Chronic stress is a potent contributor to many illnesses, including depression and other affective disorders (5
). However, the basic effects of chronic stress on the neurons in the amygdala that modulate emotion are unknown. While it has previously been demonstrated that stress can increase LAT-dependent behaviors (3
), this study demonstrates for the first time that chronic stress causes a hyperexcitability of LAT pyramidal neuron membrane excitability, which may underlie impairments of affective behavior. Furthermore, this study provides evidence that a KCa
channelopathy underlies this abnormality, and provides a pharmacological target for the reversal of these effects of chronic stress.
Plasticity of membrane properties has been observed after prolonged conditions, such as epilepsy, drug addiction and experience (50
). The effects of chronic stress in the amygdala are unique, and opposite to changes in the hippocampus (53
), whose function is markedly diminished after chronic stress (55
). The magnitude of this effect has several contributors, including depolarization of the membrane potential and increased neuronal responsiveness to subthreshold stimuli. However, most important was the increased action potential firing caused by a reduction of the AHP. Because the effects of chronic stress on excitability are sensitive to KCa
channel manipulations, and are associated with a decrease of the AHP, our data are consistent with chronic stress increasing excitability through a mechanism that likely involves a reduction in the function or number of KCa
There are several types of KCa
channels that contribute to LAT neuronal excitability, and to different AHPs in the LAT (27
). Furthermore, KCa
channels can regulate amygdala-related behaviors (57
). This study indicates involvement of the channels that underlie the mAHP and sAHP in the effects of chronic stress, most likely SK channels that produce intermediate or small KCa
currents. There are a number of factors and ion channels that contribute to measurements of membrane excitability, as quantified here. The contribution of GABAergic influences on excitability may be minor, as intracellular blockade of Cl−
channels had little impact on the effects of chronic stress. However, a change in GABAergic systems may play significant roles in the effects of stress on other aspects of neuronal function (39
) that were not examined here. Also not tested here is the possible role of norepinephrine, a modulator that decreases activity of KCa
channels and the AHP in the BLA(58
), and whose effectiveness may be altered by chronic stress (61
Increased excitability is expected to result in greater output of LAT neurons. The greater action potential firing in response to a stimulus allows the LAT to exert a more potent influence over other brain regions, such as the prefrontal cortex, central amygdala and nucleus accumbens, resulting in more affect-driven behavior. The impact of chronic stress on fear conditioning and extinction observed in other studies is consistent with this notion (3
). An inappropriately large contribution of the LAT may produce some of the behavioral abnormalities observed after chronic stress.
1-EBIO, a compound that increases SK channel activity and both the sAHP and mAHP (69
), diminished the in vivo excitability of LAT neurons after chronic stress (above). 1-EBIO was administered systemically, an approach that prevents definitive statements about its site of action (however, the effects of 1-EBIO on LAT neurons were blocked when Cd2+
was included in the recording electrode). The effect of 1-EBIO on LAT excitability is not likely due to non-specific actions of 1-EBIO, as it had much weaker effects in control animals. 1-EBIO was also effective at reversing the stress-induced impairments of exploration in the EPM, further supporting a role for KCa
channel disruption after chronic stress.
A long-term increase of LAT excitability after chronic stress is expected to lead to heightened emotional lability. This imbalance of LAT activity may exacerbate abnormalities present in individuals with psychiatric illnesses, or introduce a dysregulation in those already predisposed to psychiatric illnesses. This study provides a basic cellular mechanism for the effects of chronic stress on emotion, providing a potential pharmacological intervention for the harmful effects of chronic stress on mental health.