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Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents.

Liu ZP, Song C, Wang M, He Y, Xu XB, Pan HQ, Chen WB, Peng WJ, Pan BX - Mol Brain (2014)

Bottom Line: 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.The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment.We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, China. panbingxing@ncu.edu.cn.

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

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The ambient GABA is similar in LA from control and CIS mice. A, Representative traces showing GABAAR currents in an outside-out patch evoked by a short-lasting tetanus applied to the LA of control (left) and CIS mice (right). Slices were consecutively perfused with ACSF (top), SKF 89976A (middle) and BIC (bottom). Note that SKF 89976A enhanced the GABAAR currents in both mice. The stimulus artifacts were truncated for clarity. B-C, Comparisons of the increased amplitude (B) and charge transfer (C) of GABAAR currents by SKF 89976A in control and CIS mice.
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Figure 2: The ambient GABA is similar in LA from control and CIS mice. A, Representative traces showing GABAAR currents in an outside-out patch evoked by a short-lasting tetanus applied to the LA of control (left) and CIS mice (right). Slices were consecutively perfused with ACSF (top), SKF 89976A (middle) and BIC (bottom). Note that SKF 89976A enhanced the GABAAR currents in both mice. The stimulus artifacts were truncated for clarity. B-C, Comparisons of the increased amplitude (B) and charge transfer (C) of GABAAR currents by SKF 89976A in control and CIS mice.

Mentions: Tonic GABAergic inhibition is generally known to result from the opening of peri- or extrasynaptic GABAAR upon binding the ambient GABA diffused outside of synapses. To investigate whether chronic stress had long lasting influence on the phasic versus tonic GABAAR currents in LA PNs, we recorded both currents from control mice and CIS mice having 10 days of recovery from stress (Figure 1). We found that the tonic GABAAR currents was conspicuously decreased in CIS mice relative to those in control mice (p = 0.007, Figure 1A-B). By contrast, the phasic GABAAR currents, as measured by sIPSCs in PNs, did not differ between the two groups (Figure 1C-G). The parameters depicting the sIPSCs, including their amplitude (p = 0.884), frequency (p = 0.560) and dynamic properties (10-90% rise time, p = 0.698; decay constant, p = 0.458) were all similar between groups, implying that CIS exposure preferentially suppressed the tonic but not phasic GABAAR currents in LA. To test whether the loss of tonic inhibition was a common response evident for exposure to different types of stressors, we next measured the two forms of currents in CUS mice. The tonic currents in these mice were also weaker than those in control mice (F(2, 32) = 7.675, p = 0.002, Figure 1A-B) but similar to those in CIS mice (p = 0.388). Their sIPSCs did not differ from those in control and CIS mice (amplitude: F(2, 44) = 0.352, p = 0.705; frequency: F(2, 44) = 0.048, p = 0.953; 10-90% rise time: F(2, 44) = 0.712, p = 0.496; decay constant: F(2, 44) = 1.894, p = 0.162; n = 17, Figure 1C-G). Thus, the loss of tonic GABAAR currents might represent a common feature of the deficits in GABAergic signaling induced by prolonged exposure to diverse stressors. Since the tonic GABAAR currents in brain are activated by the ambient GABA outside of the inhibitory synapses and its content is largely limited by the activity of GABA transporter, the loss of tonic inhibition subsequent to CIS may reflect decreased GABA diffusion resulting from an enhanced GABA transporter. To test this, we employed a GABAAR-containing outside-out patch as a sensor of ambient GABA and compared the efficacy of GABA transport in control and CIS mice by monitoring the changes of tetanus-evoked GABAAR currents in response to 10 μM SKF 89976A, a GABA uptake inhibitor. We found that the SKF 89976A readily enhanced the amplitude and charge transfer of GABAAR current in both groups of mice and the enhancement was only slightly but insignificantly stronger in CIS mice than those in control mice (control: n = 8; CIS: n = 8; amplitude, p = 0.302; charge transfer, p = 0.171, Figure 2). Thus, it appeared that the GABA transport did not display considerable changes upon 10 days’ removal from CIS and the enduring loss of tonic inhibition in CIS mice was mainly not due to an altered GABA diffusion.


Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents.

Liu ZP, Song C, Wang M, He Y, Xu XB, Pan HQ, Chen WB, Peng WJ, Pan BX - Mol Brain (2014)

The ambient GABA is similar in LA from control and CIS mice. A, Representative traces showing GABAAR currents in an outside-out patch evoked by a short-lasting tetanus applied to the LA of control (left) and CIS mice (right). Slices were consecutively perfused with ACSF (top), SKF 89976A (middle) and BIC (bottom). Note that SKF 89976A enhanced the GABAAR currents in both mice. The stimulus artifacts were truncated for clarity. B-C, Comparisons of the increased amplitude (B) and charge transfer (C) of GABAAR currents by SKF 89976A in control and CIS mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4012764&req=5

Figure 2: The ambient GABA is similar in LA from control and CIS mice. A, Representative traces showing GABAAR currents in an outside-out patch evoked by a short-lasting tetanus applied to the LA of control (left) and CIS mice (right). Slices were consecutively perfused with ACSF (top), SKF 89976A (middle) and BIC (bottom). Note that SKF 89976A enhanced the GABAAR currents in both mice. The stimulus artifacts were truncated for clarity. B-C, Comparisons of the increased amplitude (B) and charge transfer (C) of GABAAR currents by SKF 89976A in control and CIS mice.
Mentions: Tonic GABAergic inhibition is generally known to result from the opening of peri- or extrasynaptic GABAAR upon binding the ambient GABA diffused outside of synapses. To investigate whether chronic stress had long lasting influence on the phasic versus tonic GABAAR currents in LA PNs, we recorded both currents from control mice and CIS mice having 10 days of recovery from stress (Figure 1). We found that the tonic GABAAR currents was conspicuously decreased in CIS mice relative to those in control mice (p = 0.007, Figure 1A-B). By contrast, the phasic GABAAR currents, as measured by sIPSCs in PNs, did not differ between the two groups (Figure 1C-G). The parameters depicting the sIPSCs, including their amplitude (p = 0.884), frequency (p = 0.560) and dynamic properties (10-90% rise time, p = 0.698; decay constant, p = 0.458) were all similar between groups, implying that CIS exposure preferentially suppressed the tonic but not phasic GABAAR currents in LA. To test whether the loss of tonic inhibition was a common response evident for exposure to different types of stressors, we next measured the two forms of currents in CUS mice. The tonic currents in these mice were also weaker than those in control mice (F(2, 32) = 7.675, p = 0.002, Figure 1A-B) but similar to those in CIS mice (p = 0.388). Their sIPSCs did not differ from those in control and CIS mice (amplitude: F(2, 44) = 0.352, p = 0.705; frequency: F(2, 44) = 0.048, p = 0.953; 10-90% rise time: F(2, 44) = 0.712, p = 0.496; decay constant: F(2, 44) = 1.894, p = 0.162; n = 17, Figure 1C-G). Thus, the loss of tonic GABAAR currents might represent a common feature of the deficits in GABAergic signaling induced by prolonged exposure to diverse stressors. Since the tonic GABAAR currents in brain are activated by the ambient GABA outside of the inhibitory synapses and its content is largely limited by the activity of GABA transporter, the loss of tonic inhibition subsequent to CIS may reflect decreased GABA diffusion resulting from an enhanced GABA transporter. To test this, we employed a GABAAR-containing outside-out patch as a sensor of ambient GABA and compared the efficacy of GABA transport in control and CIS mice by monitoring the changes of tetanus-evoked GABAAR currents in response to 10 μM SKF 89976A, a GABA uptake inhibitor. We found that the SKF 89976A readily enhanced the amplitude and charge transfer of GABAAR current in both groups of mice and the enhancement was only slightly but insignificantly stronger in CIS mice than those in control mice (control: n = 8; CIS: n = 8; amplitude, p = 0.302; charge transfer, p = 0.171, Figure 2). Thus, it appeared that the GABA transport did not display considerable changes upon 10 days’ removal from CIS and the enduring loss of tonic inhibition in CIS mice was mainly not due to an altered GABA diffusion.

Bottom Line: 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.The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment.We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, China. panbingxing@ncu.edu.cn.

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus