Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents
- Zhi-Peng Liu†1,
- Chen Song†1,
- Min Wang1,
- Ye He1, 2,
- Xiao-Bin Xu1,
- Han-Qing Pan1,
- Wen-Bing Chen1,
- Wei-Jie Peng2 and
- Bing-Xing Pan1Email author
© Liu et al.; licensee BioMed Central Ltd. 2014
Received: 27 February 2014
Accepted: 19 April 2014
Published: 24 April 2014
Chronic stress is generally known to exacerbate the development of numerous neuropsychiatric diseases such as fear and anxiety disorders, which is at least partially due to the disinhibition of amygdala subsequent to the prolonged stress exposure. GABA receptor A (GABAAR) mediates the primary component of inhibition in brain and its activation produces two forms of inhibition: the phasic and tonic inhibition. While both of them are critically engaged in limiting the activity of amygdala, their roles in the amygdala disinhibition subsequent to chronic stress exposure are largely unknown.
We investigated the possible alterations of phasic and tonic GABAAR currents and their roles in the amygdala disinhibition subsequent to chronic stress. We found that both chronic immobilization and unpredictable stress led to long lasting loss of tonic GABAAR currents in the projection neurons of lateral amygdala. By contrast, the phasic GABAAR currents, as measured by the spontaneous inhibitory postsynaptic currents, were virtually unaltered. The loss of tonic inhibition varied with the duration of daily stress and the total days of stress exposure. It was prevented by pretreatment with metyrapone to block corticosterone synthesis or RU 38486, a glucocorticoid receptor antagonist, suggesting the critical involvement of glucocorticoid receptor activation. Moreover, chronic treatment with corticosterone mimicked the effect of chronic stress and reduced the tonic inhibition in lateral amygdala of control mice. The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment.
Our study suggests that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress. We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases.
KeywordsAmygdala Chronic stress GABA Electrophysiology Tonic inhibition Corticosterone Glucocorticoid receptor Neuronal excitability
Repeated exposure to stress has enduring detrimental influence on the brain and body function. It enhances the sufferers’ reactivity to the environmentally threatening or emotionally challenging events and at the extreme, leads to the development of a series of mental disorders including anxiety disorders and depression[2, 3]. Amygdala, an almond-shape brain nucleus complex located deep within the temporal lobe, is critically engaged in the acquisition, retrieval and expression of aversive memories[4–6]. Mounting evidence has demonstrated that amygdala is one of the primary targets of chronic stress[7, 8]. Under resting conditions, the amygdala is inhibited by the extensive GABAergic network and exhibits low neuronal firing. By contrast, the amygdala is disinhibited and shows heightened activation upon chronic stress[10, 11], resulting in the increased sensitivity of amygdala to the environmental cues and individual’s hypervigilance which persist even after long period of recovery.
Studies on the neuronal and molecular underpinnings of chronic stress-induced amygdala hyperresponsiveness have revealed the involvement of multiple factors such as the structural remodeling of amygdala neurons inducing the dendritic arborization and spine hypertrophy[12, 13] and the decreased expression of calcium-activated potassium channel (KCa) in the cytoplasmic membrane. The enlarged pools of spines facilitate amygdala neurons to receive and integrate the incoming signals from thalamocortical sensory domains and from the higher order cortical areas such as prefrontal cortex. The reduction of KCa activity, on the other hand, enhances the neuronal intrinsic excitability, thereby contributing to the overexcitation of amygdala as a consequence of chronic stress.
Besides these, chronic stress exposure was also reported to result in the attenuation of GABAergic signaling, shifting the amygdala to a more excitable state[9, 15, 16]. GABAARs mediate the majority of the inhibitory tone in central nervous system and their activation produces two forms of inhibition, the phasic and tonic inhibition[17, 18]. They coexist in numerous brain areas and are thought to be mediated by intra- and extrasynaptic GABAARs respectively. In amygdala, both forms of inhibition are engaged in constraining the neuronal activity[20, 21]. However, their specific roles in amygdala disinhibition subsequent to chronic stress are largely unknown.
In this study, we investigated the possible effects of chronic immobilization and unpredictable stress on the phasic versus tonic GABAAR currents in mice LA with effort to examine their roles in subsequent amygdala disinhibition. Since the adverse effects of chronic stress always persist even upon the cessation of stress exposure, we conducted the study in mice experiencing 10 or 30 days of stress-free recovery from chronic immobilization or unpredictable stress exposure to explore the possible enduring alterations of GABAAR signaling. We found that chronic stress exposure led to long lasting loss of tonic but not phasic GABAAR currents through corticosterone (CORT) production with subsequent activation of glucocorticoid receptor (GR). The loss of tonic inhibition contributed substantially to the disinhibition of neuronal activity in LA following prolonged stress exposure.
Chronic stress causes long lasting loss of tonic but not phasic GABAAR currents in LA PNs
We next investigated whether the effect of stress on tonic inhibition also varied with the total days of immobilization exposure. For this, we randomly assigned the mice into different groups which were given 1 hour daily immobilization for 2, 4, 6 or 8 consecutive days respectively. 10 days after the cessation of stress exposure, the tonic GABAAR currents were measured in LA (Figure 4C). As depicted in Figure 4D-E, the tonic GABAAR currents declined progressively with the increase of exposure days and one-way ANOVA revealed a significant effect of exposure days on the tonic inhibition (F(4, 41) = 3.459, p = 0.017). Whereas 2 or 4 days of immobilization failed to have significant effect on the tonic GABAAR currents (IS-2d: n = 7, p = 0.806 vs control; IS-4d: n = 7, p = 0.256 vs control) in LA PNs, 6 or 8 consecutive days of immobilization markedly decreased the currents (IS-6d: n = 8, p = 0.035 vs control; IS-8d: n = 9, p = 0.026 vs control). Collectively, the above results strongly suggested that CIS-evoked loss of tonic inhibition in LA was primarily contingent on both the duration of daily immobilization and the total days of exposure.
CORT is required for CIS-induced loss of tonic GABAAR currents in LA
CIS weakens tonic GABAAR currents through activation of glucocorticoid receptors
In brain, CORT functions through binding to GR and mineralocorticoid receptor (MR) in the target areas. To identify their roles in CIS-induced loss of tonic GABAARs currents, we pretreated the CIS mice 30 minutes prior to the daily immobilization with either RU 38486 (20 mg/kg/day), a GR antagonist or spironolactone (100 mg/kg/day), a MR antagonist (Figure 5A). While spironolactone pretreatment had no effect, pretreatment with RU 38486 effectively prevented the decline of tonic GABAAR currents subsequent to CIS (spironolactone: n = 7; RU 38486: n = 8, F(2, 19) = 10.538, p < 0.001, Figure 5B-C). Thus, these results implied a pivotal role of GR but not MR in the disruption of tonic inhibition mediated by CORT.
Loss of tonic GABAAR current impairs GABAergic control over neuronal excitability in LA
Effect of GABA on the properties of action potential in lateral amygdala from different groups of mice
Control (n = 8)
CIS (n = 8)
CIS + metyrapone (n = 7)
AP threshold (mV)
AP amplitude (mV)
Half AP width (ms)
Since our above findings have demonstrated that corticosteroid modulation was a kernel process for CIS-evoked reduction of tonic GABAAR currents, we hypothesized that blocking CORT synthesis might be effective in preventing the disruption of GABAergic control over neuronal excitability in CIS mice. We pretreated the CIS mice with metyrapone and examined its potential role in reversing the altered GABAergic control over neuronal excitability. The basal properties of action potential in metyrapone-treated CIS mice did not differ from those in control or CIS mice (threshold, F(2, 21) = 2.21, p = 0.099; amplitude, F(2, 21) = 1.86, p = 0.158; half width, F(2, 21) = 0.871, p = 0.482, Table1). However, GABA caused a far greater decrease of the number of action potential in these mice relative to that in CIS mice (the main effect of group, F(1, 69) = 7.098, p = 0.009, Figure 7C-F), revealing substantial improvement in GABAergic dysfunction by metyrapone pretreatment. Together with its ability to rescue the loss of tonic GABAAR currents following CIS, theses results suggested that CORT production was critically engaged in the removal of inhibition in amygdala subsequent to chronic stress.
Here, we find that chronic exposure to either immobilization or unpredictable stress results in enduring loss of tonic GABAAR current in LA while leaving the phasic GABAARs unaffected. Such loss is primarily due to the production of CORT with subsequent activation of GR and leads to an impaired GABAergic control over the neuronal excitability in amygdala. Given the essential role of amygdala GABAAR in maintaining the appropriate expression of emotion such as fear and anxiety, we propose that the defective tonic inhibition may represent one of the key mechanisms through which prolonged stress exerts its persistent and detrimental action on brain’s processing of the emotionally salient events.
The GABAARs mediating the tonic and phasic inhibition in CNS differ considerably in terms of their subunit composition, subcellular localization, kinetic and pharmacological properties. Despite these, they both are exquisitely sensitive to the changes in their environment. For instance, the elevated level of steroid hormone progesterone during the ovarian cycle alters the expression of both δ and γ2 subunits of GABAARs, which are the kernel subunits of GABAARs responsible for tonic and phasic inhibition respectively in many brain areas. Accumulating evidence has shown that stress exposure exerts wide actions on GABAARs, ranging from changing their orthosteric and allosteric binding sites[25, 26] to modulating the mRNA and protein expression of GABAAR subunits[26–28]. In amygdala, chronic stress has been reported to regulate the expression of several GABAAR subunits[29, 30]. Yet, it is unknown whether these effects result in the changes of tonic and phasic inhibition in amgydala. Here, we reveal that both CIS and CUS produce enduring decline of tonic GABAAR currents while having negligible effects on their phasic counterparts. The loss of tonic inhibition persists even 30 days after the cessation of stress exposure, implying a striking temporal persistence of the altered tonic inhibition by chronic stress. These findings, however, do not reconcile with recent studies showing that acute immobilization stress impairs the evoked inhibitory currents in amygdala[16, 31]. One possible explanation for this discrepancy is that the impaired phasic inhibition following immobilization stress is reversed after long term stress-free recovery, making it undetectable after 10 or 30 days of stress removal.
As generally known, the adversity of chronic stress is highly correlated with the severity of stressor and the duration of exposure. We find it is also the case for the altered tonic inhibition in LA. It varies dramatically with the duration of daily immobilization and the total days of immobilization stress. When the daily immobilization duration was set for 1 hour, short-term exposure (2 or 4 days) failed to affect the tonic inhibition and increasing the days of exposure (6 or 8 days) caused the reduction. On the other hand, when the immobilization exposure was set for a total of 10 days, 15 minutes of daily immobilization failed to have significant influence on the tonic inhibition, which could be readily suppressed by extending daily exposure to 1 or 2 hours. Somewhat surprisingly, the phasic GABAAR currents do not experience remarkable changes, suggesting a type-specific effect of chronic stress. The exact cellular mechanisms for this are not yet known. However, accumulating studies have documented that stress regulates the expression and function of GABAAR in a subunit- and area-specific manner. For example, chronic stress exposure decreases the expression of β1/2 subunits but has no effect on α1/2 subunits in periventricular nucleus. By contrast, it increases the expression of β subunits in the hippocampus. In view of the heterogeneity of the modulation of GABAAR by chronic stress and the marked differences between tonic and phasic inhibition, the selective reduction of tonic GABAAR currents may thus raise a possibility that chronic stress preferentially regulate the expression and/or function of the GABAAR subunits associated with tonic inhibition. It is worth noting that whereas CIS and CUS have been shown to exert distinct effects on the structural remodeling in the limbic systems, we find that they both impair the tonic inhibition in amygdala. We propose that it may serve as a common mechanism for the aberrant activation of amygdala in response to both paradigms of chronic stress[14, 33, 34].
We next observe that CORT mediates the impaired tonic inhibition in LA subsequent to chronic stress. Blocking CORT production with metyrapone during CIS effectively prevents the decline of tonic inhibition. In addition, chronic administration of CORT mimics the effects of chronic stress and results in a substantial drop of tonic GABAAR currents in LA. CORT administration has been shown to have a wide range of effects on GABAAR. It regulates the expression and function of GABAAR[26, 34] and alters the driving force of GABAAR-mediated chloride currents. Although the exact cellular mechanisms for these CORT actions remain undetermined, the altered GABAAR functionality by CORT may contribute to the loss of tonic inhibition and amygdala disinhibition subsequent to prolonged stress exposure. Such a speculation seems not to reconcile with the unaltered sensitivity of synaptic GABAARs to GABA by CORT, as shown in the current study. However, considering that synaptic versus extrasynaptic GABAAR differs a lot from each other in their subunit composition and dynamic modulation, CORT may regulate the expression and function of extrasynaptic versus synaptic GABAAR in different manners. Actually, these two types of GABAARs exhibit contrasting alterations under some pathological conditions. For example, the expression of synaptic GABAAR was increased in temporal lobe epilepsy while that of the δ subunit of GABAAR, a subunit located exclusively in extrasynaptic space, was decreased[37, 38]. A substantial number of studies have also demonstrated that excessive CORT secretion accounts for the neuronal restructuring and the altered glutamatergic transmission in hippocampus, amygdala and prefrontal cortex[39–42], which are thought to be the primary mechanisms for the involvement of CORT in emotional and cognitive dysfunction by chronic stress[43–45]. Given the long lasting loss of tonic inhibition in response to chronic stress or CORT administration, we speculate it may provide an alternative mechanism through which CORT mediates the persistent deleterious effects of chronic stress.
In the brain, CORT functions primarily through GR and MR. While both receptors are colocalized in amygdala, we observe that it is GR rather than MR that mediates the disruption of tonic inhibition subsequent to chronic stress. This is likely to be associated with their distinct pharmacological properties. The CORT affinity of MR is ten times higher than that of GR. The high CORT affinity makes MR to be heavily occupied by basal level of CORT. By contrast, GR is heavily occupied only when the circulating CORT is elevated under conditions such as stress exposure, which renders GR ideal for mediating the biological function of stress. Consistent with the pivotal role of GR in the diminished tonic inhibition, a wealth of data has also documented the involvement of GR in the dysregulation of HPA axis and memory deficits following chronic stress[49, 50] and antagonism of GR signaling has been proposed as a therapeutic target in stress-related psychiatric diseases[51, 52].
Lastly, we find that along with the long lasting loss of tonic inhibition, the ability of GABA to suppress neuronal firing is greatly impaired subsequent to chronic stress. Since the phasic GABAAR currents do not experience considerable changes, this GABAergic dysfunction is most likely due to the loss of tonic inhibition. It has been shown that the charge carried by the activation of tonically active GABAARs is three to five times larger than that carried by phasic inhibition[17, 19]. Thus, it is not surprising that the deficit of tonic inhibition is sufficient to lead to the disruption of GABAergic control over neuronal excitability. Recently, a few studies have implicated the defective tonic inhibitory tone in amygdala in the pathogenesis of some neuropsychiatric disorders[53, 54]. Further studies are needed to uncover its functional role in the adverse effects of chronic stress on the brain and behavior.
We have shown in this study that chronic stress exposure triggers enduring loss of tonic but not phasic GABAAR currents in amygdala which is dependent on stress-evoked CORT production with subsequent GR activation. We conclude that the loss of tonic inhibition contributes to amygdala disinhibition following chronic stress and may thus account for the development of neuropsychiatric disorders.
Male C57BL/6 J mice were subjected to chronic stress exposure at age of 28–35 days except for those stated in Figure 3C. All animals were housed in groups of 3–5 with ad libitum access to food and water unless specified in stressed mice and maintained in a temperature and humidity controlled room with a light/dark cycle of 12 hours. All experimental procedures followed the guidelines of National Institutes of Health and were approved by the ethics committee of Nanchang University.
Models of chronic stress
Chronic immobilization stress (CIS) and chronic unpredictable stress (CUS) were employed in the present experiment. Mice assigned to CIS were placed in a restraint cylinder at around 2 pm for 1 hour per session, one session per day and for 10 consecutive days, unless stated otherwise. For the CUS paradigm, the mice were given 2 stressors per day for 10 consecutive days. The stressors applied were randomly selected from 8 stressors and thus unpredictable for the mice. The 8 stressors included forced swim for 4 min, lights on overnight, lights off for 3 hr during the light period of the light/dark cycle, cold room exposure (temperature was set at 10°C) for 1 h, food and water deprivation overnight, gentle cage shaking for 1 h, immobilization for 1 h and wet bedding overnight. The control mice were transferred in their home cages to the experimental room, gently handled for 2–4 minutes and returned back to the feeding room about 1 hour later.
Animals were anesthetized with ether at around 1-2 pm and the blood was collected through cardiac puncture into heparinized tubes. Samples were centrifuged at 3000 rpm for 20 minutes at 4°C. Sera were collected and stored at -80°C until assayed. Plasma CORT was measured by specific radioimmunoassay with ELISA kit (Abcam). To avoid the potential inter-assay variation, all samples were measured in the same assay. The standard curve (1–100 ng/mL) and samples were run in triplicate.
CORT was freshly prepared in the drinking water and delivered in opaque bottles to protect it from light. The stock solution of RU 38486, spironolactone and metyrapone were made using EtOH (<0.1% at final concentration) and administered intraperitoneally 30 minutes prior to the daily immobilization. CORT was purchased from Sigma-Aldrich and the others were from Tocris Bioscience.
Amygdala slices were prepared as previously described. Briefly, mice were sacrificed by decapitation and brains were quickly removed to ice-cold oxygenated (95% O2/5% CO2) artificial cerebrospinal fluid (ACSF) containing (in mM): 124 NaCl, 2.5 KCl, 1 MgSO4, 2.5 CaCl2, 10 glucose, and 26 NaHCO3 (pH = 7.30). Slices containing lateral amygdala (LA) of about 350 μm were cut with a Leica VT 1000S tissue slicer and maintained at room-temperature for at least one hour before recording. Slices were transferred to a recording chamber continuously superfused with ACSF at a constant rate of about 60 ml/h. The whole-cell patch clamp was made in the projection neurons (PNs) of LA with an Axon 700B amplifier. The patch pipettes for recording GABAergic currents were filled with (in mM): 100 CsCl, 30 Cs-methanesulfonate, 5 NaCl, 2 MgCl2, 10 HEPES, and 0.2 EGTA, 2 ATP-Na, 0.1 GTP-Na. The pH was adjusted to 7.3 with CsOH and osmolarity to 285 mOsm with sucrose. In experiments where action potentials were evoked, CsCl and Cs-methanesulfonate were replaced by equal concentrations of Kgluconate. To record the phasic and tonic GABAAR currents, 20 μM APV, 20 μM DNQX and 5 μM CGP 52432 were routinely added into the bath solution to block the ionotropic glutamate receptors and B type GABA receptors. In experiments where tonic GABAAR currents were recorded, 20 μM GABA was included in the ACSF to ensure the activation of extrasynaptic GABAARs. The spontaneous inhibitory postsynaptic currents (sIPSCs) were collected 2–3 minutes prior to GABA application. To evoke action potentials in the PNs, cells were recorded at current clamp mode and the depolarizing current pulses of increasing amplitude were delivered. To measure GABA diffusion in amygdala slice from control and CIS mice, we performed an outside-out patch containing GABAAR and inserted this patch into slice. The GABAAR currents in response to the diffused GABA following a short-lasting tetanus delivered to LA (4 stimuli, 100 Hz) were recorded and the effects of GABA uptake inhibitor were monitored. The pipette resistance was 3–7 MΩ. The membrane potential was held at -70 mV and the junction potential of about 12 mV were uncorrected. Series resistance (Rs) was in the range of 10–20 MΩ and monitored throughout the experiments. If Rs changed more than 20% during recording, the data were not included in analysis.
Data analysis and statistics
Data were low-pass filtered (3KHz) and digitized at 10 KHz. Tonic GABAAR currents were defined as the currents blocked by bicuculline (BIC) and measured as previously described. The amplitude, frequency and dynamic parameters of sIPSCs were analyzed offline using MiniAnalysis (Synaptosoft, Inc). The spike threshold was identified at the point where the action potential was initiated and showed a >10 fold change in the rising rate. The amplitude of AP was measured as the voltage difference between the threshold and the peak of the action potential. The half AP width was measured at half-height between the threshold and the peak of the action potential. All data were expressed as Means±SEM. The comparisons of the intensity of tonic inhibitory currents and the parameters depicting sIPSCs or action potential were obtained by using ANOVAs followed by post hoc t test. Statistical significances were considered at p < 0.05.
Chronic immobilization stress
Chronic unpredictable stress
Spontaneous inhibitory postsynaptic currents
This work was supported by grants from the National Natural Science Foundations of China (No: 81071096, 31160208, 91332123), the Major State Basic Research Development Program of China (No: 2014CB846100) and “555 Talents project” of Jiangxi Province. It was also supported by the Program for New Century Excellent Talents in Universities of China to Dr. B-X Pan.
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