Facilitation of the inhibitory transmission by gastrin-releasing peptide in the anterior cingulate cortex
© Cao et al; licensee BioMed Central Ltd. 2010
Received: 23 July 2010
Accepted: 13 September 2010
Published: 13 September 2010
Gastrin-releasing peptide (GRP) has been proposed as a peptidergic molecule for behavioral fear and itching. Immunohistochemistry and in situ hybridization studies have shown that GRP and GRP receptor are widely distributed in forebrain areas. Less information is available for the functional action for GRP in the prefrontal cortex including the anterior cingulate cortex (ACC). Here we used whole-cell patch-clamp recording technique to study the modulation of synaptic transmission by GRP in the ACC. We found that GRP increased the frequency of sIPSCs recorded while had no significant effect on sEPSCs in ACC pyramidal neurons. The facilitatory effect of GRP on sIPSCs was blocked by the GRP receptor antagonist, RC3095. In the presence of TTX, however, GRP had no effect on the mIPSCs. Therefore, activation of GRP receptor may facilitate the excitation of the interneurons and enhanced spontaneous GABAergic, but not glutamatergic neurotransmission. Similar results on GRP modulation of GABAergic transmission were observed in the insular cortex and amygdala, suggesting a general possible effect of GRP on cortical inhibitory transmission. Our results suggest that GRP receptor is an important regulator of inhibitory circuits in forebrain areas.
Gastrin-releasing peptide (GRP) is a mammalian analogue of bombesin (BB), a 14 amino acid-containing peptide first isolated from the skin of the frog Bombina bombina [1, 2]. Anatomic studies have shown that GRP and its receptors are widely distributed in the central nervous system, in addition to the gastrointestinal (GI) tract [2–10]. GRP has been implicated in many physiological and pathological conditions such as the regulation of the circadian rhythm, exocrine and endocrine secretions, smooth muscle contraction, inflammation, feeding, fear and behavioral itch [11–17].
Recent studies on GRP in sensory systems have triggered new interests on GRP. At the level of the spinal cord, it has been reported that GRP may serve as a selective signaling transmitters for itching sensation [14, 15]. In the amygdala, it has been reported that GRP may contribute to regulation of neuronal excitability, and contribute to behavioral fear . Although it has been known that GRP is distributed in cortical areas, less is known about the possible modulatory effects of GRP on cortical circuits. The anterior cingulate cortex (ACC), a key structure of the prefrontal cortex, plays an established role in learning and memory, drug addiction, and chronic pain [19–22]. In the present study, we have investigated the effects of GRP on both excitatory and inhibitory transmission in the ACC. Our results show that the GRP selectively facilitate GABAergic but not glutamatergic neurotransmission. The facilitation may result from the GRP-induced inward current and firing of GABAergic interneurons in the ACC.
Adult male C57BL/6 mice were purchased from Charles River (6-10 weeks old). All mice were maintained on a 12 h light/dark cycle with food and water provided ad libitum. All protocols used were approved by The Animal Care and use Committee at the University of Toronto and conform to NIH guidelines.
Whole-cell Patch Clamp Recordings
Adult male mice were anesthetized with 1-2% halothane and decapitated. Coronal slices (300 μm) containing the ACC, amygdala or insular cortex will be prepared using routine methods used in our laboratory [23, 24]. Slices were then transferred to a submerged recovery chamber with oxygenated (95% O2 and 5% CO2) ACSF at room temperature. After a one-hour recovery period, slices were placed in a recording chamber on the stage of an Axioskop 2FS microscope (Zeiss) equipped with infrared DIC optics for visually-guided whole cell patch clamp recordings. Pyramidal neurons or interneurons in Layer II-III in the ACC were recorded with an Axon 200B amplifier (Molecular device, Union city, CA). Recording electrodes (2-5 M) contained an internal solution composed of (in mM): Kgluconate, 120; NaCl, 5; MgCl2 1; EGTA, 0.5; Mg-ATP, 2; Na3GTP, 0.1; HEPES, 10; pH 7.2; 280-300 mOsmol. The membrane potentials were held at -70 mV throughout all experiments. When recording GABAA receptor-mediated currents, K-gluconate was replaced by Cs-MeSO3 and a holding potential of 10 mV. Spontaneous EPSCs were recorded in the presence of GABAA receptor antagonist, picrotoxin (100 μM) and spontaneous IPSCs were recorded in the presence of a NMDA receptor antagonist, AP5 (100 μM) and a non-NMDA receptor antagonist, CNQX (20 μM). GRP and its receptor antagonist RC3095 were purchased from Sigma. To examine the mIPSCs, TTX (1 μM) was bath-applied in the perfusion solution. The sIPSCs/mIPSCs were analyzed with the Mini Analysis Program v5.2.4 (Synaptosoft Inc., Decatur, GA). Access resistance was 15-30MO and monitored throughout the experiments. Data were discarded if access resistance changed > 15% during an experiment. Signals were filtered at 1 kHz, digitized at 10 kHz.
Passive and Active Membrane Properties
Off-line analysis was performed using Clampfit version 9 (Axon Instruments). Resting membrane potential (RMP) was the low-pass readout of the electrode amplifier and was not corrected for liquid junction potential (~12 mV) after terminating the recording. The membrane potential was measured immediately after establishing the whole-cell configuration. Only neurons that had a resting membrane potential more negative than -60 mV were further investigated. Conductance was determined from the linear slope (between -60 mV to -80 mV) of the current-voltage (I-V; Vhold = -70 mV) relationships. Action potentials (APs) were detected in response to suprathreshold current injections from a holding potential around -70 mV. Depolarizing currents of 5~200 pA (400-ms duration) were delivered in increments of 5 pA until an AP was evoked. The rheobase was defined as the minimum current required to evoke an action potential. The AP voltage threshold (Vthreshold) was defined as the first point on the rising phase of the spike at which the change in voltage exceeded 50 mV/ms. The spike amplitude was quantified as the difference between the Vthreshold and the peak voltage. The spike width was measured at 1/2 of the total spike amplitude (measured from the Vthreshold level). The amplitude of the afterhyperpolarization (AHP) was estimated as the difference between the Vthreshold and the peak of AHP.
Mice were deeply anesthetized with halothane and perfused transcardially with 50-100 ml saline followed by 150-500 ml of cold 0.1 M phosphate buffer (PB) containing 4% paraformaldehyde. Brains were removed and post-fixed in 4% paraformaldehyde/PBS and then will be placed in 30% sucrose in 0.2 M PBS, embedded in the OCT compound and frozen. Coronal sections (30 μM thickness) were cut using a cryostat. For dual fluorescent immunohistochemistry, sections were incubated overnight with anti-GRPR (1:50; rabbit polycolonal, Santa Cruz Biotecnology) and anti-GAD67 (1:300; mouse monoclonal, Chemicon) antibodies at 4°C. Sections were then be washed 3 times with PBS 0.1 M and incubated for 2 hours with anti Mouse-FITC and rabbit-rhodamine conjugated secondary antibodies (1:200; Chemicon). Images of the ACC areas of at 0.7-μm intervals with 20× lens were obtained with Bio-Rad Laboratories MRC 1000 laser-scanning confocal fluorescent imaging system.
Results were expressed as mean ± standard error of the mean (S. E. M.). Statistical comparisons were performed with the use of one- or two-way analysis of variance (ANOVA) with the post-hoc Scheffe F-test in immunocytochemical experiments. Analysis of mIPSCs/sEPSCs was performed with cumulative probability plots and was compared using the Kolmogorov-Smirnov (K-S) test for significant differences. In all cases, P < 0.05 was considered statistically significant.
The expression of GRP and GRP receptors in the ACC
Morphological and electrophysiological properties of interneurons and pyramidal neurons in the ACC
Basic electrophysiological properties of ACC pyramidal and inhibitory neurons
Number of neurons tested
Resting membrane potential, mV
-73.0 ± 1.0
-61.4 ± 1.9
P < 0.001
Input resistance, M Ω
124.3 ± 6.3
332.4 ± 48.1
P < 0.001
Rheobase current, pA
95.7 ± 7.3
56.8 ± 11.8
P < 0.01
Action potential threshold, mV
-35.4 ± 0.4
-43.0 ± 0.9
P < 0.001
Action potential amplitude, mV
93.8 ± 0.8
88.2 ± 2.6
P < 0.01
Action potential half-width, ms
1.50 ± 0.03
1.00 ± 0.05
P < 0.001
Amplitude of after-hyperpolarization, ms
-6.9 ± 0.3
-24.8 ± 2.5
P < 0.001
GRP induced inward currents in interneurons but small or undetectable currents in pyramidal neurons
To examine the function of GRP receptor in the ACC, GRP was applied through bath solution and the responses of pyramidal neurons and interneurons were recorded. At holding potential of -70 mV a short application of GRP (300 nM) induced a slowly developing inward current (peak 16.9 ± 1.8 pA) that recovered slowly over 10 min (n = 8/10 interneurons). However, in pyramidal neurons there was undetectable currents upon GRP application (300 nM, n = 7). In the presence of GRP receptor antagonist, RC3095 (3 μM), the effect of GRP induced inward current in interneurons (n = 7) was completely blocked (data not shown). These results indicate that GRP selectively activated interneuronal GRP receptor in the ACC.
Activation of GRP receptors enhances spontaneous GABAergic, but not glutamatergic transmission
Increase of GABA release by GRP is action potential dependent
Activation of GRP receptor also increased the frequency of sIPSCs in pyramidal neurons in the basolateral anygdala (BLA) and insular cortex (IC)
In the present study, we used whole-cell patch-clamp recording to study the actions of GRP on ACC neurons in adult mice. Our results provide strong electrophysiological evidence that GRP receptor facilitates inhibitory GABA release in the ACC. Activation of GRP receptor preferentially modulated GABAergic, but not glutamatergic transmission. Furthermore, somatodendritic GRP receptor mediated action potential-dependent GABA release in the ACC occurred in other regions, such as the BLA and IC, indicating a general role of GRP receptor in the modulation of cortical GABAergic transmission.
How GRP facilitate GABAergic transmission and modulate the neuronal circuits in the ACC? Several lines of evidence in the present study suggest that GRP acts on somatodendritic GRP receptor in GABAergic neurons to induce neuronal firing and GABA release in interneurons, thereby decreasing the excitability of pyramidal neurons. Bath application of GRP facilitated sIPSC frequency in a concentration- dependent manner, but GRP had little effect on either frequency or amplitude of mIPSCs. These results are similar to the modulatory effects of the GRP/GRP receptor system on GABAergic transmission in lateral amygdala and hippocampus [18, 26]. Interestingly, in the present study, although ACC pyramidal neurons are shown to express GRP receptors, we found little direct effect of GRP on these cell bodies nor on the frequency and amplitude of sEPSC. We cannot completely rule out other possible modulation of GRP on excitatory transmission that cannot be revealed in the present studies. Future studies are clearly needed in further investigating the roles of GRP.
ACC neurons are multi-functional and play important roles in a wide variety of behavioral functions, including sensory pain, memory, emotional and cognitive functions [19–22, 27, 28]. Glutamate is the fast excitatory transmitter  and GABA is the inhibitory transmitter in the ACC . A balance between excitatory and inhibitory transmission is critical for many brain functions. Previous reports show that the GRP in the amygdala is inovolved in behavioral fear [18, 31–36]. In addition to the amygdala, recent studies show that lesion of the ACC produced an impairment in trace fear conditioning  and electrical stimulation of the ACC induced fear memory . The results of the present study show that GRP may facilitate the GABAergic transmission in the ACC synapses, indicating that GRP may contribute to behavioral fear or trace fear memory by affecting inhibitory transmission within the ACC.
GRP has been implicated in mediation the itch sensation in the spinal cord [14, 15]. The possible roles of GRP within the ACC in behavioral itching have not been investigated. Furthermore, a recent work in the spinal dorsal horn suggests that alteration of inhibitory transmission in the spinal cord is important for behavioral itching . It is possible that GRP may also affect spinal inhibitory transmission, in addition to act as a potential transmitter for itch from the periphery. Future studies are clearly needed in the spinal cord. Furthermore, direct evidence for GRP to act as a neurotransmitter for itching is still lacking. In human studies, ACC and IC have been shown to be involved in itch processing [40–45]. Future studies are required to address whether the modulation of GRP in the ACC inhibitory circuit would contribution to itch sensation. In summary, we report here that GRP play an important role in modulating inhibitory transmission within the ACC, IC and amygdala. It is likely that supraspinal GRP may contribute to a wide range of physiological and pathological functions, rather than act as a selective transmitter for itch as reported at the level of spinal cord.
Conflict of interests
The authors declare that they have no competing interests.
This work was supported by Grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, Canada Research Chair, NeuroCanada, and CIHR operating grants (CIHR66975 and CIHR81086) (M. Z.). M.Z. is also supported by the World-Class University (WCU) program of the Ministry of Education, Science and Technology in Korea through KOSEF (R32-10142).
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