Hippocampal GABAB(1a) Receptors Constrain Generalized Contextual Fear

Abstract

Many anxiety disorders are characterized by generalization of fear responses to neutral or ambiguous stimuli. Therefore, a comprehensive understanding of the mechanisms contributing to generalized fear is essential for formulating successful treatments for anxiety disorders. Previous research shows that GABA-mediated presynaptic inhibition has a critical role in cued fear generalization, as animals with genetically deleted presynaptic GABAB(1a) receptors cannot discriminate between CS+ and CS- tones. Work from our laboratory has further identified that GABAB(1a) receptors are necessary for maintaining contextual memory precision, thereby constraining generalized contextual fear. We previously found that GABAB(1a) KO mice show generalized fear to a neutral context 24 h after training, but not 2 h after training. A similar pattern was observed with object location and recognition, suggesting that this receptor subtype affects consolidation and/or retrieval of precise contextual and spatial memories. Here we sought to specifically examine the involvement of GABAB(1a) receptors in consolidation or retrieval of a precise fear memory. To do so, we infused a selective GABAB(1a) receptor antagonist, CGP 36216, intracerebroventricularly (ICV), or locally into the dorsal hippocampus, ventral hippocampus, or anterior cingulate cortex (ACC), during consolidation and retrieval of context fear training. Blockade of GABAB(1a) receptors through ICV, dorsal hippocampal, or ventral hippocampal infusions 'after' training (consolidation) resulted in fear generalization to the neutral context when mice were tested 24, but not 6 h after training. Post-training infusions of CGP into the ACC, however, did not promote generalized fear. In addition, ICV, dorsal hippocampal, ventral hippocampal, or ACC infusions immediately 'before' testing (retrieval) did not result in context fear generalization. These data suggest that GABA-mediated presynaptic inhibition is not critical for retrieval of precise contextual memory, but rather has an important role in the long-term consolidation of precise contextual memories and constrains generalized fear responses.