*P. ZHU1, W. HUANG2, D. KALIKULOV2, J. YOO3, A. PLACZEK1, L. STOICA1, H. ZHOU1, J. C. BELL5, M. J. FRIEDLANDER1, K. KRNJEVIC6, J. L. NOEBELS4, M. COSTA-MATTIOLI1;
TL;DR: Knocking out protein kinases R made mouse learn faster and remember better, but also changed network activity to a state often seen in epilepsy. Up for discussion: are they smarter and are they useful in future research?
Another protein kinase in the spotlight! The double stranded RNA-activated protein kinase (PKR) was previously identified as a sensor of virus infection, and proposed to have a role in ethanol-induced protein synthesis inhibition and apoptosis (cell death). Lo and behold! By studying a novel strain of mutant mice, the PKR double knockout (PKR-/-), researchers report that lacking the kinase led to faster learning and better memory retention in the mutant mice compared to their field-born brethren.
The researchers first looked to see if knocking out the PKR gene resulted in changed synaptic signalling in the brains of transgenic animals. They found decreased spontaneous and evoked inhibitory signalling in the knock-outs (mediated by GABAA receptors). So the hippocampus seemed to be more active at basal level. (For those interested, PKR seems to act on GABAR through interferon-gamma and trascription factor EIF2alpha. This is not very surprising as PKR is a mediator of virus-induced immunoresponse in the periphery.)
They then looked at long-term potentiation, which has been proposed as a molecular basis for learning and memory after decades of research. They found enhanced LTP, which suggests that the animals may be able to learn faster and better.
So the researchers quizzed the mice to see if they are “smarter”. In the first test, the animals were placed in a water maze filled with opaque liquid, which forced them to swim until they found a hidden platform in a certain location of the maze. During the week of training, the knockout mice learned faster than their counterparts. On the day of testing, the platform was removed, but the knockouts still spend more time around the area which previously housed their resting spot compared to the control mice.
In the second test, the animals were placed in a chamber where they received mild shocks. This forms a link between the specific training chamber with the shock memory, making the mice fear the chamber as well. When the mice were returned to the chamber, the knockout mice consistently showed greater fear (behaviourally seen as more freezing) compared to the normal mice, suggesting that they had stronger emotional memories of the initial experience. Importantly, the knockouts behaved normally when placed into an unrelated chamber, showing that the fear memory is specific to the context in which it was formed. To probe another brain circuit, the researchers also taught the animals to be fearful of a certain tone, and again the knockouts had better recall.
All the cellular and molecular experiments were also done in normal mice given a PKR inhibitor. Pharmacological inhibition caused normal mice to behave like their knock-out counterparts.
People may still remember the previously reported “smart mice” Doogie, which have overexpressed NR2B, a subunit of the NMDA receptor, which is known to be involved in learning and memory. Do we have another smart mouse on our hands?
Probably not. One consequence of knocking out the PKR gene is that the mice showed enhanced network rhythmicity in the hippocampus, a phenomenon often associated with epilepsy. Furthermore, learning and memory is not only about encoding important information, but also pruning/supressing irrelevant ones. Inhibitory activity by GABAA receptors has a complex role in the function of cells and networks that mediate memory, so further testing is most certainly needed to see if turning “smarter” is the only consequence of knocking down PKR.