Adolescent-onset GABAA1 silencing regulates reward-related decision making

The GABA(A) receptor mediates fast, inhibitory signaling, and cortical expression of the 1 subunit increases during postnatal development. Certain pathological stimuli such as stressors or prenatal cocaine exposure can interfere with this process, but causal relationships between GABA(A)1 deficiency and complex behavioral outcomes remain unconfirmed. We chronically reduced GABA(A)1 expression selectively in the medial prefrontal cortex (prelimbic subregion) of mice using viral-mediated gene silencing of Gabra1. Adolescent-onset Gabra1 knockdown delayed the acquisition of a cocaine-reinforced instrumental response but spared cocaine seeking in extinction and in a cue-induced reinstatement procedure. To determine whether response acquisition deficits could be associated with impairments in action-outcome associative learning and memory, we next assessed behavioral sensitivity to instrumental contingency degradation. In this case, the predictive relationship between familiar actions and their outcomes is violated. Adolescent-onset knockdown, although not adult-onset knockdown, delayed the expression of goal-directed response strategies in this task, resulting instead in inflexible habit-like modes of response. Thus, the maturation of medial prefrontal cortex GABA(A)1 systems during adolescence appears necessary for goal-directed reward-related decision making in adulthood. These findings are discussed in the light of evidence that prolonged Gabra1 deficiency may impair synaptic plasticity.