Tonic Inhibitory Control of Dentate Gyrus Granule Cells by a5-Containing XXXX Receptors Reduces Memory Interference.

@entity146 @entity19 @entity73 @entity4779 @entity2414 @entity8771
Interference between similar or overlapping memories formed at different times poses an important challenge on the @entity2414 . Difficulties in managing interference are at the core of disabling @entity73 in @entity146 . Computational models have suggested that, in the normal brain, the sparse activation of the dentate gyrus granule cells maintained by tonic inhibitory control enables pattern separation, an orthogonalization process that allows distinct representations of memories despite interference. To test this mechanistic hypothesis, we generated @entity19 with significantly reduced expression of the a5-containing @entity8771 ( @entity8771 ) receptors selectively in the granule cells of the dentate gyrus (a5DGKO @entity19 ). a5DGKO @entity19 had reduced tonic inhibition of the granule cells without any change in fast phasic inhibition and showed increased activation in the dentate gyrus when presented with novel stimuli. a5DGKO @entity19 showed @entity73 characterized by high interference, without any deficiencies in low-interference tasks, suggesting specific @entity73 . Reduction of fast phasic inhibition in the dentate gyrus through granule cell-selective knock-out of a2-GABAARs or the knock-out of the @entity8771 in the downstream @entity4779 area did not detract from pattern separation abilities, which confirms the anatomical and molecular specificity of the findings. In addition to lending empirical support to computational hypotheses, our findings have implications for the treatment of interference-related @entity73 in @entity146 , particularly considering the availability of pharmacological agents selectively targeting @entity8771 . SIGNIFICANCE STATEMENT: Interference between similar memories poses a significant limitation on the @entity2414 , and impaired interference management is a cognitive symptom in many disorders. Thus, understanding mechanisms of successful interference management or processes that can lead to interference-related @entity2414 has high theoretical and translational importance. This study provides empirical evidence that tonic inhibition in the dentate gyrus (DG), which maintains sparseness of neuronal activation in the DG, is essential for management of interference. The specificity of findings to tonic, but not faster, more transient types of neuronal inhibition and to the DG, but not the neighboring brain areas, is presented through control experiments. Thus, the findings link interference management to a specific mechanism, proposed previously by computational models.
