SUMMARY The double-stranded RNA-activated protein kinase (PKR) was originally identified as a sensor of virus infection, but its function in the brain remains unknown. Here, we report that the lack of PKR enhances learning and memory in several behavioral tasks while increasing network excitability. In addition, loss of PKR increases the late phase of long-lasting synaptic potentiation (L-LTP) in hippocampal slices. These effects are caused by an interferon-γ (IFN-γ)-mediated selective reduction in GABAergic synaptic action. Together, our results reveal that PKR finely tunes the network activity that must be maintained while storing a given episode during learning. Because PKR activity is altered in several neurological disorders, this kinase presents a promising new target for the treatment of cognitive dysfunction. As a first step in this direction, we show that a selective PKR inhibitor replicates the Pkr−/− phenotype in WT mice, enhancing long-term memory storage and L-LTP.

Efficiency of synaptic transmission within the neocortex is regulated throughout life by experience and activity. Periods of correlated or uncorrelated presynaptic and postsynaptic activity lead to enduring changes in synaptic efficiency [long-term potentiation (LTP) and long-term depression (LTD), respectively]. The initial plasticity triggering event is thought to be a precipitous rise in postsynaptic intracellular calcium, with higher levels inducing LTP and more moderate levels inducing LTD. We used a pairing protocol in visual cortical brain slices from young guinea pigs with whole-cell recording and calcium imaging to compare the kinetic profiles of calcium signals generated in response to individual pairings along with the cumulative calcium wave and plasticity outcome. The identical pairing protocol applied to layer 2/3 pyramidal neurons results in different plasticity outcomes between cells. These differences are not attributable to variations in the conditioning protocol, cellular properties, inter-animal variability, animal age, differences in spike timing between the synaptic response and spikes, washout of plasticity factors, recruitment of inhibition, or activation of different afferents. The different plasticity outcomes are reliably predicted by individual intracellular calcium transients in the dendrites after the first few pairings. In addition to the differences in the individual calcium transients, the cumulative calcium wave that spreads to the soma also has a different profile for cells that undergo LTP versus LTD. We conclude that there are biological differences between like-type cells in the dendritic calcium signals generated by coincident synaptic input and spiking that determine the sign of the plasticity response after brief associations.

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