Increased Basolateral Amygdala Pyramidal Cell Excitability May Contribute to the Anxiogenic Phenotype Induced by Chronic Early-Life Stress

Adolescence represents a particularly vulnerable period during which exposure to stressors can precipitate the onset of psychiatric disorders and addiction. The basolateral amygdala (BLA) plays an integral role in the pathophysiology of anxiety and addiction. Acute and chronic stress promote increases in BLA pyramidal cell firing, and decreasing BLA excitability alleviates anxiety measures in humans and rodents. Notably, the impact of early-life stress on the mechanisms that govern BLA excitability is unknown. To address this gap in our knowledge, we used a rodent model of chronic early-life stress that engenders robust and enduring increases in anxiety-like behaviors and ethanol intake and examined the impact of this model on the intrinsic excitability of BLA pyramidal cells. Adolescent social isolation was associated with a significant increase in the intrinsic excitability of BLA pyramidal cells and a blunting of the medium component of the afterhyperpolarization potential, a voltage signature of calcium-activated potassium (K-ca) channel activity. Western blot analysis revealed reduced expression of small-conductance K-ca (SK) channel protein in the BLA of socially isolated (SI) rats. Bath application of a positive SK channel modulator (1-EBIO) normalized firing in ex vivo recordings from SI rats, and in vivo intra-BLA 1-EBIO infusion reduced anxiety-like behaviors. These findings reveal that chronic adolescent stress impairs SK channel function, which contributes to an increase in BLA pyramidal cell excitability and highlights BLASK channels as promising targets for the treatment of anxiety disorders and comorbid addiction.