The double-stranded RNA-activated protein kinase (PKR) was originally identified as part of the immune surveillance mechanism against viruses. Zhu et al. found that the neuronal networks of mice deficient in PKR (Pkr–/–) showed increased activity compared with those of wild-type mice. Electrophysiological analyses of hippocampal slices from Pkr–/– mice or from wild-type mice that were treated with an inhibitor of PKR (PKRi) suggested that the enhanced activity could not be attributed to increases in intrinsic excitability or excitatory neurotransmission. Instead, the hippocampal slices showed suppressed inhibitory neurotransmission, including reduced release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Decreased GABAergic synaptic transmission can facilitate the induction of long-term potentiation (LTP), a form of synaptic plasticity that is associated with learning and memory. Induction of LTP was increased in brain slices from Pkr–/– mice or from wild-type mice that were treated with PKRi. Compared with wild-type mice, Pkr–/– mice showed enhanced spatial learning, faster contextual fear extinction, and enhanced long-term fear memories. In addition, the latter type of learning was enhanced in wild-type mice by administration of PKRi. A mechanism by which PKR could suppress GABAergic synaptic transmission is by inhibiting the translation of the mRNA encoding the cytokine interferon-γ (IFN-γ), which reduces the release of GABA. The increased excitability of hippocampal slices from Pkr–/– mice was attenuated with an antibody directed against IFN-γ. Furthermore, PKRi treatment did not facilitate the induction of LTP in slices from Ifn-γ–/– mice and did not enhance long-term fear memories in Ifn-γ–/– mice. Thus, PKR promotes inhibitory neurotransmission by relieving IFN-γ–mediated suppression of GABAergic signaling.
P. J. Zhu, W. Huang, D. Kalikulov, J. W. Yoo, A. N. Placzek, L. Stoica, H. Zhou, J. C. Bell, M. J. Friedlander, K. Krnjević, J. L. Noebels, M. Costa-Mattioli, Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell 147, 1384–1396 (2011). [Online Journal]