Figure 4.

Targeting GABA_BR signaling to improve working memory. (A) Likely in response to excess GABA_BR-mediated inhibition, expression of the subunits that together form postsynaptic GABA_BRs (GABA_BR1b and GABA_BR2) is reduced in the aged medial prefrontal cortex (mPFC) [11,14]. The downregulation of postsynaptic GABA_BRs receptor might serve to compensate for the excess inhibition described above as well as help to preserve the persistent activity of pyramidal neurons that is required for working memory maintenance. In support of this hypothesis, the bottom-right panel shows that, among aged rats, lower GABA_BR1b and GABA_BR2 expression strongly predicts better working memory. (B) If the downregulation of GABA_BRs is a crucial mechanism for preserved working memory in aging, then blockade of GABA_BR signaling should restore working memory in impaired aged subjects. The line graph shows performance of a cohort of aged rats (red circles) that are impaired relative to young adult rats (blue circles) on the delayed-response task. Using a within-subjects design, in which the same aged subjects shown in red were administered a GABA_BR antagonist CGP55845 (CGP) directly into the PFC (green circles), aged rat performance is restored to that of young adults. Data reproduced from [14].