQX in the bathing solution. In this manner both inward NMDAR-dependent EPSCs and outward GABAAR-mediated IPSCs may occur at depolarized potentials. In addition, mGluRs of type II/III were blocked by CPPG to exclude other forms of heterosynaptic modulation (Piet et al. 2003). The cells were dialysed at –70 mV for at least 3 min. IPSC frequency has previously been shown to be constant for this length of time (Brussaard et al. 1996). Then we slowly depolarized the membrane potential from –70 to –30 mV over 30 s to relieve the magnesium block of the NMDARs, while also allowing the inactivation of voltage-dependent calcium channels (Fig. 5A). The frequency of the outward detected GABAergic IPSCs declined rapidly to 55% of control level after the membrane potential of –30 mV was reached and NMDARs were mostly responsible for glutamatergic transmission (Fig. 5B–D).
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In the presence of the NMDAR antagonist D-APV, the observed reduction in frequency of GABAergic IPSCs was strongly prevented (Fig. 5E, 2-way ANOVA, P < 0.01; Fig. 5F, Kruskal-Wallis test with Dunn's multiple comparisons test, P < 0.01) and this was dose dependent (Fig. 5F). In addition, in the presence of D-APV (10–50 µM) the modulation of GABAA amplitude at holding potentials of –30 mV was observed in only 3 out of 12 experiments (data not shown). These results show that ongoing glutamatergic transmission modulates GABAergic transmission, which is to a large extent dependent on NMDAR activation.
To test whether the NMDAR-dependent suppression of GABAergic transmission is mediated by the release of oxytocin from the postsynaptic neurone, we tested whether the suppression of GABAergic transmission at –30 mV was sensitive to the oxytocin receptor antagonist d(CH2)5-OVT. Indeed, in the presence of d(CH2)5-OVT the suppression of GABAergic transmission was only 25% (compared to 50% under control conditions, Fig. 5F, Kruskal-Wallis test, P < 0.01), showing that NMDAR activation induces oxytocin release that then acts presynaptically to suppress GABAergic transmission. Furthermore, in the presence of d(CH2)5-OVT, changes in IPSC amplitude were never observed (n = 6, data not shown). The presence of D-APV and d(CH2)5-OVT by themselves did not alter the basal frequency of GABAergic transmission (ANOVA, P > 0.05). Importantly, NMDAR-mediated oxytocin release was not dependent on action potential firing, suggesting that the modulation of GABAergic transmission occurs only locally and does not involve the entire neurone.
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Discussion |
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Hence, we propose that, at the moment of parturition, when an initial surge of glutamate input onto the oxytocin neurones occurs (Herbison et al. 1997), the following cascade of events is triggered. (a) Activation of either synaptic or extrasynaptic NMDARs by endogenous glutamatergic synaptic transmission induces postsynaptic calcium influx. (b) This calcium influx may be sufficient to induce local release of vesicles containing oxytocin (and possibly adenosine), already occurring in the absence of back-propagating action potentials in the postsynaptic cell. (c) The neuroactive substances released act as retrograde messengers, thereby reducing the GABAergic synaptic input (Fig. 6). This retrograde effect of NMDA-induced vesicular secretion becomes apparent as a subsequent decrease in the frequency of IPSCs, an effect that is most likely to be mediated via presynaptic oxytocin and other receptors (de Kock et al. 2003), whereas in addition a reduction of the IPSC amplitude was observed, which is mediated via postsynaptic oxytocin receptors (Brussaard et al. 1996). Once the postsynaptic cells start firing, a diffuse action of additional messengers (including endocannabinoids) may condition the input–output setting of this neural system for prolonged periods of time.
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To characterize the vesicular nature of the initial somatodendritic release directly, we used capacitance measurements on nucleated giant outside-out patches pulled from identified neurones in living brain slices. This preparation has previously been used extensively to study ligand- and voltage-gated channels in combination with the fast application of agonists (Sather et al. 1992; Rozov et al. 1998; Bekkers, 2000). Here, we show that membrane capacitance of the nucleated patch is increased in a number of instances after calcium influx through VGCCs or NMDARs, which is highly indicative of somatodendritic release of vesicles. Thus capacitance measurements on nucleated patches provide a powerful tool with which to study vesicle release from non-synaptic (i.e. somatodendritic) locations.
In addition to exocytosis, we observed negative changes in the membrane capacitance upon NMDA applications in a number of instances, in particular at the virgin stage, and under conditions of reduced calcium influx through NMDA channels. These changes were classified as endocytosis-like changes that occurred during NMDA current measurements. Indeed rapid endocytosis (or vesicle retrieval) may occur with relatively fast kinetics (Artalejo et al. 2002) and in a calcium-dependent manner (Mansvelder & Kits, 1998). The rapid endocytosis was shown to be kinetically complex with three time constants (ultrafast 
300 ms, fast 3 s and slower 13 s, Artalejo et al. 2002). This scenario appears to hold true particularly for the virgin state (Fig. 4), where steady-state negative capacitance changes were observed more frequently. In addition, after excessive exocytosis, the tail of rapid endocytosis becomes visible in the pooled overall average capacitance trace (Figs 2C, and 3A and B), as well as in individual traces (see for instance Fig. 2A).
It is noteworthy that the balance between exocytosis and endocytosis may shift depending on the extent of local calcium accumulation (von Gersdorff & Matthews, 1994). Thus at 500 nM calcium a half-inhibition of endocytosis was observed, whereas at higher local concentrations (900 nM) endocytosis may be entirely absent. In line with this, during lactation under fortified conditions of calcium influx (i.e. in the presence of 5 mM calcium), we observed exocytosis-like events more often than endocytosis, whereas under normal recording conditions (lactation, but physiological calcium) or during the virgin stage, the ratio of exocytosis to endocytosis was apparently shifted. We propose therefore that the retrieval of non-clathrin-coated large dense core vesicles that may be observed during capacitance recording as decay after intial exocytosis but also as ‘excess retrieval’ in the first round of stimulation (Artalejo et al. 2002) most likely accounts for the negative changes in membrane capacitance that were observed.
Excitability of SON neurones during the reproductive cycle
The increased exocytosis: endocytosis ratio of NMDA responses that can be observed by comparing lactating and virgin animals may be an important mechanism in bringing about robust shifts in the modality of excitability of the SON neurones, such as during late pregnancy (Summerlee, 1981; Leng et al. 1999). It is reminiscent of the up-regulation of VGCC-induced somatodendritic secretion of oxytocin that we have previously described (de Kock et al. 2003). At the moment of parturition, a surge of glutamate input is initially observed in the SON (Herbison et al. 1997), which may induce local depression of GABAergic synapses leading to disinhibition of the oxytocin neurones (Brussaard et al. 1997). Since this form of heterosynaptic modulation appears to be independent of postsynaptic action potential firing and is triggered by calcium influx through NMDARs, this implies that SON neurones have a local mechanism that sets the synaptic efficacy of nearby GABA synapses. Once the oxytocin neurones start firing, other local dendritic mechanisms may become actively involved in regulating the excitability of these neurones (Ludwig et al. 2002).
Oxytocin neurones express different NMDAR subunit types (Al-Ghoul et al. 1997). Although most subunit combinations are sensitive to magnesium block at hyperpolarized membrane potentials, all subunit combinations can conduct calcium at subthreshold membrane potentials, i.e. below –45 mV (Burnashev et al. 1995). The NMDARs that mediated oxytocin release could be either synaptic or extrasynaptic. Indeed, extrasynaptic glutamate concentrations increase significantly during lactation due to glia withdrawal and enhanced glutamate release (Stern et al. 2000; Oliet et al. 2001). Using a fixed glutamate concentration, we found no difference in the amplitude of the NMDA current between lactating and virgin stages and thus glutamate availability might be the limiting factor for inducing somatodendritic oxytocin release during the virgin state. We also found that the ratio of observing exocytosis versus responses < 5 fF was significantly increased during lactation. We hypothesize that a reduction in the calcium-dependent endocytosic (or membrane) retrieval is responsible for this shift. If in addition during lactation there is enhanced glutamate release, it is likely that extrasynaptic NMDARs make a significant contribution to local dendritic secretion of retrograde-acting substances.
Physiological setting of heterosynaptic modulation
We would argue that the functional significance of NMDAR-mediated release of oxytocin in particular is important under conditions where glutamate input is thought to be involved as a key trigger in bringing about a robust shift in the modality of excitability of the SON neurones, such as during late pregnancy (Brussaard & Herbison, 2000), and during induction of lactation reflexes. During pregnancy the oxytocin neurones are electrically quiescent for 21 days, but at the end of the term need to become synchronously active in order to facilitate the contractions of the uterus during the parturition (delivery) phase. Also, at the onset of each suckling reflex during the lactation stage, glutamate-induced local feedback of oxytocin may be more important than during subsequent conditions when the firing activity of oxytocin neurones is strongly increased. Thus, depending on the extent to which glutamate input is activated at such stages, there will be a suppression of the synaptic input of GABA.
Paracrine actions of oxytocin in the SON have been reported previously (Neumann et al. 1993, 1994). Thus, NMDAR-induced oxytocin release and suppression of GABA synapses may not be limited to GABA synapses on neighbouring regions of the same postsynaptic dendrite, but oxytocin may also suppress GABA synapses on neighbouring dendrites of other oxytocin neurones. This may be one of the first steps to recruiting large groups of oxytocin neurones in the SON nuclei, leading to simultaneous firing bursts of action potentials, thereby giving rise to synchronous pulsatile secretion of oxytocin into the bloodstream at the posterior pituitary. Similar short-term heterosynaptic mechanisms might come into play in other brain areas, such as the dorsal raphe nucleus and the midbrain dopamine system, where somatodendritic release modulates the excitability of surrounding neurones (Bunin & Wightman, 1999; Morin, 1999; Monti & Monti, 2000; Cooper, 2002; Grillner & Mercuri, 2002). Serotonin can induce dendritic GABA release from thalamic interneurones without the activation of voltage-gated calcium channels (Munsch et al. 2003). In preliminary experiments we found that NMDAR activation induces capacitance changes in nucleated patches of serotonin neurones from dorsal raphe nucleus (
Cm
= 15.7 ± 2.82 fF; n
= 9). Therefore, this type of heterosynaptic modulation may be functional in more brain areas outside the hypothalamus.
Other cell systems
Several other studies have previously reported that postsynaptic neurones may be capable of modulating presynaptic targets by releasing retrograde messengers from somatodendritic locations (Kombian et al. 1997; Zilberter et al. 1999; Liu et al. 2000). While in the SON neurones, retrograde feedback at the level of the dendrites appears to be involved in autodisinhibition, at the level of 5-HT-containing neurones in the dorsal raphe nucleus, a similar retrograde feedback mechanism may be involved in autoinhibition (Liu et al. 2000). As outlined in the Introduction, at such electrophysiological stages, mechanisms of heterosynaptic plasticity as described in this paper may be particularly important. In general, local somatodendritic release of retrograde messengers by NMDA receptor activation may increase the spatiotemporal resolution of incoming synaptic inputs, in particular under conditions when the postsynaptic neurones have been quiescent. A similar phenomenon has been previously identified at the so-called reciprocal synapse in the olfactory bulb (Halabisky et al. 2000). Together these data suggest that heterosynaptic plasticity mechanisms and retrograde signalling by local dendrites may contribute to the regulation of the excitability of the large groups of neurones shifting from electrically silent toward firing, and vice versa. Similar mechanisms of retrograde modulation are probably relevant for other brain functions, including motor behaviour, mood and sensory processing (Jaffe et al. 1998; Chen et al. 2000; Liu et al. 2000).
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Artalejo
CR, Elhamdani
A
&
Palfrey
HC (2002). Sustained stimulation shifts the mechanism of endocytosis from dynamin-1-dependent rapid endocytosis to clathrin- and dynamin-2-mediated slow endocytosis in chromaffin cells. Proc Natl Acad Sci U S A
99, 6358–6363.
Bekkers
JM (2000). Properties of voltage-gated potassium currents in nucleated patches from large layer 5 cortical pyramidal neurones of the rat. J Physiol
525, 593–609.
Brussaard
AB, Devay
P, Leyting-Vermeulen
JL
&
Kits
KS (1999). Changes in properties and neurosteroid regulation of GABAergic synapses in the supraoptic nucleus during the mammalian female reproductive cycle. J Physiol
516, 513–524.
Brussaard AB & Herbison AE (2000). Long-term plasticity of postsynaptic GABAA-receptor function in the adult brain: insights from the oxytocin neurone. Trends Neurosci 23, 190–195.[CrossRef][Medline]
Brussaard AB, Kits KS, Baker RE, Willems WP, Leyting-Vermeulen JW, Voorn P, Smit AB, Bicknell RJ & Herbison AE (1997). Plasticity in fast synaptic inhibition of adult oxytocin neurones caused by switch in GABAA receptor subunit expression. Neuron 19, 1103–1114.[CrossRef][Medline]
Brussaard AB, Kits KS & de Vlieger TA (1996). Postsynaptic mechanism of depression of GABAergic synapses by oxytocin in the supraoptic nucleus of immature rat. J Physiol 497, 495–507.[Medline]
Bunin MA & Wightman RM (1999). Paracrine neurotransmission in the CNS: involvement of 5-HT. Trends Neurosci 22, 377–382.[CrossRef][Medline]
Burnashev N, Zhou Z, Neher E & Sakmann B (1995). Fractional calcium currents through recombinant GluR channels of the NMDA, AMPA and kainate receptor subtypes. J Physiol 485, 403–418.[Medline]
Chen QX & Wong RK (1995). Suppression of GABAA receptor responses by NMDA application in hippocampal neurones acutely isolated from the adult guinea-pig. J Physiol 482, 353–362.[Medline]
Chen WR, Xiong W & Shepherd GM (2000). Analysis of relations between NMDA receptors and GABA release at olfactory bulb reciprocal synapses. Neuron 25, 625–633.[CrossRef][Medline]
Chevaleyre V & Castillo PE (2003). Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472.[CrossRef][Medline]
Cooper DC (2002). The significance of action potential bursting in the brain reward circuit. Neurochem Int 41, 333–340.[CrossRef][Medline]
de Kock
CP, Wierda
KD, Bosman
LW, Min
R, Koksma
JJ, Mansvelder
HD, Verhage
M
&
Brussaard
AB (2003). Somatodendritic secretion in oxytocin neurones is upregulated during the female reproductive cycle. J Neurosci
23, 2726–2734.
Di L, Malcher-Lopes R, Halmos KC & Tasker JG (2003). Nongenomic glucocorticiod inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 15, 4850–4857.
Freund
TF, Katona
I
&
Piomelli
D (2003). Role of endogenous cannabinoids in synaptic signaling. Physiol Rev
83, 1017–1066.
Galante
M
&
Diana
MA (2004). Group 1 metabotropic glutamate receptors inhibit GABA release at interneuron-Purkinje cell synapses through endocannabinoid production. J Neurosci
24, 4865–4874.
Ghetti
A
&
Heinemann
SF (2000). NMDA-dependent modulation of hippocampal kainate receptors by calcineurin and Ca2+/calmodulin-dependent protein kinase. J Neurosci
20, 2766–2773.
Grillner P & Mercuri NB (2002). Intrinsic membrane properties and synaptic inputs regulating the firing activity of the dopamine neurones. Behav Brain Res 130, 149–169.[CrossRef][Medline]
Halabisky
B, Friedman
D, Radojicic
M
&
Strowbridge
BW (2000). Calcium influx through NMDA receptors directly evokes GABA release in olfactory bulb granule cells. J Neurosci
20, 5124–5134.
Herbison
AE, Voisin
DL, Douglas
AJ
&
Chapman
C (1997). Profile of monoamine and excitatory amino acid release in rat supraoptic nucleus over parturition. Endocrinology
138, 33–40.
Hirasawa
M, Schwab
Y, Natah
S, Hillard
CJ, Mackie
K, Sharkey
KA
&
Pittman
QJ (2004). Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain. J Physiol
559, 611–624.
Hou-Yu A, Lamme AT, Zimmerman EA & Silverman AJ (1986). Comparative distribution of vasopressin and oxytocin neurones in the rat brain using a double-label procedure. Neuroendocrinology 44, 235–246.[Medline]
Jaffe
EH, Marty
A, Schulte
A
&
Chow
RH (1998). Extrasynaptic vesicular transmitter release from the somata of substantia nigra neurones in rat midbrain slices. J Neurosci
18, 3548–3553.
Kombian SB, Mouginot D & Pittman QJ (1997). Dendritically released peptides act as retrograde modulators of afferent excitation in the supraoptic nucleus in vitro. Neuron 19, 903–912.[CrossRef][Medline]
Kreitzer AC, Carter AG & Regehr WG (2002). Inhibition of interneurone firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 34, 787–796.[CrossRef][Medline]
Leng G, Brown CH & Russell JA (1999). Physiological pathways regulating the activity of magnocellular neurosecretory cells. Prog Neurobiol 57, 625–655.[CrossRef][Medline]
Lindau M & Neher E (1988). Patch-clamp techniques for time-resolved capacitance measurements in single cells. Pflugers Arch 411, 137–146.[CrossRef][Medline]
Liu R, Jolas T & Aghajanian G (2000). Serotonin 5-HT(2) receptors activate local GABA inhibitory inputs to serotonergic neurones of the dorsal raphe nucleus. Brain Res 873, 34–45.[CrossRef][Medline]
Ludwig M & Pittman QJ (2003). Talking back: dendritic neurotransmitter release. Trends Neurosci 26, 255–261.[CrossRef][Medline]
Ludwig M, Sabatier N, Bull PM, Landgraf R, Dayanithi G & Leng G (2002). Intracellular calcium stores regulate activity-dependent neuropeptide release from dendrites. Nature 418, 85–89.[CrossRef][Medline]
Mansvelder
HD
&
Kits
KS (1998). The relation of exocytosis and rapid endocytosis to calcium entry evoked by short repetitive depolarizing pulses in rat melanotropic cells. J Neurosci
18, 81–92.
Monti JM & Monti D (2000). Role of dorsal raphe nucleus serotonin 5-HT1A receptor in the regulation of REM sleep. Life Sci 66, 1999–2012.[CrossRef][Medline]
Morin LP (1999). Serotonin and the regulation of mammalian circadian rhythmicity. Ann Med 31, 12–33.[Medline]
Morris JF, Christian H, Ma D & Wang H (2000). Dendritic secretion of peptides from hypothalamic magnocellular neurosecretory neurones: a local dynamic control system and its functions. Exp Physiol 85, 131S–138S.[Abstract]
Munsch
T, Freichel
M, Flockerzi
V
&
Pape
HC (2003). Contribution of transient receptor potential channels to the control of GABA release from dendrites. Proc Natl Acad Sci U S A
100, 16065–16070.
Neumann I, Koehler E, Landgraf R & Summy-Long J (1994). An oxytocin receptor antagonist infused into the supraoptic nucleus attenuates intranuclear and peripheral release of oxytocin during suckling in conscious rats. Endocrinology 134, 141–148.[Abstract]
Neumann I, Russell JA & Landgraf R (1993). Oxytocin and vasopressin release within the supraoptic and paraventricular nuclei of pregnant, parturient and lactating rats: a microdialysis study. Neuroscience 53, 65–75.[CrossRef][Medline]
Oliet
SH, Piet
R
&
Poulain
DA (2001). Control of glutamate clearance and synaptic efficacy by glial coverage of neurones. Science
292, 923–926.
Oliet
SH
&
Poulain
DA (1999). Adenosine-induced presynaptic inhibition of IPSCs and EPSCs in rat hypothalamic supraoptic nucleus neurones. J Physiol
520, 815–825.
Pak CW & Curras-Collazo MC (2002). Expression and plasticity of glutamate receptors in the supraoptic nucleus of the hypothalamus. Microsc Res Tech 56, 92–100.[CrossRef][Medline]
Piet R, Bonhomme R, Theodosis DT, Poulain DA & Oliet SH (2003). Modulation of GABAergic transmission by endogenous glutamate in the rat supraoptic nucleus. Eur J Neurosci 17, 1777–1785.[CrossRef][Medline]
Piomelli D (2003). The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4, 873–884.[CrossRef][Medline]
Pow DV & Morris JF (1989). Dendrites of hypothalamic magnocellular neurones release neurohypophysial peptides by exocytosis. Neuroscience 32, 435–439.[CrossRef][Medline]
Rozov
A, Zilberter
Y, Wollmuth
LP
&
Burnashev
N (1998). Facilitation of currents through rat Ca2+-permeable AMPA receptor channels by activity-dependent relief from polyamine block. J Physiol
511, 361–377.
Sather
W, Dieudonne
S, MacDonald
JF
&
Ascher
P (1992). Activation and desensitization of N-methyl-D-aspartate receptors in nucleated outside-out patches from mouse neurones. J Physiol
450, 643–672.
Stern
JE, Hestrin
S
&
Armstrong
WE (2000). Enhanced neurotransmitter release at glutamatergic synapses on oxytocin neurones during lactation in the rat. J Physiol
526, 109–114.
Summerlee
AJ (1981). Extracellular recordings from oxytocin neurones during the expulsive phase of birth in unanaesthetized rats. J Physiol
321, 1–9.
von Gersdorff H & Matthews G (1994). Inhibition of endocytosis by elevated internal calcium in a synaptic terminal. Nature 370, 652–655.[CrossRef][Medline]
Zilberter Y, Kaiser KM & Sakmann B (1999). Dendritic GABA release depresses excitatory transmission between layer 2/3 pyramidal and bitufted neurones in rat neocortex. Neuron 24, 979–988.[CrossRef][Medline]
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, n
= 77 measurements from N
= 9 animals). After NMDA application, the relative membrane capacitance was significantly increased (from 0.12 ± 0.29 to 5.75 ± 0.89 fF, Kolmogorov-Smirnov, P < 0.00001). F, frequency distribution of capacitance responses from all responses (n
= 77) on nucleated patches from N
= 9 L7–9 females in 5 mM extracellular calcium. Dashed lines indicate separators to define exocytosis (> 5 fF), failures (> –5 fF but < 5 fF) or endocytosis (< –5 fF).
