Forskolin reverses the O-GlcNAcylation dependent decrease in GABAAR current amplitude at hippocampal synapses possibly at a neurosteroid site on GABAARs.

GABAergic transmission is influenced by post-translational modifications, like phosphorylation, impacting channel conductance, allosteric modulator sensitivity, and membrane trafficking. O-GlcNAcylation is a post-translational modification involving the O-linked attachment of ß-N-acetylglucosamine on serine/threonine residues. Previously we reported an acute increase in O-GlcNAcylation elicits a long-term depression of evoked GABAAR inhibitory post synaptic currents (eIPSCs) onto hippocampal principal cells. Importantly, O-GlcNAcylation and phosphorylation can co-occur or compete for the same residue; whether they interact in modulating GABAergic IPSCs is unknown. We tested this by recording IPSCs from hippocampal principal cells and pharmacologically increased O-GlcNAcylation, before or after increasing serine phosphorylation using the adenylate cyclase activator, forskolin. Although forskolin had no significant effect on baseline eIPSC amplitude, we found that a prior increase in O-GlcNAcylation unmasks a forskolin-dependent increase in eIPSC amplitude, reversing the O-GlcNAc-induced eIPSC depression. Inhibition of adenylate cyclase or protein kinase A did not prevent the potentiating effect of forskolin, indicating serine phosphorylation is not the mechanism. Surprisingly, increasing O-GlcNAcylation also unmasked a potentiating effect of the neurosteroids 5α-pregnane-3α,21-diol-20-one (THDOC) and progesterone on eIPSC amplitude, mimicking forskolin. Our findings show under conditions of heightened O-GlcNAcylation, the neurosteroid site on synaptic GABAARs is accessible to agonists, permitting strengthening of synaptic inhibition.

Forskolin reverses the O-GlcNAcylation dependent decrease in GABAAR current amplitude at hippocampal synapses possibly through a neurosteroid site on GABAARs.

GABAergic transmission is influenced by post-translational modifications, like phosphorylation, impacting channel conductance, allosteric modulator sensitivity, and membrane trafficking. O-GlcNAcylation is a post-translational modification involving the O-linked attachment of ß-N-acetylglucosamine on serine/threonine residues. Previously we reported an acute increase in O-GlcNAcylation elicits a long-term depression of evoked GABAAR inhibitory post synaptic currents (eIPSCs) onto hippocampal principal cells. Importantly O-GlcNAcylation and phosphorylation can co-occur or compete for the same residue; whether they interact in modulating GABAergic IPSCs is unknown. We tested this by recording IPSCs from hippocampal principal cells and pharmacologically increased O-GlcNAcylation, before or after increasing serine phosphorylation using the adenylate cyclase activator, forskolin. Although forskolin had no significant effect on baseline eIPSC amplitude, we found that a prior increase in O-GlcNAcylation unmasks a forskolin-dependent increase in eIPSC amplitude, reversing the O-GlcNAc-induced eIPSC depression. Inhibition of adenylate cyclase or protein kinase A did not prevent the potentiating effect of forskolin, indicating serine phosphorylation is not the mechanism. Surprisingly, increasing O-GlcNAcylation also unmasked a potentiating effect of the neurosteroids 5α-pregnane-3α,21-diol-20-one (THDOC) and progesterone on eIPSC amplitude, mimicking forskolin. Our findings show under conditions of heightened O-GlcNAcylation, the neurosteroid site on synaptic GABAARs is accessible to agonists, permitting strengthening of synaptic inhibition.

The lasting memory enhancements of retrospective attention.

Behavioral research has shown that spatial cues that orient attention toward task relevant items being maintained in visual short-term memory (VSTM) enhance item memory accuracy. However, it is unknown if these retrospective attentional cues ("retro-cues") enhance memory beyond typical short-term memory delays. It is also unknown whether retro-cues affect the spatial information associated with VSTM representations. Emerging evidence suggests that processes that affect short-term memory maintenance may also affect long-term memory (LTM) but little work has investigated the role of attention in LTM. In the current event-related potential (ERP) study, we investigated the duration of retrospective attention effects and the impact of retrospective attention manipulations on VSTM representations. Results revealed that retro-cueing improved both VSTM and LTM memory accuracy and that posterior maximal ERPs observed during VSTM maintenance predicted subsequent LTM performance. N2pc ERPs associated with attentional selection were attenuated by retro-cueing suggesting that retrospective attention may disrupt maintenance of spatial configural information in VSTM. Collectively, these findings suggest that retrospective attention can alter the structure of memory representations, which impacts memory performance beyond short-term memory delays.