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REPORT
Vollum Institute, Oregon Health and Science University, Portland, Oregon
Submitted 8 June 2007; accepted in final form 18 January 2008
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ABSTRACT |
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INTRODUCTION |
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; Seal and Edwards 2006). For instance, glutamate can be co-released with acetylcholine in tadpole and mouse spinal neurons (Li et al. 2004; Nishimaru et al., 2005). Glutamate also can be released with dopamine or serotonin in cultured brain stem neurons (Johnson 1994; Sulzer et al. 1998). The two fast-acting inhibitory transmitters, GABA and glycine, are co-released in the spinal cord and auditory brain stem (Jonas et al. 1998; Kotak et al. 1998; O'Brien and Berger 1999).
In the olfactory bulb, periglomerular cells are generally considered as GABAergic interneurons, but some periglomerular cells express tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis along with the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) (Gall et al. 1987; Kosaka et al. 1985). These TH+ cells are considered to be dopaminergic based on the lack of staining for dopamine-β-hydroxylase (Halasz et al. 1977), but the effects of endogenously released dopamine have not been tested. Within the glomerulus, dopamine and GABA receptors are expressed on afferent nerve terminals. Exogenous applications of dopamine can activate D2 receptors on ORN terminals and inhibit transmitter release (Coronas et al. 1997; Ennis et al. 2001; Hsia et al. 1999; Koster et al. 1999; Nickell et al. 1991). Evoked release of GABA from periglomerular cells also inhibits ORN terminals by activating GABAB receptors (Aroniadou-Anderjaska et al. 2000; Bonino et al. 1999; Margeta-Mitrovic et al. 1999; McGann et al. 2005; Murphy et al. 2005) and mitral cells by activating GABAA receptors (Isaacson and Strowbridge 1998; Schoppa et al. 1998). Some periglomerular cells modulate their excitability by activating GABAA autoreceptors (self-inhibition) (Smith and Jahr 2002).
We examined the transmitter phenotype of dopaminergic periglomerular cells using transgenic mice that expressed EGFP under control of the TH promoter (Sawamoto et al. 2001). Whole cell recordings in brain slices of mice at PND 14–21 revealed that dopamine and GABA were released from TH-EGFP+. Spontaneous dopamine release in the presence of cocaine caused presynaptic inhibition. Step depolarization of a single TH-EGFP+ cell was sufficient to cause GABA-mediated self-inhibition but not dopamine-mediated presynaptic inhibition.
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METHODS |
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All animal protocols were approved by the institutional IACUC and followed National Institutes of Health guidelines for the ethical treatment of animals. Olfactory bulb slices were prepared from 14- to 21-day-old transgenic DBA/2J mice that expressed EGFP in a subset of periglomerular cells (pTH-GFP) (Sawamoto et al. 2001). Only heterozygous mice were used in the experiments. These mice were obtained by breeding a heterozygous animal with a wild type. Mice were deeply anesthetized with isoflurane and then decapitated. Bulbs were rapidly removed and immersed in ice-cold oxygenated (95% O2-5% CO2) dissection buffer containing (in mM) 83 NaCl, 2.5 KCl, 1 NaH2PO4, 26.2 NaHCO3, 22 glucose, 72 sucrose, 0.5 CaCl2, and 3.3 MgSO4. Horizontal slices (290 µM) were cut using a vibrating blade vibrotome (VT1000S; Leica, Bannockburn, IL), incubated in dissection buffer for 30–45 min at 37°C, and then stored at room temperature.
Slices were visualized using infrared differential interference contrast microscopy (IR/DIC, Zeiss Axioskop) and a CCD camera (XC-ST30, Sony). Individual periglomerular cells expressing EGFP were visualized with epifluorescent illumination and a x40 Zeiss water-immersion (0.75 numerical aperture) objective. All recordings were done at 31–34°C.
Electrophysiology
For all experiments, artificial cerebrospinal fluid (ACSF) was oxygenated (95% O2-5% CO2) and contained (in mM) 125 NaCl, 25 NaHCO3, 1.25 NaH2PO4, 3 KCl, 25 dextrose, 1 MgCl2, and 2 CaCl2, pH 7.3. Patch pipettes were fabricated from borosilicate glass (TW150F-6; WPI, Sarasota, FL) to a resistance of 4–7 M
for periglomerular cell somatic recordings. Pipettes were filled with (in mM) 125 Kgluconate, 10 HEPES, 4 Mg-ATP, 0.3 Na-GTP, 0.1 EGTA, and 10 phosphocreatine and 0.05% biocytin, adjusted to pH 7.3 with KOH. For recording of GABA-mediated self-inhibition, Kgluconate was replaced with CsCl; for most of these experiments, 10 mM GABA was added to the pipette to allow for stable long-term recording of GABAergic responses (Smith and Jahr 2002). In some experiments, synaptic currents were blocked with 100 µM D,L-2-amino-5-phosphonopentanoic acid (D,L-AP5), 10 µM 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulfonamide (NBQX), 5 µM Gabazine (Tocris, Ballwin, MO), and 0.5 µM TTX. Sulpiride, CGP55845 and +baclofen were obtained from Tocris. Cocaine was obtained from NIDA (National Institutes of Health). Current signals recorded with a Multiclamp 700A amplifier (Axon instruments, Foster City, CA) were filtered at 2 kHz using a built-in Bessel filter and digitized at 10 kHz. Data were acquired using Axograph 4.9 (Axon instruments). Data acquisition was terminated when series resistance was >15 M. For voltage-clamp recordings, mitral cells were held at –60 mV. Mitral cells in current clamp were held at –58 to –65 mV by continuous current injection.
Immunohistochemistry
Fixed sections (50 µm) were permeabilized with 0.4% Triton X-100/PBS for 30 min at room temperature (RT) followed by PBS wash (3 times, 10 min). The sections were then blocked with 4% normal goat serum for 2 h and incubated with chicken polyclonal anti-EGFP antibody (1:5,000; Ab16901; Chemicon) in PBS overnight at 4°C. After PBS washing (3 time, 10 min), slices were incubated with goat anti-chicken conjugated with Alexa Fluor 488 (1:5,000; Molecular Probes) for 2 h at RT. Following PBS wash (3 times, 10 min), slices were incubated with either sheep polyclonal anti-TH antibody (1:1,000; Ab1542, Chemicon), rabbit polyclonal anti-GAD65/67 (1:1,000; Ab1511; Chemicon), or guinea pig polyclonal anti-GABA (1:1,000; Ab175; Chemicon) in PBS overnight at 4°C. After PBS washing (3 times, 10 min), slices were incubated with goat anti-sheep, goat anti-rabbit, or goat anti-guinea pig antibodies at 1:5,000 in PBS for 2 h at RT, respectively. These antibodies were conjugated with Alexa Fluor 647 (Molecular Probes). Slices were washed and mounted on slides with ProLong Antifade (Invitrogen), and imaged on a confocal microscope (Olympus, Melville, NY) with a x20 objective.
Data analysis and statistics
All analyses were performed using AxoGraph 4.9 on a Macintosh computer. Estimates of charge for self-inhibition currents were measured by integrating the currents starting at the peak of the response. For all experiments, statistical significance was determined using ANOVA or Student's t-test as appropriate (Microsoft EXCEL, Richmond, WA). Averaged data values are reported as means ± SE.
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RESULTS |
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We used immunolabeling to verify that EGFP+ periglomerular cells expressed TH and GAD, the biosynthethic enzymes necessary for production of dopamine and GABA, respectively. Similar to previous reports with the pTH-GFP mice (Saino-Sato et al. 2004), the cell bodies of EGFP+ cells ringed each glomerulus and were immunoreactive for tyrosine hydroxylase (Fig. 1, A–C). As expected, the majority of EGFP+ cells were also immunopositive for TH although there were a few EGFP+ cells that did not have detectable TH (Fig. 1C). These cells also expressed GAD and GABA as observed with immunolabeling with an antibody against the two GAD subtypes, GAD65/67 (Fig. 1, D–F) as well as GABA (Fig. 1, G–I). The subpopulation of EGFP+ cells that had no detectable immunlabeling with TH or GAD/GABA may represent immature periglomerular cells as EGFP+ cells could be seen in other layers (Baker et al. 2001). These results confirm the co-expression of TH and GABA in a population of periglomerular cells (Gall et al. 1987; Kosaka et al. 1985), and thus the TH- EGFP+ animals provide a useful tool to examine dopamine and GABA co-transmission in the glomerulus.
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Exogenous application of dopamine can inhibit ORN inputs onto mitral, tufted and periglomerular cells by activation of presynaptic D2 receptors (Ennis et al. 2001; Hsia et al. 1999). However, endogenous release of dopamine has never been examined in the olfactory bulb. Similar to other dopaminergic neurons in the brain, dopaminergic periglomerular cells display spontaneous action potential firing (Pignatelli et al. 2005; Puopolo et al. 2005). Therefore we first looked for spontaneous release of dopamine in the slices. We recorded the evoked EPSC in EGFP+ cells during stimulation of ORN inputs (0.1 Hz) in the presence of the dopamine transporter blocker cocaine (Fig. 2A). Bath application of cocaine (5 µM) strongly inhibited the EPSC (40.4 ± 6.2% of control; n = 12; P < 0.02) without altering the holding current, and this effect was reversed by the D2 receptor antagonist sulpiride in the 7/12 cells where it was applied (107.9 ± 22.6% of control; n = 7; P < 0.05; 4 µM, Fig. 2, B and D). In the absence of cocaine, sulpiride had no effect on EPSC amplitude (n = 6, Fig. 2D), suggesting that there was not a tonic dopamine-mediated inhibition.
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In some cells, dopamine release requires bursts of action potentials (Chergui et al. 1994; Gonan 1988; Suaud-Chagny et al. 1992). We tested whether stimulation of a single periglomerular cell released sufficient dopamine to cause inhibition of the incoming afferent EPSC. However, we did not observe dopamine-mediated inhibition of EPSCs using trains of action potentials or depolarizing voltage steps in voltage clamp (0 mV, 25–100 ms) that preceded the afferent stimulation (n = 12, not shown).
TH-EGFP-positive periglomerular cells release GABA
The activation of GABAB receptors on ORN nerve terminals (Murphy et al. 2005) as well as self-inhibition by GABAA receptors (Smith and Jahr 2002) have only been observed in a subset of periglomerular cells. Because EGFP+ cells express GAD, we tested these cells for GABAergic inhibition and self-inhibition. All EGFP+ cells showed self-inhibition (Fig. 3A). Self-inhibition was present at the onset of whole cell recording but was more stable in recordings when GABA was added to the pipette (Smith and Jahr 2002). However, self-inhibition currents were also present using GABA-free pipette solutions (n = 3, data not shown). Brief depolarizing voltage steps (10 ms, +10 mV) in chloride-loaded cells produced an inward tail current that was completely blocked by gabazine (5 µM, Fig. 3B, 4.5 ± 1.01 pC control vs. 1.14 ± 0.37 pC gabazine, n = 7; P < 0.004). Self-inhibition reflected vesicular release of GABA because the gabazine-sensitive tail currents were completely blocked by Cd2+ (Fig. 2, C and D; 3.04 ± 0.72 pC control vs. 0.28 ± 0.18 pC Cd2+, n = 5; P < 0.02). Thus dopaminergic periglomerular cells show Ca2+-dependent release of GABA.
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DISCUSSION |
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The most common form of co-transmission is co-release of neuropeptides with classical fast-acting neurotransmitters (Hökfelt et al. 2000). However, there are now examples of co-localization and co-release of glutamate and GABA with each other as well as other transmitters (reviewed in Seal and Edwards 2006), including co-localization of dopamine and GABA in Aplysia neurons (Díaz-Ríos and Miller 2005). Although GABA and glycine may be released from the same vesicles at the same sites (Jonas et al. 1998), co-transmission in other cases may involve discrete groups of vesicles or release sites as seems to be the case with co-release of dopamine and glutamate from ventral midbrain neurons (Sulzer et al. 1998).
In mammalian systems, glutamate has been the only fast-acting transmitter identified thus far that is co-released with dopamine. Cultured dopamine and serotonin neurons release quantal amounts of glutamate, form asymmetric synapses typical of excitatory synapses (Johnson 1994; Sulzer et al. 1998), and express vesicular glutamate transporter 3 (VGLUT3). Serotonin neurons in vivo also express VGLUT3 (Fremeau et al. 2004; Gras et al. 2002; Schafer et al. 2002). Although VGLUTs have not been detected in dopamine neurons in vivo, specific stimulation of dopamine neurons in the VTA evokes a CNQX-sensitive current in the nucleus accumbens and medial prefrontal cortex (Chuhma et al. 2004; Lavin et al. 2005).
Our results provide functional evidence that dopaminergic neurons can also co-release GABA. Our evidence is supported by prior anatomical data showing colocalization of the synthesizing enzymes, TH and GAD (Gall et al. 1985; Kosaka et al. 1987). In fact, Gall et al. (1985) reported that virtually all TH+ immunoreactive cells in the glomerulus also were GABA-immunoreactive. Because TH is the first enzyme in dopamine biosynthesis and is a reliable marker for dopaminergic neurons, this suggests that all dopaminergic periglomerular cells also release GABA. Although we were unable to demonstrate evoked dopamine release from individual EGFP+ cells, there are no centrifugal terminals containing dopamine (Halasz et al. 1977). Thus the source of DA transmission in the olfactory bulb must be TH+ periglomerular cells. It is possible that not all TH+ cells at the developmental state we studied (PND 14–21) are capable of robust dopamine release. TH+ periglomerular cells originate from stem cells in the lateral ventricular zone and migrate along the rostral migratory stream into the olfactory bulb (Hack et al. 2005). However, TH expression does not occur until the cells incorporate into a glomerulus where TH levels are upregulated by afferent input (McLean and Shipley 1988; Saino-Saito et al. 2004).
Functional consequences
Periglomerular cells function as interneurons to modulate both afferent input and the excitability of mitral cells, the principal cells in the glomerulus. Co-transmission of a modulatory transmitter dopamine with GABA expands the modulatory capability of periglomerular cells. Perhaps the most likely is that release of the dopamine requires either strong stimulation or the activation of multiple dopaminergic neurons to affect ORN terminals. GABA release has been detected following individual stimulation of periglomerular cells (Murphy et al. 2005). However, we were unable to observe dopaminergic or GABAergic presynaptic inhibition after depolarization of individual TH+ periglomerular cells. This result may indicate that there are discrete functional groups of periglomerular cells. Postsynaptically, GABA rapidly depolarizes periglomerular cells at resting membrane potentials, reducing input resistance and shunting excitatory conductances. This results in self-inhibition (Smith and Jahr 2002) and lateral inhibition (Murphy et al. 2005). Whether dopamine also plays an intraglomerular function remains to be determined.
GABA and dopamine can both act on ORN terminals to reduce transmitter release. This is likely to be important to sensory processing given the convergence of thousands of axons onto a single glomerulus and the high release probability of ORN terminals (Murphy et al. 2004; Shepherd 1972). Although TH+ periglomerular cells spontaneously fire rhythmic action potentials (Pignatelli et al. 2005; Puopolo et al. 2005), the effect of dopamine in our experiments was only apparent in the presence of a transport blocker. However, ORN input directly activates dopaminergic periglomerular cells, thus convergence of many inputs may be required to evoke dopamine release as has been observed in other systems (Beckstead et al. 2004; Chergui et al., 1994; Gonon 1988; Suaud-Chagny et al. 1992).
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. L. Westbrook, Vollum Institute, Oregon Health and Science University L474, Portland, OR 97239 (E-mail: westbroo{at}ohsu.edu)
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ABSTRACT
INTRODUCTION
